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Review

Harnessing the Potential of Chimeric Antigen Receptor T-Cell Therapy for the Treatment of T-Cell Malignancies: A Dare or Double Dare?

by
Rita Assi
1 and
Huda Salman
2,*
1
Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY 11794, USA
2
Division of Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Cells 2022, 11(24), 3971; https://doi.org/10.3390/cells11243971
Submission received: 16 November 2022 / Revised: 3 December 2022 / Accepted: 6 December 2022 / Published: 8 December 2022
(This article belongs to the Special Issue CAR T Cells: A Road Trip to Tumor Elimination)
Browse Figure
Review Reports Versions Notes

Abstract

:
Historical standard of care treatments of T-cell malignancies generally entailed the use of cytotoxic and depleting approaches. These strategies are, however, poorly validated and record dismal long-term outcomes. More recently, the introduction and approval of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the therapy of B-cell malignancies. Translating this success to the T-cell compartment has so far proven hazardous, entangled by risks of fratricide, T-cell aplasia, and product contamination by malignant cells. Several strategies have been utilized to overcome these challenges. These include the targeting of a selective cognate antigen exclusive to T-cells or a subset of T-cells, disruption of target antigen expression on CAR-T constructs, use of safety switches, non-viral transduction, and the introduction of allogeneic compounds and gene editing technologies. We herein overview these historical challenges and revisit the opportunities provided as potential solutions. An in-depth understanding of the tumor microenvironment is required to optimally harness the potential of the immune system to treat T-cell malignancies.

1. Background on T-Cell Malignancies

1.1. Historical Challenges

T-cell malignancies are a heterogeneous spectrum of orphan diseases generally associated with dismal outcomes [1]. They are broadly categorized, according to the maturity level of affected T-cell, into T-cell lymphomas (TCLs) that account for 10% to 15% of all non-Hodgkin lymphomas (NHLs) in adults, and T-cell leukemias (T-ALL) [2]. TCLs could be further subclassified into peripheral TCLs (PTCLs) and cutaneous TCLs (CTCLs) [2,3]. The initial management of T-cell malignancies generally consists of intensive combination chemotherapy, often producing acceptable response rates at the expense of profound toxicity [4,5,6]. The recent introduction of brentuximab vedotin in addition to chemotherapy for the frontline treatment of CD30-expressing PTCLs improved survival outcomes according to the ECHELON2 phase III trial [7]. Nevertheless, these findings are generally pertinent to patients with the anaplastic large cell lymphoma (ALCL) subtype who accounted for 75% of ECHELON2 population; the extended benefit of this combination to CD30+ beyond ALCL remains therefore uncertain. Patients with advanced CTCL derive even lower benefits with initial systemic therapy and the progression-free survival (PFS) improvement for responders is less than 50% [8].
When compared to B-cell malignancies, the use of these frontline strategies has often proved inefficient to maintain remission and subsequent salvage therapy is generally suboptimal, leading to an overall detrimental prognosis [9,10]. Indeed, for the small percentage of eligible relapsed and refractory (R/R) patients with TCLs achieving complete remission (CR) after salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (HSCT) has historically remained the only curative option in 30% of cases [11,12]. The outcomes of patients with chemotherapy R/R T-cell malignancies thus continue to be unsatisfactory in view of the limited availability of effective and well-tolerated therapies.

1.2. Immunotherapy in T-Cell Malignancies: About Time

The recent emergence of immunotherapy modalities and their recorded clinical benefit in several hematological malignancies naturally paved the way for their extensive investigation into T-cell neoplasms. Beyond monoclonal antibodies (mAbs), immune checkpoint inhibitors (ICPIs), and bispecific T-cell engagers, the chimeric antigen receptor (CAR)-T cell therapy has particularly presented as a promising strategy for the treatment of several R/R hematologic malignancies [13].
The first CARs converged T-cells to target CD19, a ubiquitous antigen universally expressed on the surface of lymphoid B-cells, generating impressive response rates and leading to the first FDA-approved T-cell therapy for cancer [14,15,16,17]. Beyond CD19, the successful performance of several CAR-T products in treating several R/R B-cell malignancies [17,18] has prompted an expansion of this strategy to different tumors. More specifically, the growing success of CAR-T therapy in B-cell malignancies sparked the development of huge efforts to mirror this breakthrough in T-cell malignancies. As B- and T-cells share several biological architecture and functions, applying CAR T-cell therapy to T-cell neoplasms initially seemed natural until the unfolding of serious practical concerns of fratricide and severe immunosuppression secondary to aplasia of normal T-cells. These findings are further complicated by a strongly protumor immunosuppressive microenvironment that facilitates the development and progression of T-cell malignancies, mostly TCLs [19,20,21].
In this review, we discuss the potential target antigens, as well as the preclinical and clinical efforts invested in adapting CAR-T therapy for T-cell malignancies. We also examine the challenges involved in translating the application of this strategy from bench to bedside. Lastly, we highlight potential novel approaches and proposed solutions to optimize the successful implementation of CAR-T therapy in the realm of T-cell malignancies.

1.3. Fundamentals of CAR-T Structure and Mechanisms of Action

CAR constructs are synthetic fusion proteins that endow specific effector cells such as T or natural killer (NK) cells with the property to channel their cytotoxicity toward a designated tumor cell mutually expressing the loaded CAR antigen. Each CAR molecule, therefore, comprises four domains: an antigen recognition domain consisting of an extracellular binding site generally involving a single-chain fragment of the variable region (scFv) of a monoclonal antibody against a specific antigen (e.g., CD19, CD20, etc.); a transmembrane domain and an intracellular signaling domain [22,23]. Nanobodies (also known as VHH) [24] and various toxins have also been used instead of monoclonal antibodies for the same purpose [25]. scFv connects with the transmembrane domain through a hinge/spacer anchor derived from IgG4 or CD8 molecules to initiate signal transduction [26], thereby partially regulating the activity and safety of CAR-T cells. The intracellular pocket subsequently operates as a signaling domain through the CD3ζ chain of the CD3 complex of the T-cell receptor (TCR), and one or two costimulatory domains such as CD28, ICOS, 4-1BB (CD137), or OX40 (CD134). Of note, the presence of costimulatory domains in CAR constructs maintains the activation, proliferation, and persistence of T-cells [27].
CAR transgenes are integrated into T-cells either transiently through mRNA electroporation, or permanently using lentiviral or gammaretroviral gene delivery [28,29].
Unlike normal T-cells that operate through TCR-based ligand recognition, CAR-T cells recognize and eliminate unprocessed tumor antigens independently of the human leukocyte antigen (HLA) complex. This property allows the CAR products to overcome major pathways of tumor escape including lower expression of HLA class I molecules as well as abnormal antigen editing and processing by antigen-presenting cells (APCs) [30].
Once CAR products recognize tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) on the target cancer cell, the intracellular signaling domains activate the immune effector and memory functions of the CAR-T cells. Accumulating on the surface, CAR-T cells then form an immunological synapse with subsequent activation and proliferation of T-cells, infiltration of tumor sites, cytokines secretion, cytolytic degranulation, the release of perforin and granzyme B, and eventual direct lysis of the tumor cell through several kinetics, dependent on the whether the CAR harbors CD4+ or CD8+ T-cells [31].
While the kinetics of CAR-T operations remain to be fully elucidated, it is imperative that these cells possess the necessary machinery of trafficking and homing to tumor sites, including the hard-to-reach spots, in order to recognize their target antigen and initiate an appropriate cytolytic activity.

1.4. Evolution of CARs Design

Since the first conceptualization of engineered T-cells in the late 1980s, CAR manufacturing and design have considerably evolved, mostly over the last few years. CAR T-cell products are currently classified into five generations according to the number of co-stimulatory molecules within the intracellular domain. The first-generation CAR lacked co-stimulatory domains and comprised a CD3ζ chain as an essential carrier of endogenous TCR signals [32]. Despite promising preclinical results and relative success in phase I trials, isolated CD3ζ stimulation was insufficient to mount optimal T-cell signaling, activation, and expansion upon antigen exposure, resulting in impaired antitumor activity [33].
Second-generation CAR-T constructs were subsequently built with a CD3ζ chain and an intracellular signaling domain carrying a co-stimulatory molecule, typically CD28 and 4-1BB (CD137), as well as OX40 (CD134) and induction T-cell stimulator (ICOS, CD278), each with a different effect on T-cells [32,34]. This strategy was evaluated in patients with relapsed B-acute lymphoblastic leukemia, resulting in excellent CR rates [35].
In parallel, third-generation CARs involve two signaling domains along with the CD3ζ chain, such as the CD3ζ -CD28-OX40, leading to more effective anti-tumor responses when compared to second-generation products [36]. While signaling through CD28 generates rapid T-cell activation with loaded cytokine production, aerobic glycolysis, and decreased T-cell persistence, the 4-1BB pathway enhances oxidative metabolism and T-cell persistence despite a slower T-cell response and milder cytokine secretion.
The fourth generation of CARs known as “T-cells redirected for antigen-unrestricted or universal cytokine-initiated killing” or “TRUCK” are actually second-generation CAR-based receptors armored with transgenic payloads such as cytokines and other pro-inflammatory molecules [32,34]. For instance, these CARs can stimulate the secretion of IL-12 that attracts the innate immune cells towards malignant cells, a strategy particularly promising for the treatment of solid tumors where CARs lack the ability to target antigen-negative neoplastic cells [37].
Finally, the fifth generation of CARs shares vast similarities with the fourth generation with the exception of an intracellular domain harboring a cytokine receptor instead of a cytokine expression stimulator [38]. These constructs facilitate a target antigen-dependent activation of the JAK-STAT pathway that further amplifies their proliferation while blocking terminal differentiation [38].
It is important to note that all commercially available CARs present several limitations as they belong to the second generation, they comprise genetically modified patient-derived (autologous) peripheral blood T cells and use viral vectors for the delivery of CAR transgenes into T-cells [39].

1.5. Challenges to CAR T-Cell Therapy in T-Cell Malignancies (Figure 1)

As the downstream signaling pathways inducing T-cell activation operate independently of the MHC complex, any surface antigen whose expression is confined to neoplastic rather than normal cells could therefore present as a potential target for CAR-T therapy [40]. The mainstay of developing any safe and effective CAR-T cell therapy is the identification of an ideal surface target antigen that is highly sensitive for the underlying malignancy and uniformly specific to circumvent on-target off-tumor toxicities. In general, hematological malignancies represent a heterogeneous population where an optimal antigen, theoretically expressed on all malignant cells with a robust intensity, rarely exists.
The development of CAR-T therapy against T-cell neoplasms remains specifically problematic when compared to that in the B-cell compartment. Resetting T-cells to eliminate malignant T-cells while sparing normal T-cells is a complicated task. The major obstacle stems from the limited availability of T-cell malignancy-specific target antigens to construct a CAR molecule. Indeed, the majority of antigens (such as CD3, CD5, and CD7) targeted by CAR-T products against T-cell malignancies are readily expressed by normal T cells [41,42,43]. This overlapping expression complicates the isolation of healthy T-cells from patients with T-cell malignancies to engineer autologous CAR-T products where normal and malignant T-cells are jointly recovered during leukapheresis. In this situation, the autologous CAR-T product possibly incorporates T-cells generated from malignant T lymphocytes. This “impurity” subsequently generates CAR-T-mediated ablation of normal T-cells after product infusion, a potentially fatal phenomenon of profound immunodeficiency known as T-cell aplasia [44]. Finally, a CAR-T construct targeting a TAA jointly expressed by different populations of T-cells can blindly intercept malignant T-cells, normal T-cells, and other CAR T-cells [45]. When the latter express a target antigen on their surface, a mechanism of fratricide develops during manufacturing whereby CAR-T cells attack and annihilate each other, eventually disrupting their in vivo expansion, persistence, and tumoricidal function [46].
All of the aforementioned obstacles have greatly hindered the development of successful CAR-T therapy for the treatment of T-cell malignancies. As seen in B-cell malignancies, therapeutic failure of CAR-T therapy in T-cell malignancies also seems to sequester around two major patterns: inherent resistance signaling the absence of significant disease response after therapy or acquired resistance in which patients enjoy a transient response followed by disease recurrence. All models of CAR-T failure appear to stem from tumor-intrinsic evasion mechanisms that are either antigen-dependent (loss of antigen expression, fratricide, etc.), or independent. Additionally, pre- and/or post-exposure T cell dysfunction could occur, leading to resistance to CAR-T therapy and/or disease relapse. Based on all these observations, several groups have subsequently devised various products and strategies, including the targeting of more restricted T-cell antigens such as CD4, CD30, CD37, and CCR4 (Table 1). All antigens, however, present variably even within the same type of T-cell malignancies. Therefore, choosing the right target and considering the potential for adverse events is an area of unmet need in CAR-T therapy for T-cell malignancies.
Other alternative antigens, such as the myeloid markers CD13 and CD33, have also emerged as potential targets owing to their aberrant expression on the surface of precursor T-cell leukemia that possibly portends a worse disease prognosis [47]. It is important to note that despite these potential solutions, the development of CAR-T cell therapy remains burdened by a set of serious adverse events, such as cytokine release syndrome (CRS), neurotoxicity, off-target toxicity, as well as high costs.

2. Addressing Fratricide

2.1. Targeting Pan-T Antigens

2.1.1. CD3

CD3 is a historically favorable target for the use of immunotherapy in T-cell malignancies owing to its restricted expression to the hematopoietic compartment, specifically mature T-cells. CD3 forms a complex with the TCR, thereby stimulating target antigen recognition with subsequent T-cell activation [42]. CD3-based immunotherapy, in the form of mAbs was extensively evaluated for the treatment of several T-cell malignancies with marginal clinical efficacy [48,49]. The subsequent use of CD3 as a target for CAR-T therapy was largely hindered by fratricide, [50,51] secondary to the overlapping expression of CD3 on the normal and malignant T-cells. These observations generated the need for fratricide-resistant products or incorporating different effector cells that lack the expression of the target antigen.
A proposed solution entailed the design of a novel third-generation CD3-based CAR embedded in the NK-92 cell line [52]. Of note, NK cells lack CD3 expression, possess shorter lifecycles when compared to T-cells, and express the IgG Fc fragment. The latter is a low affinity less proinflammatory III receptor (FcRYIII) that endows NK cells with the potential to execute antibody-dependent cell-mediated cytotoxicity without risk of graft versus host disease (GvHD) [52,53,54]. Chen et al. demonstrated that the CD3CAR transduced NK-92 cells possess significant dose-dependent cytotoxic activity in vitro, as well as an in vivo effects against CD3-expressing PTCL samples and several T-acute lymphoblastic leukemia/lymphoma (T-ALL) cell lines, as well as prolonged survival in preclinical models engrafted with the Jurkat cell line [50]. Furthermore, the study established the specific potential of CD3CAR NK-92 cells to target CD3 antigen without off-target effects. These preclinical data could pilot the investigation of CD3CAR modified NK cells for the treatment of CD3+ T-cell malignancies, thereby serving as a bridge to HSCT or other definitive therapies.
More recently, gene-editing technologies, such as the transcription activator-like effector nuclease (TALEN), have been increasingly utilized to disrupt the CD3/TCR complex and prohibit the endogenous TCR expression on T-cells, before manipulating these cells to express the CD3ε-targeting CARs [51]. Such a method produced specific and significant tumoricidal activity against pediatric samples of T-ALL, as demonstrated in preclinical models engrafted with the CD3+ Jurkat cell line [51].

2.1.2. CD5

CD5 is a membrane-based glycoprotein with an extracellular domain normally restricted to thymocytes, peripheral T cells, and a subset of B lymphocytes known as B-1a cells [41]. This antigen is also commonly expressed in several T-cell malignancies such as T-ALL and PTCL [55,56]. CD5 promotes the survival of lymphocytes while negatively regulating TCR signaling pathway [57,58], and has therefore been historically considered a suitable target for use in immunotherapeutic strategies [59].
Earlier studies by Mamonkin et al. of CD5CAR-T therapy against T-ALL and TCL samples showed complete antitumor response in vitro, but only limited tumoricidal activity in animal models [45]. Disease recurrence was attributed to a phenomenon of partial and transient fratricide (primarily against naïve and central memory cells) that subsided 3 days post-administration.
To overcome this limitation, Chen and colleagues incorporated NK-92 cell lines in the design of a third-generation CD5-redirected CAR, as NKs lack CD5 expression on their surface [60]. Preclinical data showed a steady expansion of the composite product ex vivo, with selective and significant tumoricidal activity towards several T cell lines including Jurkat, CCRF-CEM, and MOLT-4, as well as against primary CD5+ cells of human PTCL and T-ALL samples [60]. More specifically, mouse xenograft models of T-ALL demonstrated improved survival as well as substantial reduction in their tumoral mass [60].
Similar results were replicated by using CRISPR-Cas9 technology to knockout CD5 in T cells before embedding the CAR transgene into Jurkat and primary patients’ cells. This experiment by Raikar et al. resulted in limited fratricide and subsequent CAR persistence [61]. Mamonkin and coworkers also reported that substituting the 4-1BB co-stimulatory domain for the original CD28 in the endodomain of CD5CARs can enhance the differentiation capacity of the CAR compound, resulting in increased antitumor efficacy [62]. To avoid fratricide and target antigen exhaustion, a Tet-Off system capable of interfering with CAR transduction was implemented in the presence of doxycycline ex vivo, sustaining the recovery and expansion of CAR surface expression in vivo in the absence of immediate fratricide [62]. A more recent study comparing the use of the 2B4 and 4-1BB costimulatory domains in CAR-NK compounds found a similar in vitro selective tumoricidal activity [63]. Notably, CAR-NKs harboring the 2B4 co-stimulatory domain further demonstrated an improved antileukemic activity in xenograft T-ALL preclinical models [63].
In a phase I clinical trial (NCT03081910; MAGENTA trial) of 14 patients with R/R TCL patients, autologous second-generation CD28-costimulated CD5CAR-T therapy resulted in sufficiently durable tumoricidal responses that enabled a transition to HSCT without significant T-cell aplasia or high-grade CRS [64]. It is noteworthy that responses did not correlate with infused doses or level of T-cell expansion, findings attributed to a shortened manufacturing with cryopreservation for 3–5 days post-transduction instead of a standard 7-day expansion [64].

2.1.3. CD7

CD7 is a glycoprotein member of the Ig superfamily that is normally expressed on T and NK cells [65] and aberrantly on T-ALLs and TCLs [55], subsequently posing a risk of fratricide when used as target for of CAR-T cell therapy. Gomes-Silva et al. therefore adopted CRISPR-Cas9 genome editing to disrupt the CD7 expression before its manipulation for CAR integration [43]. This approach resulted in enhanced CAR expansion, strong and selective tumoricidal activity against several CD7-expressing cell lines (Jurkat, CCRF, MOLT-4, Sup-T1, and Hut78), as well as against human T-ALL samples and xenograft models with variable levels of CD7 expression [43].
CRISPR-Cas9 was also utilized to engineer CD7-redirected CAR-T products lacking CD7 and TCR alpha chain (TRAC) expression [46]. This fratricide-resistant construct demonstrated significant antitumor activity against T-ALL cell lines and primary human samples, as well as tumor regression in preclinical models with the absence of GvHD [46]. Strategies involving gene-editing tools might prove useful for the production of allogeneic CAR-T models while minimizing donor-derived T cells’ alloreactivity before the use of off-shelf products. Such an approach was adopted in the design of the universal CD19-targeted CAR-T cell product for the treatment of B-NHL [66,67], whereby healthy donors derived allogeneic CAR-T cells can substitute patient-derived inefficient T cells and reduce the cost and time of production.
Blockade of CD7 expression in T cells is another suggested approach to mitigate fratricide. Png et al. designed a protein expression blocker (PEBL) system composed of a CD7-targeting scFv fused to a retention domain that intercepts CD7 in the ER/Golgi, thereby blocking its normal expression [68]. This strategy prevented fratricide while preserving CARs expansion and their tumoricidal activity, as well as INF-γ and TNF-α response. More importantly, such CARs exhibited pronounced antileukemic activity against several CD7-expressing cell lines and patient-derived xenografts models of T-ALL [68].
Owing to their aforementioned properties, NK cells have also been manipulated for the production of CAR-T cells. You et al. designed monovalent and bivalent composite constructs using NK-92MI cells and CD7-specific nanobodies as the targeting domain [69]. While both CAR-NKs products showed selective and effective tumoricidal activity towards cell lines and tumor samples of T-ALL, the bivalent model scored superior antitumor effects and generated higher levels of granzyme B and IFN-γ. These results were subsequently reproduced in preclinical assessments of xenograft models of T-ALL [69]. Early results of the first-in-human clinical trial (NCT04004637) utilizing allogeneic CD7NKCAR-Ts in patients with CD7+R/R T-ALL or T-cell lymphoblastic lymphoma pre- or post-HSCT were recently reported [70]. The study showed CR at 30 days in 18 out of 20 (90%) patients, allowing 37% of responders to proceed to HSCT. Of the 12 patients who did not receive HSCT, 9 remain in remission at a median follow-up of 6.3 months. Normal T and NK cell aplasia were seen, leading to opportunistic infections in some patients. The majority of these patients had, however, recovery of small numbers of CD7– peripheral T and NK cells. Other clinical trials (NCT04033302 and NCT03690011) are currently evaluating the feasibility and efficacy of this target antigen for the treatment of several T-cell malignancies (Table 1).

2.2. Targeting Antigens with Restricted Expression

2.2.1. CD1a

CD1a is expressed on the surface of developing cortical thymocytes and T-ALL cells, and absent on T cells and CD34+ progenitor hematopoietic cells [71,72]. This characteristic pattern of expression allowed CD1a to present as a fratricide-resistant target for CAR-T therapy with robust tumoricidal activity and considerable persistence against CD1a-expressing T-ALL cell lines and primary cells of cortical T-ALL samples [73]. Moreover, CD1aCAR-Ts offer the potential for minimal on-target off-tumor toxicities. Further clinical assessments are needed to establish the real suitability of CD1a for CAR-T therapy of cortical T-ALL patients.

2.2.2. CD4

CD4-based immunotherapy in the form of mAbs has been extensively investigated for the treatment of TCLs, with acceptable clinical activity, safety profile, and low immunogenicity [74,75,76,77], making CD4 an attractive target for use in CAR-T therapy. Early preclinical data of a third-generation CD8+CD4CAR-T construct demonstrated the selective activity of the construct against CD4-expressing cell line (KARPAS 299 cells) and patient-derived PTCL samples while conserving their memory stem cell-like phenotype [78]. Furthermore, the experiment showed that the CD4-manipulated CARs possessed antitumor activity in mouse models, leading to prolonged survival when compared to the control GFP-expressing T-cells. To avoid the risk of T-cell aplasia and related opportunistic infections, another third-generation CD4-redirected CAR-NK was engineered using the NK-92 cell line [79], owing to its shortened persistence and lower risk of GvHD, as detailed above. This construct exhibited a dose-dependent selective tumoricidal capacity against several aggressive CD4-expressing patient-derived cell samples and cell lines of T-ALL and TCLs, with positive effects on the survival of the preclinical xenograft models [78,79]. Altogether, these robust preclinical data strongly support the potential role of CD4CAR NK cells as a conditioning regimen bridging to definitive HSCT, or as a possibly self-sufficient curative option for certain patients with T-cell malignancies.
Despite the use of NK cells, CD4CAR T-cells remain a problematic approach as the inadvertent massive eradication of normal CD4+ T-cells leads to T-cell aplasia and an HIV/AIDS-like syndrome [80]. If this phenomenon is anticipated to be profound and irreversible, it necessitates the use of a physiologic “safety switch” that aborts the heightened activity of CD4CARs post-administration and achievement of tumoricidal activity. Ma et al. incorporated the CD52-specific humanized mAb alemtuzumab for this purpose since CD52 is expressed on the surface of both normal and malignant lymphocytes [81]. Alemtuzumab achieved >95% depletion in the number of circulating CD4CAR-T at 6 and 48 h after its administration, suggesting its potential role in hindering unwanted toxicities [81]. An ongoing clinical trial is currently evaluating the clinical safety and efficacy of a third-generation CD4CAR-T for the treatment of T-cell malignancies (NCT03829540) (Table 1).

2.2.3. CD30

CD30, or TNFRSF8, is a member of the TNF receptor superfamily and is expressed by small subsets of normal B and T cells, as well as in several malignancies including HL, ALCL, ATLL, and PTCL [82,83,84]. CD30 expression is thought to increase following administration of chemotherapy in T-ALL patients, hence its potential benefit for targeting in R/R cases [85].
The successful immunotherapeutic targeting of CD30 was established through brentuximab vedotin, an anti-CD30 antibody–drug conjugate (ADC) that recorded marked clinical benefits in patients with HL and some TCL subtypes [86,87]. Additionally, it has been previously shown that M2 CD163+ macrophages heavily express CD30, suggesting that the effects of brentuximab vedotin may be at least partially explained by architectural modifications in the tumor microenvironment, hence the anecdotal reports of the ADC’s activity in CD30- lymphoma [88]. However, several constraints of antibody-based therapy such as limited tumor penetration and antigen-mediated clearance with subsequently shortened response duration prompted the exploration of the CAR pathway for a more efficient CD30 targeting [89]. Studies assessing the feasibility of such an approach date back to more than 20 years [90,91] while early clinical data were recently reported from a phase I dose-escalation clinical trial (NCT01316146) of 7 R/R HL and 2 ALCL patients who received second-generation CD30CAR-Ts with no recorded toxicities [92]. Two of the seven HL patients achieved CR lasting more than 2 years and another three patients had transient stable disease. Nevertheless, CR was seen in only one of the two ALCLs and lasted 9 months [92]. Several other studies involving CD30CAR-T were conducted exclusively in HL patients, suggesting that in vivo expansion of the compound was dose-dependent and that fludarabine-based preconditioning therapy produces durable responses with an acceptable safety profile [93,94]. It is important to note that the overall results seen with this strategy were suboptimal as most patients required multiple CD30CAR-T injections to achieve a stable disease status. Additionally, extra-nodal lesions appeared to respond less than the nodal compartment and T-cells showed short persistence of around two months following infusion [92,95,96].
Guercio et al. subsequently attempted at improving the antitumor activity and homing capacity of CD30CARs through a third-generation design incorporating a combination of OX40 and CD28 costimulatory molecules, and the production machinery of IL-7 and IL-15 [97]. This construct generated prolonged persistence with increased proliferation of T-cells, along with sustained immunology against lymphomatous cells [97].
CD30 remains an important target that deserves further exploration. Ongoing clinical trials (NCT03049449, NCT02917083, NCT02663297, NTC01316146, NTC03602157, NTC0227458) will potentially clarify its role in CAR-T cell therapy for T-cell malignancies (Table 1).

2.2.4. CCR4

C–C chemokine receptor type 4 (CCR4), also known as CD194, is expressed by several normal T-cell populations including regulatory T-cells (Tregs), Th2, and Th17 cells, and overexpressed on malignant T-cell subsets of patients with PTCL, CTCL and ATLL [98,99]. CCR4 was previously targeted using the first-in-class humanized mAb Mogamulizumab that is currently approved for R/R CTCLs, with limited clinical responses [100]. Perera et al. subsequently demonstrated that allogeneic CCR4CAR-Ts achieved significant tumoricidal activity against CCR4-expressing patient-derived tumor cell lines and xenograft models of ATLL [101]. These positive findings were, however, hindered by undesirable skin toxicities such as Stevens–Johnson syndrome attributed to the expression of CCR4 on normal T-cell populations, similar to what was previously reported with the use of mogamulizumab [102,103].
Di Stasi et al. previously showed that CD30CAR-Ts armored with CCR4 as a cognate receptor for CCL17 possess improved tumor homing and tumoricidal activity compared with CD30CAR-Ts that lack CCR4 [95]. Since CD30 expression is also retained in R/R lymphoma, it is thought that a bicistronic CCR4CD30CAR-T product would be more potent mostly in CD30+ CTCL due to enhanced trafficking to the skin. Preliminary results of a clinical trial (NCT03602157) investigating the safety and activity of this approach in 10 R/R HL and CD30+ CTCLs previously treated with brentuximab vedotin showed that 75% of HL patients achieved CR while 1 of 2 CTCL patients achieved stable disease as best response [104]. While still suboptimal for T-cell malignancy patients, the trial provides a proof of concept on the feasibility and safety of this strategy to improve homing of CAR constructs.

2.2.5. CCR9

C–C chemokine receptor type 9 (CCR9), or CD199, is a seven-pass transmembrane G–coupled receptor for CCL25. CCR9 is involved in early T-cells development and migration [105]. It is expressed in gut γδ intraepithelial T-cells in mice and heavily on R/R T-ALL, on less than 5% of normal circulating T and B cells [106]. As human and murine CCR9 share around 86% of homology in their sequences, these properties make CCR9 a viable target for CAR-T therapy in T-ALL. Maciocia et al. constructed a second-generation CAR, incorporating CD8 stalk/transmembrane domain and 4-1BB-CD3zeta endodomain and using RQR8 as a suicide switch [107,108]. These CCR9CAR-T cells demonstrated significant tumoricidal activity against several in vitro and in vivo models of T-ALL, without fratricide or lysis of normal T-cells [107]. These findings warrant further exploration of this product, mostly for ETP-ALL patients, a high-risk subset with unmet needs [109].

2.2.6. CD37

CD37 is a leukocyte-exclusive antigen expressed on the surface of mature B-cells that regulates T-cell proliferation at different levels [110,111,112]. CD37 is also detected in several T-cell malignancies and the feasibility and safety of its targeting were previously investigated via an ADC named AGS67E, mostly in CTCL (NCT02175433) [113]. A CD37CAR was subsequently reported to mount an in vitro target antigen-dependent tumoricidal activity against TCLs with variable levels of CD37 expression in the absence of a significant fratricide [114]. Based on these observations, baseline screening for the expression of CD37 might be needed before considering patients with T-cell malignancies for preclinical and clinical testing with this CAR.

2.2.7. TRBC1 and TRBC2

The TCR plays a major role in normal T-cell proliferation through the recognition of antigens presented by APCs. TCR possesses an alpha chain and a beta chain with the constant region of the latter being expressed either through the T-cell receptor beta constant 1 (TRBC1) gene or the T-cell receptor beta constant 2 (TRBC2) gene [115]. While malignant T-cells significantly downregulate TCR, it remains expressed by around 30% of T-ALLs and the vast majority of PTCLs [116]. Based on the fact that a normal population of T cells expresses both TRBC1 and TRBC2 and a malignant subset expresses either one, targeting either receptor at a time could have antitumor activity while preserving a significant proportion of normal T-cells.
For this purpose, Maciocia et al. manufactured TRBC1CAR-Ts and showed that the construct spares TRBC2+ cells, in vitro [117]. Furthermore, those treated with these cells exhibited a substantial reduction in tumor burden and prolonged survival when compared to the control group [117].
In another study, gene editing technologies were used to simultaneously delete the expression of one of the TRBC genes [118]. This disruption led to the abolition of endogenous TCR from the cell surface, concluding that such a strategy could be reserved to prevent fratricide when producing autologous TRBCCAR-Ts [118]. An ongoing phase I/II clinical trial (NCT03590574) is currently evaluating the safety and efficacy of AUTO4, a TRBC1CAR-T therapy for patients with TRBC1+ TCLs including PTCL, ALCL, and angioimmunoblastic T-cell lymphoma (AITL).

3. Addressing T-Cell Aplasia

T-cell aplasia results from on-target off-tumor effects of CAR-T therapy against normal T-cells that mutually express the CAR-specific target antigen [119]. T-cell aplasia is serious toxicity owing to an increased risk of life-threatening infections that largely hinder the successful implementation of CAR-T therapy for patients with T-cell malignancies [44].
Several strategies have been investigated to prevent T-cell aplasia, including the use of target antigens largely restricted to malignant cells, as detailed above. Additionally, selective targeting of an antigen exclusively expressed in a subset of T cells could allow the intact T-cell population to develop sufficient immunity during CAR-T therapy. This strategy, adopted by Maciocia et al. who utilized TRBC1 or TRBC2 as CAR-T targets, aborted full fratricide as well as t-cell aplasia [117].
Another approach to mitigate T-cell aplasia entails the use of CAR-T constructs with controllable or limited longevity and tumoricidal activity. In particular, CAR-T products engineered using viral vector transduction generate robust expansion and persistence in vivo, leading to heightened risks of T-cell aplasia [120], while mRNA engineered CAR-T cells have shown similar tumoricidal activity with limited persistence following administration [121,122]. These results were replicated by two pilot clinical trials of R/R HL patients (NCT02277522 and NCT02624258) treated with non-viral mRNA-electroporated CD19CAR-T [120]. This approach could potentially be beneficial for patients with T-cell malignancies. However, either sequential CAR-T administration or bridging to HSCT might be needed to achieve stable and sufficient tumoricidal activity.
Equipping CAR-T products with safety switches (or suicide switches) that allow for control of transduced T-cells after injection into patients has also been suggested to limit T-cell aplasia [123]. Several forms of safety switches exist with different applicability, advantages, and inconveniences. For instance, metabolic switches, such as those transduced with herpes simplex virus thymidine kinase, can be hampered by potential immunogenicity [124], unlike the inducible human caspase (iCasp) switches [125]. The exclusive eradication of the adoptively transferred T-cells could be also performed through a specific mAb that concomitantly blocks the same antigen targeted by CAR-T constructs [126]. Nevertheless, this method predisposes individuals to undesirable adverse events caused by the inadvertent targeting of normal tissues that could simultaneously express a particular target antigen. Several studies (NCT02028455, NCT03016377, NCT01815749) evaluating the feasibility and efficacy of suicide switches are currently ongoing.

3.1. CAR-T Product Contamination with Malignant T Cells

The generation of autologous CAR-T cells for the treatment of B-cell malignancies carries a minimal risk of contamination by malignant cells whereby the target antigen becomes unrecognizable by the CAR product, leading to therapy failure [127]. In parallel, manufacturing autologous CAR-Ts from patients with T-cell malignancies portends a higher incidence of contamination during T-cell isolation due to antigen similarity between the normal and malignant compartments. While the use of a healthy donor to produce allogeneic CAR-Ts appears as a potential solution to avert contamination and possibly T-cell aplasia, these products possess a shorter in vivo persistence and involve a risk of GvHD or mass eradication by the recipient’s immune system [128].
As previously described, a very common approach has been the use of NK cells as effector cells owing to the lack of expression of certain TAAs seen on normal and malignant T-cells, their shorter longevity, and lower proinflammatory properties compared to T-cells [50,60]. CAR-modified NK cells would therefore be eliminated shortly after administration, thereby decreasing the risk of fratricide, T-cell aplasia, and GvHD in case of use of allogeneic products, and potentially removing the need for an inducible safety switch [129]. The challenges of in vitro expansion of NK cells and the CAR transduction into them are generally resolved by using the NK92 cell line as an alternative [130,131,132]. Nevertheless, serious concerns about the potential tumorigenicity of NK cell lines remain, despite the use of NK-92. For this purpose, these cell lines undergo treatment with radiation before administration to patients, a measure that increases their safety but significantly reduces their cytotoxicity [131]. The optimal irradiation dose used in this strategy remains under investigation. Finally, several studies reported the expiration of PDX models during in vivo assessment within minutes of CD3 and CD5CARNK therapy secondary to strokes induced by NK cell aggregation [50,60].
These observations strongly suggest the need for more in-depth preclinical information to conclude on the safety and feasibility of NK cell lines as allogeneic effectors for CART-cell therapy.
Cell and gene editing technologies are being increasingly utilized to develop off-the-shelf allogeneic CAR-T constructs that are resistant to fratricide without incurring a risk of GvHD. These include CRISPR-Cas9 used to develop off-the-shelf CD7CAR-T by knocking out TRAC in T cells before viral transduction [46], as well as TALEN and Zinc-finger nucleases (ZFN). Preclinical data on the feasibility of these tools have been rather investigated in hematological malignancies other than T-cell neoplasms [133].
Another approach to avoid contamination and its subsequent risks entails the use of multi-virus-specific T (VST) cells as effector cells for CAR expression. These genetically engineered cells usually lack the expression of the CAR target antigen, and are, hence fratricide resistant. Furthermore, they offer the potential for antiviral activity in the event of T-cell aplasia [134,135]. Based on these findings and the study by Melenhorst et al. suggesting that allogeneic VST cells with HLA alloreactivity do not induce GvHD in humans [136], such T cells may provide a real opportunity for producing off-the-shelf CAR-Ts.
In addition to fratricide, T-cell aplasia, and GvHD, CAR-T cells have been hampered at times by the inability to achieve optimal trafficking to difficult tumor sites, including the skin. This is likely attributed to the fact that αβ T cell subsets can poorly infiltrate such locations. γδ T cells, a smaller population accounting for only 1–5% of circulating lymphocytes, are ubiquitous in the skin, intestine, and reproductive apparel and could express chemokine receptors attracting them to home in inaccessible tumor location [137,138,139]. Furthermore, γδ T cells could extensively proliferate ex vivo and do not induce GvHD as activation of their TCR is MHC-independent [140]. A specific variant of γδ T cells, Vγ9Vδ2, possesses the potential for tumor killing through recognition of certain phosphoantigens such as isopentenyl pyrophosphate, readily accumulated in tumor cells [141,142]. These aforementioned properties enable γδ T cells to present as potential alternative effectors for allogeneic CAR-T therapy in T-cell malignancies, following serial evaluation in studies for various other malignancies [140,143,144].

3.2. Combining ICPIs and CAR-T Products in T-Cell Malignancies: An Ongoing Dilemma

The revolutionary success of ICPIs in several solid and hematologic malignancies prompted a major interest in evaluating their application in T-cell malignancies. The development of immunotherapy in these tumors was generally slower and burdened by an imbalance of exhausted malignant T-cells and stimulation of a T-cell response. Furthermore, there exist serious concerns of potential tumor hyperprogression induced by the blockade of inhibitory signals on the surface of the malignant T-cells, thereby perpetuating the proliferation of these cells [145]. The data regarding the therapeutic utility of programmed cell death protein 1 (PD-1) targeting remains controversial, especially with the discovery of its haploinsufficient tumor suppressor function in preclinical TCL models [146].
Prolonged or repeated exposure to CAR-T cells produces T-cell exhaustion with subsequent upregulation of several ICPs such as CTLA4, PD-1, CD160, CD244, TIM3, TIGIT, and LAG-3 [147]. PD-1 antibody therapy is therefore thought to synergize with CAR-T cells to avert T-cell senescence and heighten antilymphoma effects and several others, and the combination is being investigated in B-cell malignancies [147]. Mirroring this strategy in TCLs is hindered by concerns of ICPI-induced hyperproliferation of malignant T-cells and/or CAR-T cells, and clinical trials evaluating the combination are still lacking.

4. Perspective

With the expansion of CAR-T therapy, the treatment of T-cell malignancies is not a neglected field anymore. Earlier results of CD5 and CD7 CAR-Ts, and more recently CCR9CART-s, represent a large-scale milestone in the treatment of T-cell malignancies and inspiration to advance this work into further clinical investigation and future application. Several other trials, some with more sophisticated CAR constructs, are currently ongoing and their results are eagerly awaited. Generalization and validation of these results will ultimately need larger studies that should be anticipated in the foreseeable future. However, several interim questions remain unanswered regarding the optimal therapeutic construct to achieve (off-the-shelf versus autologous), the ideal application of gene editing tools, and the solutions proposed to avert CAR-T-related toxicities. With the substantial strides of preclinical data on the tumor microenvironment and immune landscape of T-cell malignancies, the improved knowledge of these diseases will ultimately identify patients most likely to harness best the power of CAR-T therapy.

Author Contributions

Conceptualization, H.S. and R.A.; resources, R.A. and H.S.; data curation, R.A.; writing—original draft preparation, R.A.; writing—review and editing, R.A. and H.S.; visualization, R.A.; supervision, H.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sehn, L.H.; Soulier, J. Introduction to the review series on T-cell malignancies. Blood J. Am. Soc. Hematol. 2017, 129, 1059–1060. [Google Scholar] [CrossRef] [Green Version]
  2. Swerdlow, S.H.; Campo, E.; Pileri, S.A.; Harris, N.L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.; Salles, G.A.; Zelenetz, A.D.; et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood J. Am. Soc. Hematol. 2016, 127, 2375–2390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Willemze, R.; Cerroni, L.; Kempf, W.; Berti, E.; Facchetti, F.; Swerdlow, S.H.; Jaffe, E.S. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood J. Am. Soc. Hematol. 2019, 133, 1703–1714. [Google Scholar] [CrossRef] [PubMed]
  4. Tsukasaki, K.; Utsunomiya, A.; Fukuda, H.; Shibata, T.; Fukushima, T.; Takatsuka, Y.; Ikeda, S.; Masuda, M.; Nagoshi, H.; Ueda, R.; et al. VCAP-AMP-VECP Compared with Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801. J. Clin. Oncol. 2007, 25, 5458–5464. [Google Scholar] [CrossRef]
  5. Maeda, Y.; Nishimori, H.; Yoshida, I.; Hiramatsu, Y.; Uno, M.; Masaki, Y.; Sunami, K.; Masunari, T.; Nawa, Y.; Yamane, H.; et al. Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: A multicenter phase II trial of West-JHOG PTCL0707. Haematologica 2017, 102, 2097–2103. [Google Scholar] [CrossRef] [Green Version]
  6. Wilcox, R.A. Optimising initial treatment for peripheral T-cell lymphoma: A tough nut to CHOP. Lancet Haematol. 2018, 5, e182–e183. [Google Scholar] [CrossRef] [Green Version]
  7. Horwitz, S.; O’Connor, O.A.; Pro, B.; Illidge, T.; Fanale, M.; Advani, R.; Bartlett, N.; Christensen, J.H.; Morschhauser, F.; Domenech, E.D.; et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): A global, double-blind, randomised, phase 3 trial. Lancet 2018, 393, 229–240. [Google Scholar] [CrossRef] [Green Version]
  8. Virmani, P.; Hwang, S.H.; Hastings, J.G.; Haverkos, B.M.; Kohnken, R.; Gru, A.A.; Mishra, A.; Fabbro, S.K.; Horwitz, S.M.; Porcu, P. Systemic therapy for cutaneous T-cell lymphoma: Who, when, what, and why? Expert Rev. Hematol. 2016, 10, 111–121. [Google Scholar] [CrossRef]
  9. Mak, V.; Hamm, J.; Chhanabhai, M.; Shenkier, T.; Klasa, R.; Sehn, L.H.; Villa, D.; Gascoyne, R.D.; Connors, J.M.; Savage, K.J. Survival of Patients with Peripheral T-Cell Lymphoma after First Relapse or Progression: Spectrum of Disease and Rare Long-Term Survivors. J. Clin. Oncol. 2013, 31, 1970–1976. [Google Scholar] [CrossRef]
  10. Ellin, F.; Landström, J.; Jerkeman, M.; Relander, T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: A study from the Swedish Lymphoma Registry. Blood J. Am. Soc. Hematol. 2014, 124, 1570–1577. [Google Scholar] [CrossRef]
  11. Selberg, L.; Stadtherr, P.; Dietrich, S.; Tran, T.H.; Luft, T.; Hegenbart, U.; Bondong, A.; Meissner, J.; Liebers, N.; Schmitt, M.; et al. The impact of allogeneic hematopoietic cell transplantation on the mortality of poor-risk non-Hodgkin lymphoma: An intent-to-transplant analysis. Bone Marrow Transplant. 2020, 56, 30–37. [Google Scholar] [CrossRef] [PubMed]
  12. Kameda, K.; Kako, S.; Kim, S.-W.; Usui, Y.; Kato, K.; Fukuda, T.; Uchida, N.; Kobayashi, H.; Wakayama, T.; Sakaida, E.; et al. Autologous or allogeneic hematopoietic cell transplantation for relapsed or refractory PTCL-NOS or AITL. Leukemia 2022, 36, 1361–1370. [Google Scholar] [CrossRef] [PubMed]
  13. Maus, M.V.; Grupp, S.A.; Porter, D.L.; June, C.H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood J. Am. Soc. Hematol. 2014, 123, 2625–2635. [Google Scholar] [CrossRef] [Green Version]
  14. Brentjens, R.J.; Davila, M.L.; Riviere, I.; Park, J.; Wang, X.; Cowell, L.G.; Bartido, S.; Stefanski, J.; Taylor, C.; Olszewska, M.; et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Sci. Transl. Med. 2013, 5, 177ra38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Maude, S.L.; Frey, N.; Shaw, P.A.; Aplenc, R.; Barrett, D.M.; Bunin, N.J.; Chew, A.; Gonzalez, V.E.; Zheng, Z.; Lacey, S.F.; et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 2014, 371, 1507–1517. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Turtle, C.J.; Hanafi, L.-A.; Berger, C.; Gooley, T.A.; Cherian, S.; Hudecek, M.; Sommermeyer, D.; Melville, K.; Pender, B.; Budiarto, T.M.; et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 2016, 126, 2123–2138. [Google Scholar] [CrossRef] [Green Version]
  17. Mullard, A. FDA approves fourth CAR-T cell therapy. Nat. Rev. Drug Discov. 2021, 20, 166. [Google Scholar] [CrossRef]
  18. Voelker, R. CAR-T Therapy Is Approved for Mantle Cell Lymphoma. JAMA 2020, 324, 832. [Google Scholar] [CrossRef]
  19. Iqbal, J.; Wright, G.; Wang, C.; Rosenwald, A.; Gascoyne, R.D.; Weisenburger, D.D.; Greiner, T.C.; Smith, L.; Guo, S.; Wilcox, R.A.; et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood J. Am. Soc. Hematol. 2014, 123, 2915–2923. [Google Scholar] [CrossRef] [Green Version]
  20. Gonzalez, B.R.; Zain, J.; Rosen, S.T.; Querfeld, C. Tumor microenvironment in mycosis fungoides and Sézary syndrome. Curr. Opin. Oncol. 2016, 28, 88–96. [Google Scholar] [CrossRef]
  21. Querfeld, C.; Leung, S.; Myskowski, P.L.; Curran, S.A.; Goldman, D.A.; Heller, G.; Wu, X.; Kil, S.H.; Sharma, S.; Finn, K.J.; et al. Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint ProfileT-cell Exhaustion in Cutaneous T-cell Lymphoma. Cancer Immunol. Res. 2018, 6, 900–909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Barrett, D.M.; Grupp, S.A.; June, C.H. Chimeric Antigen Receptor– and TCR-Modified T Cells Enter Main Street and Wall Street. J. Immunol. 2015, 195, 755–761. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Abken, H. Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors. Hum. Gene Ther. 2021, 32, 1011–1028. [Google Scholar] [CrossRef] [PubMed]
  24. Xie, Y.J.; Dougan, M.; Jailkhani, N.; Ingram, J.; Fang, T.; Kummer, L.; Momin, N.; Pishesha, N.; Rickelt, S.; Hynes, R.O.; et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc. Natl. Acad. Sci. USA 2019, 116, 7624–7631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Wang, D.; Starr, R.; Chang, W.-C.; Aguilar, B.; Alizadeh, D.; Wright, S.L.; Yang, X.; Brito, A.; Sarkissian, A.; Ostberg, J.R.; et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci. Transl. Med. 2020, 12, eaaw2672. [Google Scholar] [CrossRef] [PubMed]
  26. Hudecek, M.; Sommermeyer, D.; Kosasih, P.L.; Silva-Benedict, A.; Liu, L.; Rader, C.; Jensen, M.C.; Riddell, S.R. The Nonsignaling Extracellular Spacer Domain of Chimeric Antigen Receptors Is Decisive for In Vivo Antitumor Activity. Cancer Immunol. Res. 2015, 3, 125–135. [Google Scholar] [CrossRef] [Green Version]
  27. Zhao, Z.; Condomines, M.; Van Der Stegen, S.J.C.; Perna, F.; Kloss, C.C.; Gunset, G.; Plotkin, J.; Sadelain, M. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell 2015, 28, 415–428. [Google Scholar] [CrossRef] [Green Version]
  28. Foster, J.B.; Choudhari, N.; Perazzelli, J.; Storm, J.; Hofmann, T.J.; Jain, P.; Storm, P.B.; Pardi, N.; Weissman, D.; Waanders, A.J.; et al. Purification of mRNA Encoding Chimeric Antigen Receptor Is Critical for Generation of a Robust T-Cell Response. Hum. Gene Ther. 2019, 30, 168–178. [Google Scholar] [CrossRef]
  29. Lana, M.G.; Strauss, B.E. Production of Lentivirus for the Establishment of CAR-T Cells. In Chimeric Antigen Receptor T Cells; Springer: Berlin/Heidelberg, Germany, 2019; Volume 2086, pp. 61–67. [Google Scholar] [CrossRef]
  30. A Johnson, L.; June, C.H. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 2016, 27, 38–58. [Google Scholar] [CrossRef]
  31. Liadi, I.; Singh, H.; Romain, G.; Rey-Villamizar, N.; Merouane, A.; Adolacion, J.R.T.; Kebriaei, P.; Huls, H.; Qiu, P.; Roysam, B.; et al. Individual Motile CD4+ T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor CellsMotile Multikiller CD4+ T Cells. Cancer Immunol. Res. 2015, 3, 473–482. [Google Scholar] [CrossRef] [Green Version]
  32. Tokarew, N.; Ogonek, J.; Endres, S.; Von Bergwelt-Baildon, M.; Kobold, S. Teaching an old dog new tricks: Next-generation CAR T cells. Br. J. Cancer 2018, 120, 26–37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Duell, J.; Lurati, S.; Dittrich, M.; Bedke, T.; Pule, M.; Einsele, H.; Rossig, C.; Topp, M.S. First Generation Chimeric Antigen Receptor Display Functional Defects In Key Signal Pathways Upon Antigen Stimulation. Blood 2010, 116, 2088. [Google Scholar] [CrossRef]
  34. Yeku, O.O.; Brentjens, R.J. Armored CAR T-cells: Utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem. Soc. Trans. 2016, 44, 412–418. [Google Scholar] [CrossRef] [PubMed]
  35. Park, J.H.; Brentjens, R.J. Are all chimeric antigen receptors created equal? J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 651–653. [Google Scholar] [CrossRef]
  36. Lock, D.; Mockel-Tenbrinck, N.; Drechsel, K.; Barth, C.; Mauer, D.; Schaser, T.; Kolbe, C.; Al Rawashdeh, W.; Brauner, J.; Hardt, O.; et al. Automated Manufacturing of Potent CD20-Directed Chimeric Antigen Receptor T Cells for Clinical Use. Hum. Gene Ther. 2017, 28, 914–925. [Google Scholar] [CrossRef] [Green Version]
  37. Chmielewski, M.; Abken, H. TRUCKs: The fourth generation of CARs. Expert Opin. Biol. Ther. 2015, 15, 1145–1154. [Google Scholar] [CrossRef]
  38. Kagoya, Y.; Tanaka, S.; Guo, T.; Anczurowski, M.; Wang, C.-H.; Saso, K.; Butler, M.O.; Minden, M.D.; Hirano, N. A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nat. Med. 2018, 24, 352–359. [Google Scholar] [CrossRef]
  39. Savoldo, B.; Ramos, C.A.; Liu, E.; Mims, M.P.; Keating, M.J.; Carrum, G.; Kamble, R.T.; Bollard, C.M.; Gee, A.P.; Mei, Z.; et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients. J. Clin. Investig. 2011, 121, 1822–1826. [Google Scholar] [CrossRef] [Green Version]
  40. Wang, X.; Rivière, I. Clinical manufacturing of CAR T cells: Foundation of a promising therapy. Mol. Ther.-Oncolytics 2016, 3, 16015. [Google Scholar] [CrossRef]
  41. Berland, R.; Wortis, H.H. Origins and Functions of B-1 Cells with Notes on the Role of CD5. Annu. Rev. Immunol. 2002, 20, 253–300. [Google Scholar] [CrossRef]
  42. Birnbaum, M.E.; Berry, R.; Hsiao, Y.S.; Chen, Z.; Shingu-Vazquez, M.A.; Yu, X.; Waghray, D.; Fischer, S.; McCluskey, J.; Rossjohn, J.; et al. Molecular architecture of the αβ T cell receptor–CD3 complex. Proc. Natl. Acad. Sci. USA 2014, 111, 17576–17581. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Gomes-Silva, D.; Srinivasan, M.; Sharma, S.; Lee, C.; Wagner, D.L.; Davis, T.H.; Rouce, R.H.; Bao, G.; Brenner, M.K.; Mamonkin, M. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood J. Am. Soc. Hematol. 2017, 130, 285–296. [Google Scholar] [CrossRef] [PubMed]
  44. Leonard, W.J. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 2001, 1, 200–208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Mamonkin, M.; Rouce, R.H.; Tashiro, H.; Brenner, M.K. A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood J. Am. Soc. Hematol. 2015, 126, 983–992. [Google Scholar] [CrossRef] [Green Version]
  46. Cooper, M.L.; Choi, J.; Staser, K.; Ritchey, J.K.; Devenport, J.M.; Eckardt, K.; Rettig, M.P.; Wang, B.; Eissenberg, L.G.; Ghobadi, A.; et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 2018, 32, 1970–1983. [Google Scholar] [CrossRef]
  47. Fathi, E.; Farahzadi, R.; Sheervalilou, R.; Sanaat, Z.; Vietor, I. A general view of CD33+ leukemic stem cells and CAR-T cells as interesting targets in acute myeloblatsic leukemia therapy. Blood Res. 2020, 55, 10–16. [Google Scholar] [CrossRef] [Green Version]
  48. Frankel, A.E.; Zuckero, S.L.; A Mankin, A.; Grable, M.; Mitchell, K.; Lee, Y.J.; Neville, D.M.; Woo, J.H. Anti-CD3 Recombinant Diphtheria Immunotoxin Therapy of Cutaneous T Cell Lymphoma. Curr. Drug Targets 2009, 10, 104–109. [Google Scholar] [CrossRef]
  49. Frankel, A.E.; Woo, J.H.; Ahn, C.; Foss, F.M.; Duvic, M.; Neville, P.H.; Neville, D.M. Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma. Haematologica 2015, 100, 794–800. [Google Scholar] [CrossRef] [Green Version]
  50. Chen, K.H.; Wada, M.; Firor, A.E.; Pinz, K.G.; Jares, A.; Liu, H.; Salman, H.; Golightly, M.; Lan, F.; Jiang, X.; et al. Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget 2016, 7, 56219–56232. [Google Scholar] [CrossRef]
  51. Rasaiyaah, J.; Georgiadis, C.; Preece, R.; Mock, U.; Qasim, W. TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy. JCI Insight 2018, 3, e99442. [Google Scholar] [CrossRef] [Green Version]
  52. Suck, G.; Odendahl, M.; Nowakowska, P.; Seidl, C.; Wels, W.S.; Klingemann, H.G.; Tonn, T. NK-92: An ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol. Immunother. 2016, 65, 485–492. [Google Scholar] [CrossRef] [PubMed]
  53. Klingemann, H. Are natural killer cells superior CAR drivers? Oncoimmunology 2014, 3, e28147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Glienke, W.; Esser, R.; Priesner, C.; Suerth, J.D.; Schambach, A.; Wels, W.S.; Grez, M.; Kloess, S.; Arseniev, L.; Koehl, U. Advantages and applications of CAR-expressing natural killer cells. Front. Pharmacol. 2015, 6, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Campana, D.; van Dongen, J.J.; Mehta, A.; Coustan-Smith, E.; Wolvers-Tettero, I.L.; Ganeshaguru, K.; Janossy, G. Stages of T-cell receptor protein expression in T-cell acute lymphoblastic leukemia. Blood 1991, 77, 1546–1554. [Google Scholar] [CrossRef] [Green Version]
  56. Patel, J.L.; Smith, L.M.; Anderson, J.; Abromowitch, M.; Campana, D.; Jacobsen, J.; Lones, M.A.; Gross, T.G.; Cairo, M.S.; Perkins, S.L. The immunophenotype of T-lymphoblastic lymphoma in children and adolescents: A C hildren’s O ncology G roup report. Br. J. Haematol. 2012, 159, 454–461. [Google Scholar] [CrossRef]
  57. Perez-Villar, J.J.; Whitney, G.S.; Bowen, M.A.; Hewgill, D.H.; Aruffo, A.A.; Kanner, S.B. CD5 Negatively Regulates the T-Cell Antigen Receptor Signal Transduction Pathway: Involvement of SH2-Containing Phosphotyrosine Phosphatase SHP-1. Mol. Cell. Biol. 1999, 19, 2903–2912. [Google Scholar] [CrossRef] [Green Version]
  58. Gary, H.; Sainz-Perez, A.; Marteau, J.-B.; Marfaing-Koka, A.; Delic, J.; Merle-Béral, H.; Galanaud, P.; Dalloul, A. Natural Phosphorylation of CD5 in Chronic Lymphocytic Leukemia B Cells and Analysis of CD5-Regulated Genes in a B Cell Line Suggest a Role for CD5 in Malignant Phenotype. J. Immunol. 2007, 179, 4335–4344. [Google Scholar] [CrossRef] [Green Version]
  59. LeMaistre, C.F.; Rosen, S.; Frankel, A.; Kornfeld, S.; Saria, E.; Meneghetti, C.; Drajesk, J.; Fishwild, D.; Scannon, P.; Byers, V. Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma. Blood 1991, 78, 1173–1182. [Google Scholar] [CrossRef] [Green Version]
  60. Chen, K.H.; Wada, M.; Pinz, K.G.; Liu, H.; Lin, K.-W.; Jares, A.; Firor, A.E.; Shuai, X.; Salman, H.; Golightly, M.; et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 2017, 31, 2151–2160. [Google Scholar] [CrossRef]
  61. Raikar, S.S.; Fleischer, L.C.; Moot, R.; Fedanov, A.; Paik, N.Y.; Knight, K.A.; Doering, C.B.; Spencer, H.T. Development of chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK and CRISPR-edited T cell lines. Oncoimmunology 2017, 7, e1407898. [Google Scholar] [CrossRef] [Green Version]
  62. Mamonkin, M.; Mukherjee, M.; Srinivasan, M.; Sharma, S.; Gomes-Silva, D.; Mo, F.; Krenciute, G.; Orange, J.S.; Brenner, M.K. Reversible Transgene Expression Reduces Fratricide and Permits 4-1BB Costimulation of CAR T Cells Directed to T-cell MalignanciesRegulated CAR Expression Minimizes Tonic Signaling. Cancer Immunol. Res. 2018, 6, 47–58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Xu, Y.; Liu, Q.; Zhong, M.; Wang, Z.; Chen, Z.; Zhang, Y.; Xing, H.; Tian, Z.; Tang, K.; Liao, X.; et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J. Hematol. Oncol. 2019, 12, 1–13. [Google Scholar] [CrossRef]
  64. Rouce, R.H.; Hill, L.C.; Smith, T.S.; Yang, L.; Boriskie, B.; Srinivasan, M.; Zhang, H.; Perconti, S.; Mehta, B.; Dakhova, O.; et al. Early Signals of Anti-Tumor Efficacy and Safety with Autologous CD5.CAR T-Cells in Patients with Refractory/Relapsed T-Cell Lymphoma. Blood 2021, 138, 654. [Google Scholar] [CrossRef]
  65. Kaufman, R.E.; Haynes, B.F.; Sempowski, G.D.; Lee, D.M. Structure and function of the CD7 molecule. Crit. Rev. Immunol. 1999, 19, 18. [Google Scholar] [CrossRef]
  66. Qasim, W.; Zhan, H.; Samarasinghe, S.; Adams, S.; Amrolia, P.; Stafford, S.; Butler, K.; Rivat, C.; Wright, G.; Somana, K.; et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 2017, 9, eaaj2013. [Google Scholar] [CrossRef]
  67. Jacobson, C.A.; Herrera, A.F.; E Budde, L.; DeAngelo, D.J.; Heery, C.; Stein, A.; Jain, M.D.; Shah, B. Initial Findings of the Phase 1 Trial of PBCAR0191, a CD19 Targeted Allogeneic CAR-T Cell Therapy. Blood 2019, 134, 4107. [Google Scholar] [CrossRef]
  68. Png, Y.T.; Vinanica, N.; Kamiya, T.; Shimasaki, N.; Coustan-Smith, E.; Campana, D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv. 2017, 1, 2348–2360. [Google Scholar] [CrossRef] [Green Version]
  69. You, F.; Wang, Y.; Jiang, L.; Zhu, X.; Chen, D.; Yuan, L.; An, G.; Meng, H.; Yang, L. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Am. J. Cancer Res. 2019, 9, 64–78. [Google Scholar]
  70. Pan, J.; Tan, Y.; Wang, G.; Deng, B.; Ling, Z.; Song, W.; Seery, S.; Zhang, Y.; Peng, S.; Xu, J.; et al. Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial. J. Clin. Oncol. 2021, 39, 3340–3351. [Google Scholar] [CrossRef]
  71. Burger, R.; E Hansen-Hagge, T.; Drexler, H.G.; Gramatzki, M. Heterogeneity of T-acute lymphoblastic leukemia (T-ALL) cell lines: Suggestion for classification by immunophenotype and T-cell receptor studies. Leuk. Res. 1998, 23, 19–27. [Google Scholar] [CrossRef]
  72. Niehues, T.; Kapaun, P.; Harms, D.; Burdach, S.; Kramm, C.; Körholz, D.; Janka-Schaub, G.; Göbel, U. A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies. Leukemia 1999, 13, 614–617. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Sanchez, D.; Baroni, M.L.; Gutiérrez-Agüera, F.; Roca-Ho, H.; Blanch-Lombarte, O.; González-García, S.; Torrebadell, M.; Junca, J.; Ramírez-Orellana, M.; Velasco-Hernández, T.; et al. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia. Blood J. Am. Soc. Hematol. 2019, 133, 2291–2304. [Google Scholar] [CrossRef]
  74. Knox, S.; Hoppe, R.; Maloney, D.; Gibbs, I.; Fowler, S.; Marquez, C.; Cornbleet, P.; Levy, R. Treatment of cutaneous T-cell lymphoma with chimeric anti-CD4 monoclonal antibody. Blood 1996, 87, 893–899. [Google Scholar] [CrossRef] [Green Version]
  75. Hagberg, H.; Pettersson, M.; Bjerner, T.; Enblad, G. Treatment of a patient with a nodal peripheral T-cell lymphoma (angioimmunoblastic T-Cell lymphoma) with a human monoclonal antibody against the CD4 antigen (HuMax-CD4). Med. Oncol. 2005, 22, 191–194. [Google Scholar] [CrossRef]
  76. Kim, Y.H.; Duvic, M.; Obitz, E.; Gniadecki, R.; Iversen, L.; Österborg, A.; Whittaker, S.; Illidge, T.M.; Schwarz, T.; Kaufmann, R.; et al. Clinical efficacy of zanolimumab (HuMax-CD4): Two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood J. Am. Soc. Hematol. 2007, 109, 4655–4662. [Google Scholar] [CrossRef]
  77. D’Amore, F.; Radford, J.; Relander, T.; Jerkeman, M.; Tilly, H.; Österborg, A.; Morschhauser, F.; Gramatzki, M.; Dreyling, M.; Bang, B.; et al. Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma. Br. J. Haematol. 2010, 150, 565–573. [Google Scholar] [CrossRef] [Green Version]
  78. Pinz, K.; Liu, H.; Golightly, M.; Jares, A.; Lan, F.; Zieve, G.W.; Hagag, N.; Schuster, M.; Firor, A.; Jiang, X.; et al. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia 2015, 30, 701–707. [Google Scholar] [CrossRef]
  79. Pinz, K.G.; Yakaboski, E.; Jares, A.; Liu, H.; Firor, A.E.; Chen, K.H.; Wada, M.; Salman, H.; Tse, W.; Hagag, N.; et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget 2017, 8, 112783–112796. [Google Scholar] [CrossRef] [Green Version]
  80. Alcantara, M.; Tesio, M.; June, C.H.; Houot, R. CAR T-cells for T-cell malignancies: Challenges in distinguishing between therapeutic, normal, and neoplastic T-cells. Leukemia 2018, 32, 2307–2315. [Google Scholar] [CrossRef]
  81. Ma, G.; Shen, J.; Pinz, K.; Wada, M.; Park, J.; Kim, S.; Togano, T.; Tse, W. Targeting T Cell Malignancies Using CD4CAR T-Cells and Implementing a Natural Safety Switch. Stem Cell Rev. Rep. 2019, 15, 443–447. [Google Scholar] [CrossRef]
  82. Falini, B.; Pileri, S.; Pizzolo, G.; Durkop, H.; Flenghi, L.; Stirpe, F.; Martelli, M.; Stein, H. CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood 1995, 85, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Bossard, C.; Dobay, M.P.; Parrens, M.; Lamant, L.; Missiaglia, E.; Haioun, C.; Martin, A.; Fabiani, B.; Delarue, R.; Tournilhac, O.; et al. Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: High correlation with mRNA levels. Blood J. Am. Soc. Hematol. 2014, 124, 2983–2986. [Google Scholar] [CrossRef] [Green Version]
  84. Sabattini, E.; Pizzi, M.; Tabanelli, V.; Baldin, P.; Sacchetti, C.S.; Agostinelli, C.; Zinzani, P.L.; Pileri, S.A. CD30 expression in peripheral T-cell lymphomas. Haematologica 2013, 98, e81–e82. [Google Scholar] [CrossRef] [PubMed]
  85. Zheng, W.; Medeiros, L.J.; Young, K.H.; Goswami, M.; Powers, L.; Kantarjian, H.H.; Thomas, D.A.; Cortes, J.; Wang, S.A. CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis. Leuk. Lymphoma 2013, 55, 624–627. [Google Scholar] [CrossRef] [Green Version]
  86. Bonthapally, V.; Wu, E.; Macalalad, A.; Yang, H.; Shonukan, O.; Liu, Y.; Chi, A.; Huebner, D. Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma post-autologous transplant: Meta-analysis versus historical data. Curr. Med Res. Opin. 2015, 31, 993–1001. [Google Scholar] [CrossRef] [PubMed]
  87. Van Der Weyden, C.; Dickinson, M.; Whisstock, J.; Prince, H.M. Brentuximab vedotin in T-cell lymphoma. Expert Rev. Hematol. 2019, 12, 5–19. [Google Scholar] [CrossRef] [PubMed]
  88. Kim, Y.H.; Prince, H.M.; Whittaker, S.; Horwitz, S.M.; Duvic, M.; Bechter, O.; Sanches, J.A.; Stadler, R.; Scarisbrick, J.; Quaglino, P.; et al. Response to brentuximab vedotin versus physician’s choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis. Eur. J. Cancer 2021, 148, 411–421. [Google Scholar] [CrossRef]
  89. Thurber, G.M.; Schmidt, M.M.; Wittrup, K.D. Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance. Adv. Drug Deliv. Rev. 2008, 60, 1421–1434. [Google Scholar] [CrossRef] [Green Version]
  90. Hombach, A.; Heuser, C.; Sircar, R.; Tillmann, T.; Diehl, V.; Pohl, C.; Abken, H. An anti-CD30 chimeric receptor that mediates CD3-ζ-independent T-cell activation against Hodgkin’s lymphoma cells in the presence of soluble CD30. Cancer Res. 1998, 58, 1116–1119. [Google Scholar]
  91. Hombach, A.; Heuser, C.; Sircar, R.; Tillmann, T.; Diehl, V.; Pohl, C.; Abken, H. Characterization of a Chimeric T-Cell Receptor with Specificity for the Hodgkin??s Lymphoma-Associated CD30 Antigen. J. Immunother. 1999, 22, 473–480. [Google Scholar] [CrossRef]
  92. Ramos, C.A.; Ballard, B.; Zhang, H.; Dakhova, O.; Gee, A.P.; Mei, Z.; Bilgi, M.; Wu, M.-F.; Liu, H.; Grilley, B.; et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes. J. Clin. Investig. 2017, 127, 3462–3471. [Google Scholar] [CrossRef]
  93. Park, S.I.; Serody, J.S.; Shea, T.C.; Grover, N.S.; Ivanova, A.; Morrison, K.; Eldridge, P.; McKay, K.; Cheng, C.J.; Covington, D.; et al. A phase 1b/2 study of CD30-specific chimeric antigen receptor T-cell (CAR-T) therapy in combination with bendamustine in patients with CD30+ Hodgkin and non-Hodgkin lymphoma. J. Clin. Oncol. 2017, 35, TPS3095. [Google Scholar] [CrossRef]
  94. Ramos, C.A.; Grover, N.S.; Beaven, A.W.; Lulla, P.D.; Wu, M.-F.; Ivanova, A.; Wang, T.; Shea, T.C.; Rooney, C.M.; Dittus, C.; et al. Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. J. Clin. Oncol. 2020, 38, 3794–3804. [Google Scholar] [CrossRef] [PubMed]
  95. Di Stasi, A.; De Angelis, B.; Rooney, C.M.; Zhang, L.; Mahendravada, A.; Foster, A.E.; Heslop, H.E.; Brenner, M.K.; Dotti, G.; Savoldo, B. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood J. Am. Soc. Hematol. 2009, 113, 6392–6402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Wang, C.M.; Wu, Z.Q.; Wang, Y.; Guo, Y.L.; Dai, H.R.; Wang, X.H.; Li, X.; Zhang, Y.J.; Zhang, W.Y.; Chen, M.X.; et al. Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I TrialCART-30 Cell Therapy for Relapsed or Refractory Hodgkin Lymphoma. Clin. Cancer Res. 2017, 23, 1156–1166. [Google Scholar] [CrossRef] [Green Version]
  97. Guercio, M.; Orlando, D.; Di Cecca, S.; Sinibaldi, M.; Boffa, I.; Caruso, S.; Abbaszadeh, Z.; Camera, A.; Cembrola, B.; Bovetti, K.; et al. CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells. Haematologica 2020, 106, 987–999. [Google Scholar] [CrossRef]
  98. Tobinai, K.; Takahashi, T.; Akinaga, S. Targeting Chemokine Receptor CCR4 in Adult T-Cell Leukemia-Lymphoma and Other T-Cell Lymphomas. Curr. Hematol. Malign-Rep. 2012, 7, 235–240. [Google Scholar] [CrossRef] [Green Version]
  99. Sugaya, M.; Morimura, S.; Suga, H.; Kawaguchi, M.; Miyagaki, T.; Ohmatsu, H.; Fujita, H.; Sato, S. CCR4 is expressed on infiltrating cells in lesional skin of early mycosis fungoides and atopic dermatitis. J. Dermatol. 2015, 42, 613–615. [Google Scholar] [CrossRef]
  100. Moore, D.C.; Elmes, J.B.; Shibu, P.A.; Larck, C.; Park, S.I. Mogamulizumab: An Anti-CC Chemokine Receptor 4 Antibody for T-Cell Lymphomas. Ann. Pharmacother. 2019, 54, 371–379. [Google Scholar] [CrossRef]
  101. Perera, L.P.; Zhang, M.; Nakagawa, M.; Petrus, M.N.; Maeda, M.; Kadin, M.E.; Waldmann, T.A.; Perera, P.-Y. Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am. J. Hematol. 2017, 92, 892–901. [Google Scholar] [CrossRef] [Green Version]
  102. Ishida, T.; Joh, T.; Uike, N.; Yamamoto, K.; Utsunomiya, A.; Yoshida, S.; Saburi, Y.; Miyamoto, T.; Takemoto, S.; Suzushima, H.; et al. Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukemia-Lymphoma: A Multicenter Phase II Study. J. Clin. Oncol. 2012, 30, 837–842. [Google Scholar] [CrossRef] [PubMed]
  103. Ogura, M.; Ishida, T.; Hatake, K.; Taniwaki, M.; Ando, K.; Tobinai, K.; Fujimoto, K.; Yamamoto, K.; Miyamoto, T.; Uike, N.; et al. Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients With Relapsed Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma. J. Clin. Oncol. 2014, 32, 1157–1163. [Google Scholar] [CrossRef] [PubMed]
  104. Grover, N.S.; Ivanova, A.; Moore, D.T.; Cheng, C.J.A.; Babinec, C.; West, J.; Cavallo, T.; Morrison, J.K.; Buchanan, F.B.; Bowers, E.; et al. CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma. Blood 2021, 138, 742. [Google Scholar] [CrossRef]
  105. Uehara, S.; Grinberg, A.; Farber, J.M.; Love, P.E. A Role for CCR9 in T Lymphocyte Development and Migration. J. Immunol. 2002, 168, 2811–2819. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Wurbel, M.-A.; Malissen, M.; Guy-Grand, D.; Meffre, E.; Nussenzweig, M.C.; Richelme, M.; Carrier, A.; Malissen, B. Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor γδ+ gut intraepithelial lymphocytes. Blood J. Am. Soc. Hematol. 2001, 98, 2626–2632. [Google Scholar] [CrossRef]
  107. Maciocia, P.M.; Wawrzyniecka, P.A.; Maciocia, N.C.; Burley, A.; Karpanasamy, T.; Devereaux, S.; Hoekx, M.; O’Connor, D.; Leon, T.E.; Rapoz-D’Silva, T.; et al. Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia. Blood 2022, 140, 25–37. [Google Scholar] [CrossRef]
  108. Philip, B.; Kokalaki, E.; Mekkaoui, L.; Thomas, S.; Straathof, K.; Flutter, B.; Marin, V.; Marafioti, T.; Chakraverty, R.; Linch, D.; et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood J. Am. Soc. Hematol. 2014, 124, 1277–1287. [Google Scholar] [CrossRef]
  109. Hamilton, B.K.; Rybicki, L.; Abounader, D.; Adekola, K.; Advani, A.; Aldoss, I.; Bachanova, V.; Bashey, A.; Brown, S.; DeLima, M.; et al. Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia. Biol. Blood Marrow Transplant. 2017, 23, 1117–1121. [Google Scholar] [CrossRef] [Green Version]
  110. Van Spriel, A.B.; Puls, K.L.; Sofi, M.; Pouniotis, D.; Hochrein, H.; Orinska, Z.; Knobeloch, K.P.; Plebanski, M.; Wright, M.D. A regulatory role for CD37 in T cell proliferation. J. Immunol. 2004, 172, 2953–2961. [Google Scholar] [CrossRef] [Green Version]
  111. Barrena, S.; Almeida, J.; Yunta, M.; López, A.; Fernández-Mosteirín, N.; Giralt, M.; Romero, M.; Perdiguer, L.; Delgado, M.; Orfao, A.; et al. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 2005, 19, 1376–1383. [Google Scholar] [CrossRef] [Green Version]
  112. Lapalombella, R.; Yeh, Y.-Y.; Wang, L.; Ramanunni, A.; Rafiq, S.; Jha, S.; Staubli, J.; Lucas, D.M.; Mani, R.; Herman, S.E.; et al. Tetraspanin CD37 Directly Mediates Transduction of Survival and Apoptotic Signals. Cancer Cell 2012, 21, 694–708. [Google Scholar] [CrossRef] [PubMed]
  113. Sawas, A.; Savage, K.J.; Perez, R.; Advani, R.H.; Butturini, A.; Lackey, J.; Trave, F.; Anand, B.; Huang, Y.; Reyno, L.; et al. A phase 1 study of the anti-CD37 antibody-drug conjugate AGS67E in advanced lymphoid malignancies. Interim results. Hematol. Oncol. 2017, 35, 49. [Google Scholar] [CrossRef] [Green Version]
  114. Scarfò, I.; Ormhøj, M.; Frigault, M.J.; Castano, A.P.; Lorrey, S.; Bouffard, A.A.; Van Scoyk, A.; Rodig, S.J.; Shay, A.J.; Aster, J.C.; et al. Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Blood J. Am. Soc. Hematol. 2018, 132, 1495–1506. [Google Scholar] [CrossRef] [PubMed]
  115. Tunnacliffe, A.; Kefford, R.; Milstein, C.; Forster, A.; Rabbitts, T.H. Sequence and evolution of the human T-cell antigen receptor beta-chain genes. Proc. Natl. Acad. Sci. USA 1985, 82, 5068–5072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Jamal, S.; Picker, L.J.; Aquino, D.B.; McKenna, R.W.; Dawson, D.B.; Kroft, S.H. Immunophenotypic analysis of peripheral T-cell neoplasms: A multiparameter flow cytometric approach. Am. J. Clin. Pathol. 2001, 116, 512–526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Maciocia, P.; A Wawrzyniecka, P.; Philip, B.; Ricciardelli, I.; Akarca, A.U.; Onuoha, S.C.; Legut, M.; Cole, D.; Sewell, A.K.; Gritti, G.; et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat. Med. 2017, 23, 1416–1423. [Google Scholar] [CrossRef]
  118. Morton, L.T.; Reijmers, R.M.; Wouters, A.K.; Kweekel, C.; Remst, D.F.G.; Pothast, C.R.; Falkenburg, J.H.F.; Heemskerk, M.H.M. Simultaneous Deletion of Endogenous TCRαβ for TCR Gene Therapy Creates an Improved and Safe Cellular Therapeutic. Mol. Ther. 2020, 28, 64–74. [Google Scholar] [CrossRef]
  119. Sun, S.; Hao, H.; Yang, G.; Zhang, Y.; Fu, Y. Immunotherapy with CAR-Modified T Cells: Toxicities and Overcoming Strategies. J. Immunol. Res. 2018, 2018, 1–10. [Google Scholar] [CrossRef]
  120. Svoboda, J.; Rheingold, S.R.; Gill, S.I.; Grupp, S.A.; Lacey, S.F.; Kulikovskaya, I.; Suhoski, M.M.; Melenhorst, J.J.; Loudon, B.; Mato, A.R.; et al. Nonviral RNA chimeric antigen receptor–modified T cells in patients with Hodgkin lymphoma. Blood J. Am. Soc. Hematol. 2018, 132, 1022–1026. [Google Scholar] [CrossRef]
  121. Birkholz, K.; A Hombach, A.; A Krug, C.; Reuter, S.; Kershaw, M.; Kampgen, E.; Schuler, G.; Abken, H.; Schaft, N.; Dörrie, J. Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer. Gene Ther. 2009, 16, 596–604. [Google Scholar] [CrossRef]
  122. Barrett, D.M.; Zhao, Y.; Liu, X.; Jiang, S.; Carpenito, C.; Kalos, M.; Carroll, R.G.; June, C.H.; Grupp, S.A. Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells. Hum. Gene Ther. 2011, 22, 1575–1586. [Google Scholar] [CrossRef] [PubMed]
  123. Di Stasi, A.; Tey, S.K.; Dotti, G.; Fujita, Y.; Kennedy-Nasser, A.; Martinez, C.; Straathof, K.; Liu, E.; Durett, A.G.; Grilley, B.; et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 2011, 365, 1673–1683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Traversari, C.; Marktel, S.; Magnani, Z.I.; Mangia, P.; Russo, V.; Ciceri, F.; Bonini, M.C.; Bordignon, C. The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood J. Am. Soc. Hematol. 2007, 109, 4708–4715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Yu, S.; Yi, M.; Qin, S.; Wu, K. Next generation chimeric antigen receptor T cells: Safety strategies to overcome toxicity. Mol. Cancer 2019, 18, 125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Safarzadeh Kozani, P.; Safarzadeh Kozani, P.; Rahbarizadeh, F.; Khoshtinat Nikkhoi, S. Strategies for dodging the obstacles in CAR T cell therapy. Front. Oncol. 2021, 11, 627549. [Google Scholar] [CrossRef]
  127. Ruella, M.; Xu, J.; Barrett, D.M.; Fraietta, J.A.; Reich, T.J.; Ambrose, D.E.; Klichinsky, M.; Shestova, O.; Patel, P.R.; Kulikovskaya, I.; et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 2018, 24, 1499–1503. [Google Scholar] [CrossRef]
  128. Depil, S.; Duchateau, P.; Grupp, S.; Mufti, G.; Poirot, L. ‘Off-the-shelf’allogeneic CAR T cells: Development and challenges. Nat. Rev. Drug Discov. 2020, 19, 185–199. [Google Scholar] [CrossRef]
  129. Simonetta, F.; Alvarez, M.; Negrin, R.S. Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation. Front. Immunol. 2017, 8, 465. [Google Scholar] [CrossRef] [Green Version]
  130. Zhang, C.; Oberoi, P.; Oelsner, S.; Waldmann, A.; Lindner, A.; Tonn, T.; Wels, W.S. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity. Front. Immunol. 2017, 8, 533. [Google Scholar] [CrossRef]
  131. Liu, Q.; Xu, Y.; Mou, J.; Tang, K.; Fu, X.; Li, Y.; Xing, Y.; Rao, Q.; Xing, H.; Tian, Z.; et al. Irradiated chimeric antigen receptor engineered NK-92MI cells show effective cytotoxicity against CD19+ malignancy in a mouse model. Cytotherapy 2020, 22, 552–562. [Google Scholar] [CrossRef]
  132. Allan, D.S.; Chakraborty, M.; Waller, G.C.; Hochman, M.J.; Poolcharoen, A.; Reger, R.N.; Childs, R.W. Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion. Mol. Ther.-Methods Clin. Dev. 2021, 20, 559–571. [Google Scholar] [CrossRef] [PubMed]
  133. Morgan, M.A.; Büning, H.; Sauer, M.; Schambach, A. Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells. Front. Immunol. 2020, 11, 1965. [Google Scholar] [CrossRef] [PubMed]
  134. Papadopoulou, A.; Gerdemann, U.; Katari, U.L.; Tzannou, I.; Liu, H.; Martinez, C.; Leung, K.; Carrum, G.; Gee, A.P.; Vera, J.F.; et al. Activity of Broad-Spectrum T Cells as Treatment for AdV, EBV, CMV, BKV, and HHV6 Infections after HSCT. Sci. Transl. Med. 2014, 6, 242ra83. [Google Scholar] [CrossRef] [Green Version]
  135. Houghtelin, A.; Bollard, C.M. Virus-Specific T Cells for the Immunocompromised Patient. Front. Immunol. 2017, 8, 1272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Melenhorst, J.J.; Leen, A.M.; Bollard, C.M.; Quigley, M.F.; Price, D.A.; Rooney, C.M.; Brenner, M.K.; Barrett, A.J.; Heslop, H.E. Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood J. Am. Soc. Hematol. 2010, 116, 4700–4702. [Google Scholar] [CrossRef]
  137. Lança, T.; Correia, D.V.; Moita, C.F.; Raquel, H.; Neves-Costa, A.; Ferreira, C.; Ramalho, J.S.; Barata, J.T.; Moita, L.F.; Gomes, A.Q.; et al. The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity. Blood J. Am. Soc. Hematol. 2010, 115, 2407–2411. [Google Scholar] [CrossRef] [Green Version]
  138. Nielsen, M.M.; Witherden, D.A.; Havran, W.L. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat. Rev. Immunol. 2017, 17, 733–745. [Google Scholar] [CrossRef] [Green Version]
  139. McCarthy, N.E.; Eberl, M. Human γδ T-cell control of mucosal immunity and inflammation. Front. Immunol. 2018, 9, 985. [Google Scholar] [CrossRef] [Green Version]
  140. Capsomidis, A.; Benthall, G.; Van Acker, H.H.; Fisher, J.; Kramer, A.M.; Abeln, Z.; Majani, Y.; Gileadi, T.; Wallace, R.; Gustafsson, K.; et al. Chimeric Antigen Receptor-Engineered Human Gamma Delta T Cells: Enhanced Cytotoxicity with Retention of Cross Presentation. Mol. Ther. 2018, 26, 354–365. [Google Scholar] [CrossRef] [Green Version]
  141. Uchida, R.; Ashihara, E.; Sato, K.; Kimura, S.; Kuroda, J.; Takeuchi, M.; Kawata, E.; Taniguchi, K.; Okamoto, M.; Shimura, K.; et al. γδT cells kill myeloma cells by sensing mevalonate metabolites and ICAM-1 molecules on cell surface. Biochem. Biophys. Res. Commun. 2007, 354, 613–618. [Google Scholar] [CrossRef]
  142. Li, J.; Herold, M.; Kimmel, B.; Müller, I.; Rincon-Orozco, B.; Kunzmann, V.; Herrmann, T. Reduced Expression of the Mevalonate Pathway Enzyme Farnesyl Pyrophosphate Synthase Unveils Recognition of Tumor Cells by Vγ9Vδ2 T Cells. J. Immunol. 2009, 182, 8118–8124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Rischer, M.; Pscherer, S.; Duwe, S.; Vormoor, J.; Jürgens, H.; Rossig, C. Human γδ T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br. J. Haematol. 2004, 126, 583–592. [Google Scholar] [CrossRef] [PubMed]
  144. Harrer, D.C.; Simon, B.; Fujii, S.I.; Shimizu, K.; Uslu, U.; Schuler, G.; Gerer, K.F.; Hoyer, S.; Dörrie, J.; Schaft, N. RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: A safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma. BMC Cancer 2017, 17, 1–17. [Google Scholar] [CrossRef] [PubMed]
  145. Ratner, L.; Waldmann, T.A.; Janakiram, M.; Brammer, J.E. Rapid Progression of Adult T-Cell Leukemia–Lymphoma after PD-1 Inhibitor Therapy. N. Engl. J. Med. 2018, 378, 1947–1948. [Google Scholar] [CrossRef] [PubMed]
  146. Ghione, P.; Moskowitz, A.J.; De Paola, N.E.K.; Horwitz, S.M.; Ruella, M. Novel Immunotherapies for T Cell Lymphoma and Leukemia. Curr. Hematol. Malign-Rep. 2018, 13, 494–506. [Google Scholar] [CrossRef] [PubMed]
  147. Hill, B.T.; Roberts, Z.J.; Xue, A.; Rossi, J.M.; Smith, M.R. Rapid tumor regression from PD-1 inhibition after anti-CD19 chimeric antigen receptor T-cell therapy in refractory diffuse large B-cell lymphoma. Bone Marrow Transplant. 2019, 55, 1184–1187. [Google Scholar] [CrossRef] [PubMed]
Cells 11 03971 g001 550
Figure 1. Challenges to the application of CAR-based therapy in T-cell malignancies and proposed solutions. CAR-T cell therapy can be complicated by fratricide, contamination of the final product by transduced tumor cells, as well as T-cell aplasia. CAR: chimeric antigen receptor; AAV: adeno-associated virus; HSCT: hematopoietic stem cell transplantation.
Figure 1. Challenges to the application of CAR-based therapy in T-cell malignancies and proposed solutions. CAR-T cell therapy can be complicated by fratricide, contamination of the final product by transduced tumor cells, as well as T-cell aplasia. CAR: chimeric antigen receptor; AAV: adeno-associated virus; HSCT: hematopoietic stem cell transplantation.
Cells 11 03971 g001
Table
Table 1. Available target antigens with their corresponding ongoing clinical trials for CAR-T therapy of T-cell malignancies.
Table 1. Available target antigens with their corresponding ongoing clinical trials for CAR-T therapy of T-cell malignancies.
Target ReceptorNotes on CAR ConstructTarget
Disease		Main
Eligibility Criteria		PhaseTarget AccrualOutcomesAge Group (Years)StatusClinicalTrials.gov
Identifier
CD4
Anti-CD4 CAR transduced with a lentiviral vectorR/R CD4+ T-NHLAfter failure of standard therapyI12Toxicity
DFS; PFS; OS		≥18RecruitingNCT04162340
Autologous LCAR-T2CT-ALL
T-NHL		PD or SD after ≥1 prior line of therapyI33DLT, AE, RP2D, PK18–75RecruitingNCT04973527
Autologous LCAR-T2CR/R CD4+
T-NHL		PD or SD after ≥1 prior line of therapyI32DLT, AE, RP2D, PK18–75RecruitingNCT04219319
Autologous T cells transduced with a lentiviral vectorR/R CD4+
T-NHL		R/R including ASCTI20Safety, feasibility
In vivo survival, clinical response		≥18Active, not recruitingNCT03829540
LB1901- autologous CD4-targeted CAR-TT-NHLFailed ≥2 prior lines of therapyI (FIH)50RP2D
ORR, TTR		≥18Active, not recruitingNCT04712864
CD5
Anti-CD5 CAR transduced with a lentiviral vectorR/R T-ALL and
T-NHL		After failure of standard therapyI20Toxicity
DFS; PFS; OS		≥8RecruitingNCT04594135
Donor-derived CD5 CAR T cellsR/R T-ALLAfter failure of standard therapyI (FIH)18DLT, AEs
ORR, BOR		1–70RecruitingNCT05032599
Autologous CD5.CAR/28zeta CAR T cells
Allogeneic CD5.CAR/28zeta CAR T cells		R/R T-ALL and
T-NHL		Suitable for ASCT
R/R post ASCT		I42DLT, ORRUp to 75Active Not recruitingNCT03081910
MAGENTA
Endogenous CD5 in CT125A cells knocked out by CRISPR/Cas9 genome editing PTCL
CD5+ R/R		Failed at ≥1 prior therapyI18DLT, AE
ORR, CR		18–70Not yet recruitingNCT04767308
CD7
BT-007, transduced with 4-1BB/CD3ζ lentiviral vector, expanded in vitroCD7+ R/R T-NHLFailed ≥1 line of therapyI15ORR, retention time and amount of CAR-T cells remaining in vivo18–70RecruitingNCT05554575
CD30
Carmelizumab + CD30 CAR-T cellsCD30+ R/R T-NHLFailed ≥2 lines of systemic treatmentII30ORR, OS, DOR, PFS, AEs18–70RecruitingNCT05320081
Allogeneic CD30.CAR-EBVSTsCD30+ R/R
T-NHL		ALK+/ALK- ALCL
PTCL		I18DLT, ORR, DOR, SD, PFS12–75RecruitingNCT04288726
CD30.CAR-EBVST cellsCD30+ R/RT-NHLALK+/ALK- ALCL
PTCL		I18DLT, ORR, DOR, SD, PFS12–75Not yet recruitingNCT04952584
Autologous 3rd generation anti-CD30 CAR T cells.CD30+ R/R
T-NHL		ATLL, ALCL, AITL, NK/TCL, PTCLI50AEs, OS, EFS, RFS, retention amount18–70RecruitingNCT04008394
Autologous, uses retroviral vectorCD30+ R/R
T-NHL		PTCL, AITL, NK/TCL, ALCL, etc.I66DLT, ORR12–75RecruitingNCT02917083
RELY-30
Autologous CAR.CD30 T CELLSCD30+ R/R
T-NHL		PTCL, AITL, NK/TCL, ALCL, etc.I9MTD, AE, ORR, DCR, DOR, PFS, OS18–70Not yet recruitingNCT05208853
CD30-Directed Genetically Modified Autologous T-CellsCD30+ R/R
T-NHL		PTCL, ALCL, NK/TCLI21DLT, ORR, DOR, PFS18–75Active, not recruitingNCT04526834
HSP-CAR30; Autologous second generation (4-1BBz)CD30+ R/R
T-NHL		ALK+/ALK- ALCL, PTCLI/II30Safety, toxicity, MTD, CR18–70RecruitingNCT04653649
Autologous CAR.CD30 T CELLSCD30+ T-NHLRelapsing after ASCT, or refractory to 2 multidrug regimens and/or anti-CD30 antibody treatment.
Newly diagnosed patients unable to receive or complete standard chemotherapy		I/II30AE, anti-tumor responses, in vivo existence16–80RecruitingNCT02259556
Autologous activated T lymphocytes (ATLs) expressing CD30 CARCD30+ R/R
T-NHL		PTCLII20PFS, BOR, ORR, DLT, OS18–99RecruitingNCT04083495
Autologous CAR.CD30 T CELLSCD30+ R/R
T-NHL		Failed >2 prior regimens. Subjects relapsed after ASCT or APSCT also eligibleIb/II402-y OS, 2-y PFS, ORR, DOR, AEs≥3RecruitingNCT02690545
Transduced with lentivirus bearing anti-CD30 antibody scFV and the activation signals of second-generation CART designation.CD30+ R/R
T-NHL		ALK+/ALK- ALCL, PTCLI20Safety, anti-tumor efficacy2–80RecruitingNCT03383965
Autologous CAR.CD30 EBV specific-CTLsNewly diagnosed and R/R T-NHLCD30+; include failure post APSCTI18Survival and anti-tumor effects in vivoAll agesActive, not recruitingNCT01192464
CARCD30
Autologous CAR.CD30 T CELLSCD30+ T-NHLCD30+; include failure post APSCTI10Safety; Survival and anti-tumor effects in vivoAll agesActive, not recruitingNCT01316146
CART CD30
Autologous CAR.CD30 T CELLS with CCR4 (ATLCAR.CD30.CCR4)CD30+ CTCLAll cutaneous CD30+ T-NHLI59AE, PFS, BOR, ORR, OS≥18RecruitingNCT03602157
Autologous CAR.CD30 T CELLS with CCR4 (ATLCAR.CD30.CCR4)CD30+ T-NHLRelapse after high dose therapy and APSCT (ATLAS)I18AEs, PFS, OS, survival of CAR in vivo≥3Active, not recruitingNCT02663297
CD37
CAR-37 T cellsCD37+ R/R T-NHLMature T cell neoplasms R/R after 2 or more prior lines of therapy or
Relapse after APSCT		I (FIH)18DLT, AE, OS, PFS, RR≥18RecruitingNCT04136275
CCR4
Autologous CAR.CD30 T CELLS with CCR4 (ATLCAR.CD30.CCR4)CD30+ CTCLAll cutaneous CD30+ T-NHLI59AE, PFS, BOR, ORR, OS≥18RecruitingNCT03602157
TRBC1/2
Autologous anti-TRBC1 CARR/R TRBC1+
T-NHL		PTCL, AITL, ALCL, T-ALLI9CAR-T cell expansion and persistence
ORR, DOR, OS, PFS		18–70RecruitingNCT04828174
AUTO4; RQR8/aTRBC1 CAR T cellsR/R TRBC1+
T-NHL		PTCL, AITL, ALCLI/II200Safety, CR+PR, AE, time to response≥18RecruitingNCT03590574
R/R: Relapsed/refractory; T-NHL: T-Non-Hodgkin’s lymphoma; T-ALL: T-acute lymphoblastic leukemia; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; PD: progressive disease; SD: stable disease; DLT: dose-limiting toxicity; AE: adverse event; RP2D: recommended phase 2 dose; PK: pharmacokinetics; ORR: overall response rate; TTR: time to response; ASCT: allogeneic stem cell transplantation; APSCT: autologous peripheral stem cell transplantation; FIH: first-in-human; BOR: best objective response; CR: complete remission; DOR: duration of response; PR: partial response; MTD: maximal tolerated dose; DCR: disease control rate; RFS: relapse-free survival; EFS: event-free survival; 2-y: 2-year; AITL: angioimmunoblastic T-cell lymphoma; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ATLL: adult T-cell leukemia/lymphoma; CCR4: C-C chemokine receptor type 4; CTCL: cutaneous T-cell lymphoma; NK: natural killer; NOS: not otherwise specified; PTCL: peripheral T-cell lymphoma; TCR: T-cell receptor; TRBC: T-cell receptor β-chain constant domain.
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Assi, R.; Salman, H. Harnessing the Potential of Chimeric Antigen Receptor T-Cell Therapy for the Treatment of T-Cell Malignancies: A Dare or Double Dare? Cells 2022, 11, 3971. https://doi.org/10.3390/cells11243971

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Assi R, Salman H. Harnessing the Potential of Chimeric Antigen Receptor T-Cell Therapy for the Treatment of T-Cell Malignancies: A Dare or Double Dare? Cells. 2022; 11(24):3971. https://doi.org/10.3390/cells11243971

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Assi, Rita, and Huda Salman. 2022. "Harnessing the Potential of Chimeric Antigen Receptor T-Cell Therapy for the Treatment of T-Cell Malignancies: A Dare or Double Dare?" Cells 11, no. 24: 3971. https://doi.org/10.3390/cells11243971

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