Search Results (162)

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL); however, a significant proportion of patients fail to achieve a durable response, underscoring the need for reliable predictive biomarkers. We characterize T-lymphocyte subpopulations in apheresis samples from 23 r/r large B-cell lymphoma (LBCL) patients who received axicabtagene ciloleucel (axi-cel) to identify pre-treatment cell biomarkers associated with CAR T-cell kinetics and clinical outcomes. Immunophenotyping of T-cells within fresh apheresis samples and monitoring of circulating CAR T-cells were performed by multiparametric flow cytometry. The median peak CAR T-cell count was 45.2 CAR T-cells/mL. Strong CAR-T expanders (≥45.2 CAR T-cells/mL) exhibited higher values of both CD4⁺ (p = 0.011) and CD8⁺ (p = 0.023) central memory T-cells (T_CM; CCR7⁺CD45RA⁻), as well as lower proportions of CD8⁺CD38⁺ T-cells in apheresis samples. In apheresis, a cut-off value of >4.3% of CD8⁺ T_CM predicted strong CAR-T expansion (AUC: 0.80; p = 0.023) and superior progression-free survival (p = 0.04) compared with patients who had CD8⁺ T_CM below the cut-off. Our data suggest that high frequencies of CD8⁺ T_CM cells in apheresis samples may represent a promising pre-treatment biomarker associated with strong CAR-T expansion and superior clinical outcome in r/r LBCL patients following axi-cel. Full article

The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared dynamic cultivation using a wave bioreactor with static expansion systems (gas-permeable and conventional T-flasks) for the production of CD99-specific CAR-T cells. CAR-T cells expanded by the wave bioreactor exhibited faster proliferation and stronger cytotoxicity during culture. Upon repeated antigen stimulation, they retained these enhanced functional properties and showed the reduced expression of immune checkpoint molecules, preferentially preserved memory-like subsets, and displayed transcriptional features consistent with memory maintenance and exhaustion resistance. Targeted metabolomic profiling revealed enhanced Tricarboxylic Acid (TCA) cycle activity and features consistent with sustained oxidative phosphorylation, supporting mitochondrial-centered metabolic reprogramming. In a Ewing sarcoma xenograft model, wave bioreactor-cultured CAR-T cells showed a greater percentage of memory-like tumor-infiltrating lymphocytes. Collectively, these results indicate that wave bioreactor-based dynamic cultivation promotes mitochondrial metabolic reprogramming, which is characterized by an enhanced TCA cycle and sustained oxidative phosphorylation, thereby sustaining CAR-T cell functionality and providing a robust platform for the manufacturing of potent and durable cellular therapeutics. Full article

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation. Full article

Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor and inhibitory regulator of T-cells. Here, we analyzed the prevalence of LAG3 rs870849 in B-cell lymphoma patients and the treatment outcomes according to the LAG3 genetic background and discovered that LAG3 germline variants may affect the risk of developing lymphoma and also affect the treatment outcome of DLBCL patients in the current CD19 CAR-T cell therapies. The LAG3 rs870849 was prevalent at high frequency in DLBCL patients. Significant differences in treatment outcomes to CAR-T cell therapy emerged in LAG3 I455hom versus I455Thet and T455hom carriers. The overall and complete response rates to CAR-T cell therapy were lower in the I455hom genetic subgroup with median PFS in the I455hom of 2 versus 20 months in the T455hom and I455Thet subgroups (p = 0.025). Median OS was 6 months in the LAG3 I455hom versus 41 months in the T455hom and I455Thet subgroups (p = 0.007). LAG3 rs870849 may affect treatment outcome in CAR-T cell therapy, with favorable outcomes in T455 carriers. Specific combinations of CTLA4 and LAG3 germline variants may cooperate to affect the response to CAR-T cell therapy. Full article

Adoptive cell therapies (ACTs) have revolutionized cancer treatment by harnessing the specificity and potency of T lymphocytes. Chimeric antigen receptor (CAR)-T cells have achieved landmark successes in B-cell malignancies and multiple myeloma. Tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells offer complementary strategies to target solid tumors and intracellular antigens. Despite these advances, ACTs face challenges including cytokine release syndrome, neurotoxicity, on-target/off-tumor effects, manufacturing scalability, and immunosuppressive tumor microenvironments. Innovative strategies, such as dual-antigen targeting, localized delivery, checkpoint blockade combinations, gene-editing, and machine-learning-guided antigen discovery, are being used to mitigate toxicity, enhance efficacy, and streamline production. As CAR-T, TIL, and TCR modalities converge with advances in manufacturing and computational biology, the next generation of “living drugs” promises broader applicability across hematologic and solid tumors, improved safety profiles, and better treatment outcomes for patients. This review details the evolution of ACTs from first-generation CAR constructs to next-generation “armored” designs. It also focuses on the development and clinical deployment of TIL and TCR therapies. Furthermore, it synthesizes mechanisms, pivotal clinical trial outcomes, and ongoing challenges of ACTs. It also highlights strategies that will drive broader, safer, and more durable applications of these therapies across hematologic and solid tumors. Full article

Richter transformation (RT) affects 2–10% of chronic lymphocytic leukemia (CLL) patients, evolving into an aggressive lymphoma—most often diffuse large B-cell lymphoma—with poor prognosis, especially when clonally related to CLL. Key risk factors include unmutated IGHV, TP53 and NOTCH1 mutations, stereotyped B-cell receptors, and complex cytogenetics. This review summarizes RT biology, clinical predictors, and treatment outcomes. Traditional chemoimmunotherapy (e.g., R-CHOP) yields complete response rates around 20–30% and median overall survival of 6–12 months; intensified regimens (R-EPOCH, hyper-CVAD) offer only modest gains. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited to fit patients due to high treatment-related mortality. Emerging therapies now include Bruton’s tyrosine kinase and BCL-2 inhibitors, which achieve partial responses but short progression-free survival. CD19-directed chimeric antigen receptor T-cell therapies produce overall response rates of 60–65%, though relapses remain frequent. Bispecific antibodies (e.g., CD3×CD20 agents epcoritamab and mosunetuzumab) show promising activity and tolerable toxicity in relapsed/refractory RT. Ongoing trials are exploring combinations with checkpoint inhibitors, triplet regimens, and novel targets such as ROR1, CD47, and CDK9. Continued research into optimized induction, consolidation, and innovative immunotherapies is essential to improve outcomes in this biologically distinct, high-risk CLL-related lymphoma. Full article

Chimeric antigen receptor (CAR) T-cell therapy directed to CD19 and B-cell maturation antigen has revolutionized treatment of B-cell leukemia and lymphoma, and multiple myeloma. However, identifying suitable targets for acute myeloid leukemia (AML) remains challenging due to concurrent expression of potential target antigens on normal hematopoietic stem cells or tissues. As the stress-induced B7H6 molecule is rarely found on normal tissues but expressed on many cancers including AML and melanoma, the NKp30-ligand B7H6 emerges as a promising target for NKp30-based CAR T therapy for these tumors. In this study, we report a comprehensive B7H6 expression analysis on primary AML and melanoma as well as on different tumor cell-lines examined by RT-qPCR and flow cytometry, and efficient anti-tumor reactivity of NKp30-CAR T cells to AML and melanoma. To overcome limitations of autologous CAR T-cell fitness-dependent efficacy and patient-tailored production, we generated CRISPR/Cas9-mediated TCR-knockout (TCR^KO) NKp30-CAR T cells as an off-the-shelf approach for CAR T therapy. Functional studies comparing NKp30-CD28 CAR or NKp30-CD137 CAR TCR⁺ and TCR^KO T lymphocytes revealed superior anti-tumoral immunity of NKp30-CD28 CAR TCR^KO T cells to AML and melanoma cell lines in vitro, and effective control of tumor burden in an NSG melanoma-xenograft mouse model. In conclusion, these findings highlight the therapeutic potential of NKp30 CAR TCR^KO T cells for adoptive T-cell therapy to B7H6-expressing cancers, including melanoma and AML. Full article

Systematic Background/Objectives: Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which pancreatic β-cells are selectively destroyed, predominantly by autoreactive T lymphocytes. Despite decades of research, the achievement of durable immune tolerance remains elusive. This review presents a historically grounded and forward-looking perspective on the evolution of immunotherapy in T1DM, from early immunosuppressive interventions to advanced precision-based cellular approaches. Specifically, we focus on systemic immunosuppressants (e.g., corticosteroids, cyclosporine), monoclonal antibodies (e.g., anti-CD3, anti-IL-1, anti-TNF), regulatory cell-based approaches (e.g., Tregs, CAR-Tregs, MDSCs), and β-cell replacement strategies using stem cell-derived islets. Methods: We analyzed major clinical and translational milestones in immunotherapy for T1DM, with particular attention to the transition from broad immunosuppression to targeted modulation of immune pathways. Emerging data on cell-based therapies, artificial intelligence (AI)-driven stratification, and personalized intervention timing have been incorporated to provide a comprehensive overview of current and future directions. Results: Initial therapies such as corticosteroids and cyclosporine offered proof-of-concept for immune modulation, yet suffered from relapse and toxicity. The introduction of monoclonal antibodies (e.g., teplizumab) marked a shift toward immune-specific intervention, particularly in stage 2 preclinical T1DM. More recent approaches include low-dose IL-2, checkpoint modulation, and antigen-specific tolerance strategies. Cellular therapies such as Treg adoptive transfer, chimeric antigen receptor Tregs (CAR-Tregs), and stem cell-derived islet replacements (e.g., VX-880) have shown promise in preserving β-cell function and modulating autoimmunity. Myeloid-derived suppressor cells (MDSCs), although still preclinical, represent a complementary avenue for immune tolerance induction. Concurrently, AI-based models are emerging as tools to stratify risk and personalize immunotherapeutic timing, enhancing trial design and outcome prediction. Conclusions: In conclusion, the historical progression from broad immunosuppression to precision-driven strategies underscores the importance of stage-specific, mechanism-based interventions in T1DM. The convergence of targeted biologics, regenerative cell therapies, and β-cell replacement approaches, supported by AI-enabled patient stratification, offers a realistic path toward durable immune tolerance and functional β-cell preservation. Continued integration of these modalities, coupled with rigorous long-term evaluation, will be essential to transform these scientific advances into sustained clinical benefit. Full article

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin’s lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

Background/Objectives: The physiological activation of cytotoxic CD8^pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARG^TPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARG^TPR makes them recognizable for pre-existing anti-CMV_pp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARG^TPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARG^TPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARG^TPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy is a novel form of adoptive cellular immunotherapy that involves modifying autologous T cells to recognize and target tumor-associated antigens (TAAs) on malignant cells, independent of major histocompatibility complex (MHC) restriction. Although CAR-T therapy has shown remarkable success in treating hematologic malignancies, its efficacy in solid tumors remains limited, largely due to the lack of tumor-specific antigens and the complexity of the tumor microenvironment. This review aims to explore the rationale for continuing the development of adoptive cellular therapies in head and neck cancer (HNC), offering insights into the diagnostic and therapeutic challenges associated with this heterogeneous group of malignancies. Methods: We conducted a comprehensive literature review using the PubMed database to identify relevant studies on the application of CAR-T cell therapy in the management of HNC. Results: HNC presented numerous barriers to CAR-T cell infiltration, primarily due to the unique characteristics of its tumor microenvironment (TME). The TME in HNC is notably immunosuppressive, with a lymphocytic infiltrate predominantly composed of regulatory T cells (Tregs) and natural killer (NK) cells. These immune cells typically exhibit low expression of the CD16 receptor, which plays a crucial role in mediating antibody-dependent cellular cytotoxicity (ADCC), thereby limiting the effectiveness of CAR-T cell therapy. Conclusions: This comprehensive review suggests a potential clinical applicability of CAR-T therapy in HNC management. Full article

In B-cell chronic lymphocytic leukemia (B-CLL), hypodiploidy is a rare but aggressive subtype of the disease with a very bad prognosis. Hypodiploidy, in contrast to normal B-CLL chromosomal aberrations, is marked by widespread genomic instability, which promotes treatment resistance and quick illness development. Its persistence after treatment implies that chromosomal loss gives cancerous clones a selection edge, which is made worse by telomere malfunction and epigenetic changes. Since thorough genetic profiling has a major impact on patient outcomes, advanced diagnostic methods are crucial for early detection. Treatment approaches must advance beyond accepted practices because of its resistance to traditional medicines. Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy are two potential new therapeutic modalities. Relapse and treatment-related morbidity continue to be limiting concerns, despite the noteworthy improvements in outcomes in high-risk CLL patients receiving HSCT. Although more research is required, CAR T-cell treatment is effective in treating recurrent B-ALL and may also be used to treat B-CLL with hypodiploidy. Novel approaches are essential for enhancing patient outcomes and redefining therapeutic success when hypodiploidy challenges established treatment paradigms. Hypodiploidy is an uncommon yet aggressive form of B-CLL that has a very bad prognosis. Hypodiploidy represents significant chromosomal loss and structural imbalance, which contributes to a disordered genomic environment, in contrast to more prevalent cytogenetic changes. This instability promotes resistance to certain new drugs as well as chemoimmunotherapy and speeds up clonal evolution. Its persistence after treatment implies that hypodiploid clones have benefits in survival, which are probably strengthened by chromosomal segregation issues and damaged DNA repair pathways. Malignant progression and treatment failure are further exacerbated by telomere erosion and epigenetic dysregulation. The need for more sensitive molecular diagnostics is highlighted by the fact that standard karyotyping frequently overlooks hypodiploid clones, particularly those concealed by endoreduplication, despite the fact that these complications make early and correct diagnosis crucial. Hypodiploidy requires a move toward individualized treatment because of their link to high-risk genetic traits and resistance to conventional regimens. Although treatments like hematopoietic stem cell transplantation and CAR T-cells show promise, long-term management is still elusive. To improve long-term results and avoid early relapse, addressing this cytogenetic population necessitates combining high-resolution genomic technologies with changing therapy approaches. Full article

Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are immunomodulatory cells which can alter the function of tumor-infiltrated immune cells in both supportive and suppressive ways. Results obtained in recently conducted experimental studies demonstrate that MSCs modulate proliferation, cytotoxicity, cytokine production and anti-tumor activity in CAR-expressing immune cells in both a juxtacrine and a paracrine manner. While MSCs can enhance CAR cell viability and persistence through trophic support, they may also impair cytotoxic function and promote an immunosuppressive phenotype under certain conditions. Understanding the dualistic nature of MSCs in CAR-based immunotherapy for malignant diseases is critical for optimizing clinical outcomes. Additionally, MSCs may serve as vehicles for targeted delivery of immunomodulatory agents, and should be considered as active components in the design of next-generation CAR-based immunotherapies. Accordingly, in this review article we emphasize molecular and cellular mechanisms involved in MSC-dependent modulation of CAR-expressing immune cells, paving the way for more efficient CAR-based immunotherapy for malignant diseases. Full article

Chimeric antigen receptor (CAR)-engineered cell therapy represents a landmark advancement in cancer immunotherapy. While αβ CAR-T therapy has demonstrated remarkable success in hematological malignancies, its efficacy in solid tumors remains constrained mainly by factors such as antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To overcome these limitations, emerging CAR platforms that utilize alternative immune effectors, including natural killer (NK) cells, macrophages, and γδ T lymphocytes, are rapidly gaining traction. This review systematically analyzes the mechanistic advantages of CAR-NK, CAR-M, and CAR-γδ T cell therapies, while critically evaluating persistent challenges in clinical translation, including limited cell persistence, manufacturing scalability, and dynamic immune evasion mechanisms. We further discuss innovative strategies to enhance therapeutic efficacy through some viable strategies. By bridging fundamental immunology with translational engineering, this work provides a roadmap for developing CAR therapies capable of addressing the complexities of solid tumor eradication. Full article