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Special Issue "Chimeric Antigen Receptor (CAR) T Cell Therapy"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2017).

Special Issue Editor

Special Issue Information

Dear Colleagues,

Cancer immunotherapy has generated tremendous excitement due to striking clinical outcomes seen in patients with chemotherapy-refractory cancers, such as lung cancer and acute leukemias. The two main cancer immunotherapies responsible for these successes are checkpoint blockade inhibitors and adoptive cell therapy with gene-engineered T cells. Both of these immunotherapies involve directing a patients T cells to their malignancy. This Special Issue will focus on adoptive T cell therapies and the chimeric antigen receptor (CAR), which genetically retargets the T cell to the patient’s cancer. The CAR includes an antigen-binding domain, derived from an antibody, hinge and transmembrane domains, and activation and costimulation domains derived from the T cell receptor. Over the past three decades, from the first description of the CAR, various groups have led the way with pre-clinical studies describing the biology of CAR T cells, as well as developing and validating their use for various malignancies. In the last several years, the efforts from these groups efforts have finally come to fruition with early and mid-stage clinical trials demonstrating outstanding clinical outcomes for pediatric and adult patients, with a heretofore fatal chemotherapy refractory disease, B-ALL. The results have been so disruptive to standard cancer therapies the first regulatory-approval for a gene-modified cell therapy for cancer is likely on the horizon. However, the clinical evaluation of this new therapy has also revealed a new set of immune-related toxicities that require careful management. In this Special Issue, we have compiled a set of articles to review pre-clinical CAR design and optimization, clinical application, CAR T cell toxicities, GMP CAR T cell production and QC/QA, as well as future pre-clinical and clinical directions.

Dr. William Chi-shing Cho
Guest Editor

Manuscript Submission Information

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Keywords

  • adoptive T cell therapy
  • chimeric antigen receptors
  • cancer immunology
  • gene therapy
  • leukemia
  • lymphoma

Published Papers (5 papers)

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Research

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Open AccessCommunication
Nanobody Based Dual Specific CARs
Int. J. Mol. Sci. 2018, 19(2), 403; https://doi.org/10.3390/ijms19020403 - 30 Jan 2018
Cited by 15
Abstract
Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due [...] Read more.
Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity. Full article
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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Open AccessArticle
BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy
Int. J. Mol. Sci. 2018, 19(1), 289; https://doi.org/10.3390/ijms19010289 - 18 Jan 2018
Cited by 2
Abstract
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential [...] Read more.
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8+ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi. Full article
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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Open AccessArticle
Lym-1 Chimeric Antigen Receptor T Cells Exhibit Potent Anti-Tumor Effects against B-Cell Lymphoma
Int. J. Mol. Sci. 2017, 18(12), 2773; https://doi.org/10.3390/ijms18122773 - 20 Dec 2017
Abstract
T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens [...] Read more.
T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR) on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG) mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP) in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies. Full article
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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Open AccessCommunication
Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia
Int. J. Mol. Sci. 2017, 18(11), 2259; https://doi.org/10.3390/ijms18112259 - 27 Oct 2017
Cited by 12
Abstract
The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric [...] Read more.
The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity. Full article
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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Review

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Open AccessReview
Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T
Int. J. Mol. Sci. 2018, 19(2), 340; https://doi.org/10.3390/ijms19020340 - 24 Jan 2018
Cited by 35
Abstract
Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being [...] Read more.
Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade. Full article
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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