Dataset Information

Adoptive T-Cell Therapy for Solid Tumors.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T-cell therapy for each tumor and propose strategies to overcome some of these limitations.

SUBMITTER: Yeku O

PROVIDER: S-EPMC5549627 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Adoptive T-Cell Therapy for Solid Tumors.

Yeku Oladapo O Li Xinghuo X Brentjens Renier J RJ

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 20170101

Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. H ...[more]

PMID: 28561728

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Project description:Tumor-reactive CD8 T cells found in cancer patients are frequently dysfunctional, unable to halt tumor growth. Adoptive T cell transfer (ACT), the administration of large numbers of in vitro-generated cytolytic tumor-reactive CD8 T cells, is an important cancer immune therapy being pursued. However, a limitation of ACT is that transferred CD8 T cells often rapidly lose effector function, and despite exciting results in certain malignancies, few ACT clinical trials have shown responses in solid tumors. Here, we developed preclinical cancer mouse models to investigate if and how tumor-specific CD4 T cells can be enlisted to overcome CD8 T cell dysfunction in the setting of ACT. In situ confocal microscopy of color-coded cancer cells, tumor-specific CD8 and CD4 T cells, and antigen presenting cells (APC), combined with functional studies, revealed that the spatial positioning and interactions of CD8 and CD4 T cells, but not their numbers, dictates ACT efficacy and anti-tumor responses. We uncover a new role of antigen-specific CD4 T cells in addition to the known requirement for CD4 T cells during priming/activation of naïve CD8 T cells. CD4 T cells must co-engage with CD8 T cells and APC cross-presenting CD8- and CD4-tumor antigens during the effector phase, forming a three-cell-cluster (triad), to license CD8 T cell cytotoxicity and mediate cancer cell elimination. Triad formation transcriptionally and epigenetically reprogram CD8 T cells, prevent T cell dysfunction/exhaustion, and ultimately lead to the elimination of large established tumors and confer long-term protection from recurrence. When intratumoral triad formation was disrupted, adoptively transferred CD8 T cells could not be reprogrammed, and tumors progressed despite equal numbers of tumor-infiltrating CD8 and CD4 T cells. Strikingly, the formation of CD4 T cell::CD8 T cell::APC triads in tumors of patients with lung cancers treated with immune checkpoint blockade was associated with clinical responses, but not CD4::APC dyads or overall numbers of CD8 or CD4 T cells, demonstrating the importance of triads in non-ACT settings in humans. Our work uncovers intratumoral triads as a key requirement for anti-tumor immunity and a new role for CD4 T cells in CD8 T cell cytotoxicity and cancer cell eradication.

Dataset Information

Adoptive T-Cell Therapy for Solid Tumors.

Publications

Adoptive T-Cell Therapy for Solid Tumors.

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