Mechanisms of resistance to CAR T cell therapy

Shah, Nirali N.; Fry, Terry J.

doi:10.1038/s41571-019-0184-6

Cited by 522 publications

(527 citation statements)

References 155 publications

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“…The emergence of immune checkpoint inhibitors and CAR T-cell technology has revolutionised the treatment of malignancy. 107 Therefore, an off-the-shelf cellular immunotherapy is an attractive proposition. metastatic melanoma and MSI-high colon cancer).…”

Section: Applications Of CD T Cells In Immunotherapymentioning

confidence: 99%

γδ T cells in cancer: a small population of lymphocytes with big implications

et al. 2019

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γδ T cells are a small population of mostly tissue‐resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the development of new cellular therapy targeted against tumor development. Nevertheless, γδ T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, γδ T‐cell subsets preferentially produce IL‐17 or IFN‐γ. While antitumor functions of murine γδ T cells can be attributed to IFN‐γ+ γδ T cells, recent studies have implicated IL‐17+ γδ T cells in tumor growth and metastasis. However, in humans, IL‐17‐producing γδ T cells are rare and most studies have attributed a protective role to γδ T cells against cancer. In this review, we will present the current knowledge and most recent findings on γδ T‐cell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.

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Section: Applications Of CD T Cells In Immunotherapymentioning

confidence: 99%

γδ T cells in cancer: a small population of lymphocytes with big implications

et al. 2019

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“…To be able to have the potential of benefit from CAR T cells, one must be able to have access to the FDA‐approved construct or be able to access and be eligible for clinical trial enrollment, successfully undergo apheresis and have a product manufactured, not have significant delays in infusion or disease progression while awaiting CAR T cells, and have adequate CAR T cells to expansion to induce tumor cytotoxicity. While many of these elements are beyond the scope of this discussion, these items have been recently reviewed by Shah et al It should be noted that due to the tremendous outcomes in CD19 CAR T‐cell approaches, understanding all of the elements which are determinants of success remain a critical component to successful outcomes. Thus, bringing together the relevant teams who contribute to those outcomes and fostering dialogue about various elements of care is essential.…”

Section: Challengesmentioning

confidence: 99%

Updates on CAR T‐cell therapy in B‐cell malignancies

Jacoby

Shahani

Shah

2019

Immunological Reviews

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By increasing disease‐free survival and offering the potential for long‐term cure, chimeric antigen receptor (CAR) T‐cell therapy has dramatically expanded therapeutic options among those with high‐risk B‐cell malignancies. As CAR T‐cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T‐cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. Compounding these challenges are the limited ability to determine differences between various CAR T‐cell constructs, understanding the generalizability of trial outcomes from multiple sites utilizing unique CAR manufacturing strategies, and comparing distinct criteria for toxicity grading while defining optimal management. Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B‐cell malignancies as the paradigm for effective CAR T‐cell therapy, this review describes advances in the field as well as current challenges and future directions.

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“…Such relapses occur due to modulation of the target antigen by the malignant cells, allowing for escape from CAR T cell detection and activity. Complete loss of the target antigen (or epitope) is the most commonly described means by which malignant cells escape CAR T cell pressure, however, decreased antigen expression has also been observed in post‐CAR T cell relapses . Data from clinical trials have demonstrated that malignant cells can escape CAR T cell pressure through the downregulation of antigen below the threshold required to elicit T cell activation.…”

Section: Antigen Low Escape and Car T Cell Activationmentioning

confidence: 99%

“…As the clinical experience with CAR T cells has matured, it has become apparent that a significant number of patients who initially achieve remission will experience a relapse of their primary cancer after CAR T cell therapy. This has been most evident in the treatment of ALL where despite the induction of remission in ~ 90% of patients, only ~ 50% of patients remained leukemia‐free 1 year after receiving CAR T cells across multiple trials . Relapses post‐CAR T cell therapy have been observed following three main patterns.…”

Section: Introductionmentioning

confidence: 99%

“…This has been most evident in the treatment of ALL where despite the induction of remission in ~ 90% of patients, only ~ 50% of patients remained leukemia-free 1 year after receiving CAR T cells across multiple trials. [29][30][31][32] Relapses post-CAR T cell therapy have been observed following three main patterns. The first pattern involves the recurrence of malignant cells which retain expression of the targeted antigen at pretreatment levels accompanied by an early loss of CAR T cells.…”

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confidence: 99%

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Immunobiology of chimeric antigen receptor T cells and novel designs

Walsh

Yang

Kohler

2019

Immunological Reviews

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Advances in the development of immunotherapies have offered exciting new options for the treatment of malignant diseases that are refractory to conventional cytotoxic chemotherapies. The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated dramatic results in clinical trials and highlights the promise of novel immune‐based approaches to the treatment of cancer. As experience with CAR T cells has expanded with longer follow‐up and to a broader range of diseases, new obstacles have been identified which limit the potential lifelong benefits of CAR T cell therapy. These obstacles highlight not only the gaps in knowledge of the optimal clinical application of this “living drug”, but also gaps in our understanding of the fundamental biology of CAR T cells themselves. In this review, we discuss the obstacles facing CAR T cell therapy, how these relate to our current understanding of CAR T cell biology and approaches to enhance the clinical efficacy of this therapy.

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Mechanisms of resistance to CAR T cell therapy

Cited by 522 publications

References 155 publications

γδ T cells in cancer: a small population of lymphocytes with big implications

γδ T cells in cancer: a small population of lymphocytes with big implications

Updates on CAR T‐cell therapy in B‐cell malignancies

Immunobiology of chimeric antigen receptor T cells and novel designs

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