Mechanisms of response and resistance to CAR T cell therapies

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Highlights

Chimeric antigen receptor (CAR) T cell therapy is successful for some B cell malignancies but remains limited for a wider range of patients and cancers. Recent advances have shown that patients with more naïve and early memory-like T cells have better response rates due to increased expansion and persistence of the CAR T cells. The costimulatory domain used in the CAR is also important for their persistence and anti-tumor activity. Modifying these domains can improve CAR T cell efficacy. Tumors escape CAR T cell targeting through loss of the target antigen or other genetic characteristics and suppressive microenvironments. Using combinations treatments or further genetically modifying CAR T cells to overcome these limitations is the focus of current research.

Introduction

CAR T cell therapy typically uses a patient’s own (autologous) T cells and genetically alters them to express a CAR specific to a tumor antigen, redirecting the T cell to target the cancer cell. CD19-targeted CAR T cells were first approved by the FDA in 2017 for the treatment of adults with relapsed or refractory diffuse large B cell lymphoma (DLBCL) or children and young adults with relapsed or refractory ALL [1, 2, 3, 4, 5]. It has significantly improved the treatment of B cell malignancies, with 83–93% of patients with B cell acute lymphoblastic leukemia (ALL) achieving complete remission [6,7]. However, many of these patients relapse [2], and the response rates in other types of B cell malignancies are much lower (43–54% in DLBCL [1,5] and 21–29% in CLL [7,8]; reviewed in Ref. [9]). While CAR T cell therapy is expanding to new targets and use in solid tumors, several challenges have risen in their broad application.

For CAR T cell treatment to be effective, the CAR T cells must find and be activated by the cancer cell, effectively kill the cancer cell, expand in the patient, and persist long enough to eliminate the tumor and prevent its relapse. This review will discuss CAR T cell characteristics that predict patient response or lead to resistance. We will highlight the recent advances in improving CAR T cell therapy, including further genetic modification of the T cells, using combination treatments to boost their function, and ways to overcome the suppressive tumor microenvironment.

Section snippets

Predictive markers of response

Response to autologous CAR T cell therapy is associated with the inherent fitness of patients’ T cells before and during CAR T cell manufacturing [10]. Multiple studies have shown that in vivo expansion of CAR T cells, and subsequent B cell aplasia from on-target off-tumor activity, correlates with patient response [8,11,12]. Increased in vivo expansion has been correlated with the differentiation state of the CAR T cell product following manufacturing and ex vivo expansion. Patients with less

CAR T cell expansion

As mentioned above, CAR T cell expansion is important for clinical response in patients and increasing expansion in vivo could improve patient outcomes. The activation, expansion, and persistence of CAR T cells in patients depends on a number of T cell intrinsic factors (Figure 1). Expansion of CAR T cells correlates with IL-6-STAT3 signaling, as inhibiting these pathways decreases proliferation [11]. This is important to consider since IL-6 is often associated with toxicity and is targeted to

Resistance due to antigen escape

The effectiveness of CAR T cell therapy can also be determined by characteristics inherent to the cancer cells (Figure 3). As with other targeted therapies, tumors can resist CAR T cell treatment by eliminating the antigen that the CAR T cell is designed to target [31]. This was first identified in CD19 CAR treated patients [2,32] but has also been observed when targeting CD22 [33] and EGFRvIII [34]. To overcome antigen escape, a main focus of CAR T cell research has been to design CARs that

Resistance in the tumor microenvironment

Solid tumors present a unique challenge for CAR T cells as target antigens are more difficult to define (discussed in resistance due to antigen escape) and T cells may not traffic optimally to the tumor site [43]. Beyond a set of commonly targeted antigens (such as mesothelin, Her2, and prostate-specific membrane antigen, PSMA), development of CAR T cell therapy for solid tumors has mainly focused on overcoming the tumor microenvironment (TME, Figure 4). Solid tumors are known to have an

Conclusions

CAR T cell therapy is one of the most exciting advances for cancer therapy in recent history. With further improvements in engineering of the CAR and its ability to respond to its extracellular environment or the use of combination treatments, CAR T cell therapy will become more broadly applicable and may represent a viable treatment option for long-term control of tumor relapse. Many of the approaches we have described are aimed at improving CAR T cell function, optimizing their elimination of

Conflict of interest statement

MVM is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital and University of Pennsylvania (some licensed to Novartis). MVM holds equity in TCR2 and Century Therapeutics and has served as a consultant for multiple companies involved in cell therapies.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Figures were created with BioRender.com.

References (55)

  • T.N. Yamamoto et al.

    T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy

    J Clin Invest

    (2019)
  • S.S. Neelapu et al.

    Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma

    N Engl J Med

    (2017)
  • S.L. Maude et al.

    Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

    N Engl J Med

    (2018)
  • S.J. Schuster et al.

    Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma

    N Engl J Med

    (2019)
  • J.H. Park et al.

    Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia

    N Engl J Med

    (2018)
  • C.J. Turtle et al.

    Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib

    J Clin Oncol

    (2017)
  • D.L. Porter et al.

    Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia

    Sci Transl Med

    (2015)
  • M.J. Frigault et al.

    State of the art in CAR T cell therapy for CD19+ B cell malignancies

    J Clin Invest

    (2020)
  • M. Leick et al.

    Wishing on a CAR: understanding the scope of intrinsic T-cell deficits in patients with cancer

    Cancer Discov

    (2019)
  • J.A. Fraietta et al.

    Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia

    Nat Med

    (2018)
  • N. Singh et al.

    Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies

    Sci Transl Med

    (2016)
  • R.K. Das et al.

    Naive T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers

    Cancer Discov

    (2019)
  • W. Zheng et al.

    PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells

    Leukemia

    (2018)
  • J.A. Fraietta et al.

    Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells

    Nature

    (2018)
  • N.N. Shah et al.

    CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial

    J Clin Oncol

    (2020)
  • K. Reinhard et al.

    An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors

    Science

    (2020)
  • Y. Akahori et al.

    Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination

    Blood

    (2018)
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