Mechanisms of response and resistance to CAR T cell therapies
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.
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