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Alex S. Woodell
In my previous article, we weathered the cytokine storm, a deadly immune response that can occur following chimeric antigen receptor T cell (CAR-T) therapy. Despite this risk, CAR-T therapy is quite effective in treating blood cancers such as acute lymphoblastic leukemia (ALL). Unfortunately, not all patients respond favorably to this immunotherapy. In this final installment, we will discuss perhaps the most significant limitation of CAR-T therapy: relapse. Relapse refers to the recurrence of cancer following a period of remission and occurs in up to 50% of pre-B cell ALL after T cell infusion. Relapse can occur early or late in the treatment cycle, and the reasons for treatment failure are different in both cases. Before diving into the details, let’s take a moment to review the mechanism of CAR-T activation.
CAR-Ts differ from regular T cells in their ability to recognize surface antigens on tumor cells without the requirement of major histocompatibility complex presentation. The binding of CARs to surface antigens triggers initial activation of T cells. However, both helper T cells and cytotoxic T cells require secondary signals to become fully activated and elicit a sustained immune response against tumor cells. One of the major secondary signals in helper T cells is provided via a protein called CD28, which interacts with different tumor antigens to promote proliferation. Alternatively, cytotoxic T cells require co-stimulation of other molecules such as CD137 to enhance survival and tumor-killing activity. In the absence of these secondary signals, T cells deactivate and lose their ability to combat tumors.
It comes as no surprise that T cell activation (or lack thereof) is a major determinant for the efficacy of CAR-T therapy. Now, let’s examine what happens during relapse both early and late in the treatment cycle and discuss ways to circumvent these issues.
Early ALL relapse is often associated with poor T cell persistence. By persistence, we mean the ability of a cell to survive and continue functioning. There are a number of factors that influence persistence, including donor T cell quality and the proportion of cytotoxic versus helper T cells within a sample. Recently, it’s been shown that the co-stimulatory domain engineered into CAR constructs also affects persistence. As an example, let’s take a look at clinical trial data for Kymriah, an anti-CD19 immunotherapy which utilizes CD137 as its secondary signaling domain. These CD137-based CAR-T cells persisted in the blood for a median duration of 168 days. By contrast, an anti-CD19 immunotherapy which utilizes CD28 as its secondary signaling domain only persisted for 30 days. Although the exact reason for this difference is not yet fully understood, we know that CD137 co-stimulation reduces T cell exhaustion caused by continuous stimulation of CARs. Future efforts to improve CAR-T persistence may involve engineering CARs with multiple secondary signaling proteins in an effort to prolong persistence.
In contrast to early ALL relapse, late relapse is often associated with tumor antigen loss or modulation. CAR-Ts recognize tumor cells based on the presence of surface antigens. Therefore, when the number of these antigens is reduced, CAR-Ts become blind and are unable to see the tumor. What causes these antigens to decrease? Experts believe that alternative splicing, a step involved in gene expression, can slightly alter the final antigen product such that CAR-Ts are unable to recognize them. Another possibility is that the transport of antigens from inside the tumor cell to the cell surface is disrupted. Regardless of how these antigens are reduced, it seems that complete antigen loss is unnecessary for relapse to occur. Even a small reduction in the number of surface antigens may be sufficient to cause CAR-T resistance, a phenomenon that has already been observed in anti-CD22 CAR-T therapy. Thus, it seems that a minimal antigen threshold is required for preserved CAR-T activity. Quantifying these antigen thresholds and identifying ways to enhance antigen expression in the tumor are paramount to overcoming this relapse-inducing obstacle.
CAR-T therapy is one of the most powerful anticancer treatments ever discovered, yet there are still many challenges that need to be resolved. These obstacles include T cell exhaustion caused by excessive tumor antigen stimulation, induction of cytokine storms following treatment, and cancer relapse mediated by poor T cell persistence and tumor antigen loss. Through careful design of CAR constructs, we can make this therapy more broadly effective for cancers beyond ALL and potentially curative for patients in need.
Edited by: Swetha Srinivasan
Shah, Nirali N., and Terry J. Fry. “Mechanisms of Resistance to CAR T Cell Therapy.” Nature Reviews Clinical Oncology, vol. 16, no. 6, 2019, pp. 372–385., doi:10.1038/s41571-019-0184-6.