Following successful clinical studies, the FDA and regulatory authorities around the world have approved the use of axicabtagene ciloleucel (Yescarta™) for patients with large-B-cell lymphomas and tisagenlecleucel (Kymriah™) for adults with certain types of non-Hodgkin lymphoma. Despite its success as a novel way of treating cancer, physician scientists are realizing that 30%-50% of patients who achieve remission with anti-CD19 CAR-T therapy will relapse, and 10%-20% of patients will fail to achieve remission after therapy treatment. As antigen-directed CAR-T therapy is more widely used, understanding its limitations will be critical to overcoming its challenges and realizing its full potential. A recently-published review article entitled Mechanisms of resistance to CAR T cell therapy discusses this rapidly evolving field, focusing on four major barriers to maximal T cell-mediated remission:
Fig 1. Barriers to durable remission following CAR-T therapy. This figure summarizes several limitations to achieving durable remission with CAR-T cell therapy (Nirali N. Shah and Terry J. Fry 2019).
For some patients, autologous CAR-T cells cannot be successfully manufactured, or CAR-T cells generated do not expand sufficiently (either during manufacturing in vitro or after administration in vivo). The lack of persistence in vivo is a potential underlying mechanism of disease relapse. Many factors such as T cell numbers, purity of affected T cells, patient heterogeneity, and CAR construct design are all critical to successful manufacturing and subsequent in vivo efficacy. Modified CAR-T cell products derived from healthy donor cells represent an alternative way to resolve issues of poor CAR-T cell quality. These allogeneic modified CAR-T cells exhibit not only consistency of purity but also prevent “fratricide” T cell killing. These allogeneic therapies are progressing rapidly through the clinical pipeline.
Up to 50% of patients will relapse with pre-B Acute lymphoblastic leukemia (ALL) 12 months after CAR-T therapy infusion. These relapses occur in two in two instances: early antigen positive leukemia or antigen escape/modulation leukemia. Antigen-related problems —the loss or downregulation of CD19 and/or CD22 on malignant B cells — enables antigen escape as a mechanism of resistance to CAR T cell therapy. Currently, multiple antigen-targeting therapies are undergoing clinical trials. Understanding the mechanisms driving relapse will help researchers and physicians to design and generate consolidative therapies. Furthermore, monitoring antigen densities in tumors will help physicians to predict the best time to intervene with other therapies.
CAR-T cell therapy has many side effects, some of which can be fatal. One of the most severe is cytokine release syndrome (CRS). Efforts have yet to yield established intervention procedures that alleviate this symptom without compromising the therapeutic effect associated with T- cell activation and expansion. Current approaches include treatment of mild CRS with steroids and severe CRS with Tocilizumab (anti-IL-6 receptor antibody). Further studies are needed in order to maximize CAR-T cell persistence while eliminating the most dangerous negative side effects associated with CAR-T therapy, such as CRS.
CAR-T therapy has had tremendous success with B cell malignancies because CD19 is ubiquitously expressed in malignant B cells. While early successes have been in hematological tumors, the solid tumor has become a new challenge for scientists. Solid tumors are inherently heterogeneous, making them difficult to target. It is likely that antigen escape is the primary reason why CAR-T therapy has been less effective in solid tumors. Targeting antigens such as disialoganglioside GD2 has proven effective in neuroblastoma patients, leading to complete remission in some patients. However, not all patients respond positively due to the tumor’s immunosuppressive microenvironment. Combinational therapies with immune checkpoint inhibitors help boost CAR-T therapy potency to combat cancer in this tumor microenvironment. One novel approach aimed at counteracting the immunosuppressive environment is to administer armored CAR-T cells that secrete pro-inflammatory cytokines.
Cancer is a moving target. We need to continue developing treatments that address the most obstinate barriers to full remission. This review article articulates the main barriers to T-cell-mediated remission, and identifies strategies under development which address them head on. To read more, find the full article here.
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