CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success

Abstract

Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of the clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer.

Keywords: CAR T cell; adoptive cell therapy; cancer; immunotherapy; microenvironment; non-hematopoietic malignancy; solid tumor.

Figure 1

Numerous immunosuppressive barriers present in the solid tumor microenvironment that can hamper the efficacy of CAR T cell therapy are schematically depicted. Several intrinsic qualities of CAR T cells that may impact the anti-tumor potency of these lymphocytes are also listed.

Figure 2

Strategies to improve the safety (e.g., tumor-sensing strategies) as well as to augment the anti-tumor efficacy of CAR T cells are shown. Genetic engineering can be accomplished using viral (e.g., lentiviruses, retroviruses) and non-viral (e.g., CRISPR/Cas9) approaches to endow CAR T cells with gain-of-function or loss-of-function alterations. The overall aim of these approaches is to improve intrinsic T cell fitness and allow these cells to elicit optimal effector activity in the setting of several extrinsic barriers operative within solid tumors, as shown in Figure 1.