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.

Facing the future: challenges and opportunities in adoptive T cell therapy in cancer

“…CAR T cell therapies for the treatment of solid tumors are now being developed, targeting for instance GD2 (neuroblastoma), and mesothelin (pancreatic, cervical, breast, ovarian cancer). However, the immunosuppressive environment in solid tumors represents a formidable challenge for T cells and to date CAR T cell treatments in solid tumors have been less successful than in hematopoietic malignancies [42].…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…The intracellular signaling domain stimulates T cell activation and proliferation to kill target cells [219]. CAR-T cell therapies are successful in the treatment of several hematopoietic malignancies [220,221] but not in the treatment of solid tumors [222]; the immunosuppressive TME is a major obstacle to the role of CAR-T cells [223]. Given the many types of immunesuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the TME [224], and the lack of chemokines to attract tumor-specific T cells, the therapeutic efficacy of CAR-T cell therapy in solid tumors is limited [222].…”

Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

“…CAR T cells containing the CD28 costimulatory domain have increased glycolysis, while 4-1BB CAR T cells upregulate fatty acid oxidation pathways [23]. Hence, 4-1BB CAR T cells have a metabolic program more suited to surviving in the tumour microenvironment [24]. In addition, the significantly higher levels of inflammatory cytokines secreted by CAR(2448)L-28z compared to CAR(2448)L-BBz is of physiological concern, considering the effects of cytokine release in other CAR constructs [25].…”