CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

Abstract

Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. The use of dual CAR designs that recognize multiple antigens at once and local administration of CAR T cells are both strategies that have been used to overcome the hurdle of localization to the tumor. Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and “armored” CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…Homing to effected tissues requires the expression of a range of chemokine receptors and adhesion molecules, which are not normally expressed by peripheral blood T cells. 106 Successful elimination of tumors is dependent on the persistence of transferred T cells, which can become exhausted. Conversely, some patients suffer detrimental side effects, such as autoimmune colitis and cytokine release syndrome.…”

Acoustogenetic Control of CAR T Cells via Focused Ultrasound

“…We chose local injection at the tumor site to deliver T cells in vivo . Local administration of CAR T cells has been tested in animals and patients to overcome the obstacle of T cell homing associated with intravenous delivery, and has achieved promising therapeutic effects ( 16, 25, 26 ). For example, since the prostate is positioned near critical organ structures including urethra and neurovascular bundles, surgery or radiation therapy targeting the whole prostate gland to treat the prevalent locally-progressed prostate cancer ( 27 ) may cause adverse effects that would significantly impact quality of life ( 28, 29 ).…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Additional problems include T cell homing to the site of the disease, penetration of T cells into solid masses, overcoming immunosuppressive tumour microenvironment (TME) and limited CAR T cell persistence after infusion [23]. Multiple strategies for improving CAR T cell therapy efficacy against solid tumours have been extensively reviewed recently and are summarised in Table 1 [22][23][24][25][26].…”

“…Efficient T cell-based therapy targets specific antigens without side effects. A long list of tumour-associated antigens (TAAs) has been published recently [25]; however, most of them are also expressed at a low level on normal cells. Thus far, clinical trials with CAR T cells in solid tumours have struggled with severe toxicities as the targeted antigens were not specific to cancer cells [35,[59][60][61].…”