Manipulating the tumor microenvironment by adoptive cell transfer of CAR T-cells

Abstract

T-cells expressing synthetic chimeric antigen receptors (CARs) have revolutionized immuno-oncology and highlighted the use of adoptive cell transfer, for the treatment of cancer. The phenomenal clinical success obtained in the treatment of hematological malignancies with CAR T-cells has not been reproduced in the treatment of solid tumors, mainly due to the suppressive and hostile tumor microenvironment (TME). This review will address the immunosuppressive features of the TME, which include the stroma, cytokine and chemokine milieu, suppressive regulatory cells and hypoxic conditions, which can all pose formidable barriers for the effective anti-tumor function of CAR T-cells. Some of the novel next generation CARs that have been developed and tested against the TME, will be discussed, to highlight the status of current research in CAR T-cell therapy for solid tumors.

CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead

“…Reduce tumor cells to immune response without immune response or low response to immune escape 4 Journal of Immunology Research…”

“…(1) Tumorinfiltrating lymphocytes (TILs) are lymphocytes that infiltrate the tumor cell stroma, and after IL-2 activation, they have a stronger antitumor effect. While melanoma patients showed a remarkable clinical response by TILs, TIL treatment was not as effective in other tumors, such as renal cell carcinoma [4,5]. (2) T cell receptor-(TCR-) T cells are heterodimeric proteins composed of two structural domains: TCRα and TCRβ.…”

“…TCR-T cells can target most tumor-specific antigens, particularly those that can rec-ognize the tumor cell antigen. Thus, TCR-T cells can recognize a broader range of antigens than the tumor antibody drugs [4,8]. (3) Chimeric antigen receptor-(CAR-) T cells are composed of extracellular, transmembrane, and intracellular domains.…”

Finding the Keys to the CAR: Identifying Novel Target Antigens for T Cell Redirection Immunotherapies

“…Antigen escape remains a major challenge to effective cell based therapies, and approaches such as dual antigen targeting have shown promising early results [21]. Systematic target antigen selection may be critical to overcoming the challenges associated with antigen escape, and treatment of solid tumours [22].…”

CARs of the future

“…Kagoya et al developed a construct that integrated downstream components of IL2‐signaling into a second‐generation CAR T cells, and demonstrated that these CAR T cells had superior in vivo potency and persistence as compared to their second‐generation counterparts Avoidance of inhibition: The tumor microenvironment is hostile and can counteract CAR T‐cell function . Synthetic approaches employed to overcome this rely on the reversing or nullifying these inhibitory signals.…”