Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

Abstract

Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.

Inflammatory abrasion of hematopoietic stem cells: a candidate clue for the post-CAR-T hematotoxicity?

“…The incidence of CAR-T hematotoxicity reported by different clinical trials has been thoroughly reviewed recently ( 6 , 10 ). Briefly, the overall incidence of severe (grade ≥ 3) neutropenia, thrombocytopenia, and anemia ranges from 29% to 95%, from 15% to 65%, and from 14% to 77%, respectively ( 6 , 10 ). However, a fewer number of studies distinguished late-phase from early-phase cytopenia.…”

“…Several reviews have discussed the possible mechanisms of CAR-T hematotoxicity ( 6 , 10 ). Maintaining HSC homeostasis, the interaction between bone marrow niches, regulation by inflammatory cytokines, disorders of cellular immunity, and others could all play a part in the complex mechanisms ( 6 , 10 ).…”

“…Several reviews have discussed the possible mechanisms of CAR-T hematotoxicity ( 6 , 10 ). Maintaining HSC homeostasis, the interaction between bone marrow niches, regulation by inflammatory cytokines, disorders of cellular immunity, and others could all play a part in the complex mechanisms ( 6 , 10 ). However, no clinical disorders referred to by these detailed reviews ( 6 , 10 ), such as acquired aplastic anemia (AA) and myelodysplastic syndromes (MDS), could fully concur with the characteristics of CAR-T late hematotoxicity.…”

“…In patients with R/R non-Hodgkin lymphoma (NHL), the long-term follow-up of Axicabtagene ciloleucel, an anti-CD19 CAR-T therapy, reported a median overall survival (OS) of 25.8 months [95% confidence interval (CI), 12.8–NE] ( 4 ), while the median OS was only 6.3 months (95% CI, 5.9–7.0) in R/R NHL patients ( n = 636) treated with chemotherapies or autologous stem cell transplantation ( 5 ). The application of CAR-T has also extended to solid carcinomas, presenting a challenging and promising prospect ( 6 ). However, specific adverse events emerge simultaneously, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B-cell aplasia, hypogammaglobulinemia, and hematotoxicity (i.e., cytopenia) ( 7 , 8 ).…”

Editorial: Complexity of tumor microenvironment: A major culprit in cancer development, volume II

“…cell-based immunotherapy has completely resketched the treatment landscape of the cancer management (28)(29)(30). Genetically modified immune cells such as CAR-T cells have produced incredible responses in some solid tumors (31)(32)(33). These immune cells have enhanced functional ability and protection from negative signals from immune checkpoints and the hostile tumor microenvironment (34).…”