Combinational CAR T-cell therapy for solid tumors: Requisites, rationales, and trials Review
| Authors: | Misawa, K.; Bhat, H.; Adusumilli, P. S.; Hou, Z. |
| Review Title: | Combinational CAR T-cell therapy for solid tumors: Requisites, rationales, and trials |
| Abstract: | Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways—most notably, the PD1/PDL1 pathway—thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers. © 2024 Elsevier Inc. |
| Keywords: | review; solid tumor; chemotherapy; biological marker; radiotherapy; antineoplastic activity; tumor antigen; cancer inhibition; immunotherapy; drug combination; chimeric antigen receptor; radiation therapy; immunosuppressive treatment; therapy; pharmacology; programmed death 1 ligand 1; checkpoint blockade; immune checkpoint inhibitor; human; t cell exhaustion; car t cells; chimeric antigen receptor t-cell immunotherapy; chimeric antigen receptor t-cell; regional delivery; combinational therapy |
| Journal Title: | Pharmacology & Therapeutics |
| Volume: | 266 |
| ISSN: | 0163-7258 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2025-02-01 |
| Start Page: | 108763 |
| Language: | English |
| DOI: | 10.1016/j.pharmthera.2024.108763 |
| PROVIDER: | scopus |
| PUBMED: | 39617146 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK authors: Hina Bhat and Prasad S. Adusumilli -- Source: Scopus |
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