Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity Journal Article
| Authors: | Vogt, K. C.; Silberman, P. C.; Lin, Q.; Han, J. E.; Laflin, A.; Gellineau, H. A.; Heller, D. A.; Scheinberg, D. A. |
| Article Title: | Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity |
| Abstract: | A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2+ normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets. Copyright © 2025 The Authors. |
| Keywords: | genetics; neurotoxicity; neoplasm; neoplasms; t lymphocyte; tumor associated leukocyte; lymphocytes, tumor-infiltrating; t-lymphocytes; mouse; animal; metabolism; animals; mice; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; tumor antigen; immunology; antigens; antigens, neoplasm; receptors, antigen, t-cell; tumor cell line; chimeric antigen receptor; cell therapy; mammals; cell adhesion; normal tissue; therapy; adoptive immunotherapy; immunotherapy, adoptive; lymphocyte antigen receptor; solid tumors; t-cells; receptor expression; tumor microenvironment; brain tissue; antigen receptors; procedures; microenvironments; humans; human; mouse brain; receptors, chimeric antigen; macroinvertebrates |
| Journal Title: | Science Advances |
| Volume: | 11 |
| Issue: | 4 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2025-01-22 |
| Start Page: | eads3403 |
| Language: | English |
| DOI: | 10.1126/sciadv.ads3403 |
| PUBMED: | 39841845 |
| PROVIDER: | scopus |
| PMCID: | PMC11753401 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record. Corresponding MSK author is David A. Scheinberg -- Source: Scopus |
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