Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 6, Issue 261, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3010162
Keywords
-
Categories
Funding
- American Association for Thoracic Surgery Third Edward D. Churchill Research Scholarship
- William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center
- NCI [R21 CA164568-01A1, R21 CA164585-01A1, R01 CA136705-06, 2T32CA9501-26A1]
- U.S. Department of Defense [PR101053, LC110202]
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- Lake Road Foundation
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant [SU2C-AACR-DT1012]
Ask authors/readers for more resources
Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through regional distribution centers. On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available