Abstract | BACKGROUND: Effective treatment of solid tumors requires multi-modality approaches. In many patients with stage IV liver disease, current treatments are not curative. Chimeric antigen receptor T cells (CAR-T) are an intriguing option following success in hematological malignancies, but this has not been translated to solid tumors. Limitations include sub-optimal delivery and elevated interstitial fluid pressures. We developed a murine model to test the impact of high-pressure regional delivery (HPRD) on trafficking to liver metastases (LM) and tumor response. MATERIALS AND METHODS: CAR-T were generated from CD45.1 mice and adoptively transferred into LM-bearing CD45.2 mice via regional or systemic delivery (RD, SD). Trafficking, tumor growth, and toxicity were evaluated with flow cytometry, tumor bioluminescence (TB, photons/sec log2-foldover baseline), and liver function tests (LFTs). RESULTS: RD of CAR-T was more effective at controlling tumor growth versus SD from post-treatment days (PTD) 2-7 (P = 0.002). HPRD resulted in increased CAR-T penetration versus low-pressure RD (LPRD, P = 0.004), suppression of tumor proliferation (P = 0.03), and trended toward improved long-term control at PTD17 (TB=3.7 versus 6.1, P = 0.47). No LFT increase was noted utilizing HPRD versus LPRD (AST/ALT P = 0.65/0.84) while improved LFTs in RD versus SD groups suggested better tumor control (HPRD AST/ALT P = 0.04/0.04, LPRD AST/ALT P = 0.02/0.02). CONCLUSIONS: Cellular immunotherapy is an emerging option for solid tumors. Our model suggests RD and HPRD improved CAR-T penetration into solid tumors with improved short-term tumor control. Barriers associated with SD can be overcome using RD techniques to maximize therapeutic delivery and HPRD may further augment efficacy without increased toxicity.
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Authors | Louis F Chai, John C Hardaway, Kara R Heatherton, Kyle P O'Connell, Jason P LaPorte, Prajna Guha, Mikayla C Lopes, Benjamin A Rabinowitz, David Jaroch, Bryan F Cox, Robert Knight, Steven C Katz |
Journal | The Journal of surgical research
(J Surg Res)
Vol. 272
Pg. 37-50
(04 2022)
ISSN: 1095-8673 [Electronic] United States |
PMID | 34929499
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 Elsevier Inc. All rights reserved. |
Chemical References |
- Receptors, Chimeric Antigen
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Topics |
- Animals
- Colorectal Neoplasms
(therapy)
- Humans
- Immunotherapy, Adoptive
(methods)
- Liver Neoplasms
(pathology)
- Mice
- Neoplasms
(therapy)
- Receptors, Chimeric Antigen
- T-Lymphocytes
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