Antigen Receptor T Cells (CAR-T) Effectively Control Tumor Growth in a Colorectal Liver Metastasis Model

• Published in: The Journal of surgical research 2022-04, Vol.272, p.37-50
• Main Authors: Chai, Louis F., Hardaway, John C., Heatherton, Kara R., O'Connell, Kyle P., LaPorte, Jason P., Guha, Prajna, Lopes, Mikayla C., Rabinowitz, Benjamin A., Jaroch, David, Cox, Bryan F., Knight, Robert, Katz, Steven C.
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Chimeric antigen receptor; Colorectal Neoplasms - therapy; Drug delivery systems; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Liver neoplasm; Liver Neoplasms - pathology; Mice; Neoplasms - therapy; Receptors, Chimeric Antigen; Solid tumor; T-Lymphocytes
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2021.11.001

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. 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). 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). 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.