Cancer Cell. 2021 Feb 8;39(2):193-208.e10. doi: 10.1016/j.ccell.2020.11.005. | PubMed

Shivani Srivastava¹, Scott N Furlan², Carla A Jaeger-Ruckstuhl³, Megha Sarvothama³, Carolina Berger³, Kimberly S Smythe³, Sarah M Garrison³, Jennifer M Specht⁴, Sylvia M Lee⁴, Robert A Amezquita⁵, Valentin Voillet⁵, Vishaka Muhunthan³, Sushma Yechan-Gunja³, Smitha P S Pillai⁶, Christoph Rader⁷, A McGarry Houghton³, Robert H Pierce³, Raphael Gottardo⁵, David G Maloney⁴, Stanley R Riddell⁴

1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: ssrivas2@fredhutch.org.
2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
5. Vaccine and Infections Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
6. Department of Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
7. Department of Immunology and Microbiology, Scripps Research Institute, Jupiter, FL, USA.

Abstract

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

Presented By Shivani Srivastava