Authors
Claire Victoria Ong, Sabina Kaczanowska, Harrish Ganesh, Emily San Andres Montalvan, Wei Ju, Jim Cronk, Sneha Ramakrishna, Rosandra Kaplan
Introduction
Chimeric antigen receptor T cells (CAR-Ts) are an emerging immunotherapy that have remarkable efficacy against leukemias and lymphomas but limited success against solid tumors. We conducted a phase I clinical trial (NCT 02107963) of GD2 CAR-T (GD2-CAR.OX40.28.z.ICD9) administration to children and young adults with neuroblastoma and, for the first time, osteosarcoma. While all patients progressed and were switched to alternative therapy, we observed a significant association between good CAR-T expanders and expression of C-X-C Motif Chemokine receptor 3 (CXCR3) on monocytes detected in pretreatment apheresis. This study seeks to uncover the possible interactions between CXCR3 and CAR-Ts that may alter CAR-T function and ultimately lead to better CAR-T expansion. We hypothesize that CXCR3+ monocytes induce functional change in CAR-Ts resulting in improved expansion.
Methods
To recapitulate the interaction between tumor, CAR-Ts and monocytes, we took 143Bs (osteosarcoma cell line) and GD2 CAR-Ts and co cultured them with THP-1s (a monocytic leukemia cell line) that were either untransduced (UTD) or transduced via lentivirus to express CXCR3 (CXCR3+). The ratio of UTD or CXCR3+ THP-1s to CAR-Ts and 143Bs was varied between co cultures. Enzyme-linked immunoassay (ELISA) for interferon gamma (IFNy) expression was run as a proxy measurement for CAR-T cell activity. Flow cytometry was used to assess for expression of activation and exhaustion markers. Differences between UTD and CXCR3+ co cultures were evaluated for statistical significance via unpaired t-test.
Results
We observed that CXCR3 was elevated on GD2 CAR-Ts co cultured with CXCR3+ monocytes. This pattern was seen most prominently in CD4+ CAR-Ts, but also subtly in CD8+ T-cells. Exhaustion markers CD39 and LAG3 were elevated in CAR-Ts co cultured with CXCR3+ monocytes. Additionally, CAR-Ts co cultured with CXCR3+ monocytes displayed greater activity via elevated IFNy expression.
Conclusion
We conclude that GD-2 CAR-T cells co cultured with CXCR3+ monocytes express elevated exhaustion markers due to possible increased activity when in the presence of CXCR3+ monocytes. Additionally, we suspect that elevated CXCR3 expression on CAR-Ts co cultured with CXCR3+ monocytes may be helping CAR-Ts better target tumor cells, thus leading to improved expansion. If CXCR3 can improve CAR-T cell function, this could lead to better optimization of CAR-Ts against solid tumors and create a viable treatment option for neuroblastoma and osteosarcoma patients.
References
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