Induction of peripheral effector CD8 T cell proliferation by combination of paclitaxel, carboplatin and bevacizumab in non-small cell lung cancer patients

Introduction: Chemotherapy has long been the standard treatment for advanced stage non-small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on immune populations associated with response to checkpoint inhibitors in peripheral blood. Methods: 223 stage IV NSCLC patients, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle. Proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and co-inhibitory receptors on these subsets were determined. Results: Whereas proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RA⁺ effector subsets. The proliferating CD8 T cells more highly expressed PD-1 and CTLA-4 compared to non-proliferating CD8 T cells. Immunological responders (>2 fold increased proliferation after treatment) did not show an improved progression free or overall survival. Conclusions: Paclitaxel/ carboplatin/ bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing co-inhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.

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