Introduction: Immune checkpoint inhibitors (ICI) have shown conflicting outcomes in the adjuvant setting for high-risk clear cell renal cell carcinoma (ccRCC) patients. There is an unmet need to identify patients who would benefit from ICI treatment and to develop new therapies for those who progress on current anti PD1/PD-L1 treatments. Our group has recently created a novel monoclonal antibody (H1A) that induces PD-L1 destabilization at the cell surface resulting in its degradation. In this study, we evaluated the T-cell killing rate in response to current FDA approved treatments as well as H1A. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from 13 subjects 3 months after nephrectomy for ccRCC. For treatment with ICI, antibodies were added at the time of activation with soluble anti-CD3 and at 20 µg/ml concentration. Human 786-O ccRCC cells was used as target cells and killing rates were measured by calcein release assay. Paired ANOVA test was used to compare efficacy of ICI. Results: The median increase in T-cell killing rate for pembrolizumab, nivolumab and atezolizumab were 37.8% (range 17.4%-57.7%), 36.6% (range 6 22.7%-65.4%) and 29.9% (range 10%-52.5%), respectively. Individual response to immune checkpoint inhibitors was heterogeneous with some patients showing stronger response with nivolumab (n=9) while others had better killing activity with pembrolizumab (n=3) and one patient with no difference between different treatments. No best response was observed with atezolizumab across all patients. Median killing rate for H1A was 41.7% (range 25%-71.2%). Overall, median killing rate was significantly higher with H1A compared to the pembrolizumab (p=0.0003) and nivolumab (p=0.003) (Figure 1). In terms of individual response, all H1A-treated patients showed improved tumor cell killing efficiency compared to other treatment groups. Conclusions: In this proof-of-concept, we showed differential T-cell cytotoxic activity in response to various FDA-approved ICI. Additionally, we demonstrated the therapeutic value of a newly developed PD-L1 monoclonal antibody that induces stronger cytotoxic tumor cell killing from ccRCC patient-derived CD8 T cells compared to other ICI. SOURCE OF Funding: This work was supported by NIH R01CA256927 (HD) and R01AI095239 (HD).
