Abstract 3212: Patient-level pharmacodynamics of response to combined ipilimumab and nivolumab for gastric cancer using a human autologous ex-vivo platform, CANscript

Background: Combined cancer immunotherapy is an emerging paradigm for the treatment of cancer. PD-L1, the cognate receptor for the programmed death receptor 1 (PD-1) is expressed in up to 40% of gastric/gastroesophageal junction (GEJ) tumors. Despite this, patients show modest responses to PD-1 inhibitors. A recent clinical trial, Checkmate-032, demonstrated superior efficacy when PD-1 inhibitor, Nivolumab, was combined with CTLA-4 inhibitor, Ipilimumab. Despite this, biomarkers that predict clinical response remain poorly understood. Methods: Here, with informed consent under IRB, fresh tumor biopsies were obtained from a randomly-selected cohort of gastric/GEJ patients (N=39). We then employed CANscript TM , a clinically-validated human autologous ex-vivo tumor platform to interrogate the pharmacodynamics and prognostic efficacy (M-Score) of nivolumab +/- ipilimumab. PDL-1 status was determined for every patient by immunohistochemistry, flow cytometry was performed to analyze intratumor CD4+ and CD8+ T-cell profiles before and after treatment, and RNA seq. gene expression was performed to understand mechanistic changes under drug pressure. Results: We predicted, based on M-Score, that single agent nivolumab results in an overall response rate (ORR) of 10%, which closely matched previous single agent results from Checkmate-032 (10%). In contrast, we determined the combination of ipi+nivo resulted in a response rate of 20%, a finding consistent with reported clinical data (Checkmate-032; ORR 18%). Interestingly, we determined that only 28% of patients who responded to the ipi+nivo combination were predicted to respond to the monotherapy, suggesting the increased efficacy of the combination. RNA seq revealed unique features of adaptive immunity in the subset of patients who were predicted to respond to the combination immunotherapy, while PD-L1 status was a less-important biomarker to predict response. Conclusions: These results demonstrate the utility of the CANscript system to profile clinical response of immunotherapy. Our efforts may better inform clinical trial design and patient stratification before therapy to improve the potential for response. Citation Format: Vidushi Kapoor, Munisha Smalley, Nandini Pal Basak, Abhishek Basu, Manjusha Biswas, Manas Kumar Mandal, Pinaki Roy, Pradip K. Majumder, Aaron Goldman. Patient-level pharmacodynamics of response to combined ipilimumab and nivolumab for gastric cancer using a human autologous ex-vivo platform, CANscript [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3212.