Abstract 6632: Simultaneous comparison of response to two different anti-PD1 drugs in the same patient using a human tumor histo-culture platform
Authors: Sankaran Satish , Das Biswajit , Jaganathan Kowshik , K Gowri Shankar , C Jayaprakash , MS Ganesh , Prabha Amritha , Pillai Vijay , V Syamkumar , Bhowal Chandan , M Rajashekar , M Oliyarasi , Malhotra Ritu , K Govindraj , Basak Nandini Pal 
Published: June 2023

Abstract
Based on preclinical and clinical study data, anti-programmed cell death protein 1 (PD-1) drugs Pembrolizumab (P), and Nivolumab (N) have been considered equivalent in terms of response efficacy. Both the antibodies have IgG4 backbone but vary considerably in terms of the PD-1 epitopes they bind to.. Given that there is almost no overlap between the PD-1 binding sites there is a definite possibility of nuanced drug-dependent differences in patient response to treatment. These differences would not be possible to discern unless the same patient with the same tumor microenvironment were evaluated with both drugs simultaneously. We attempted to address this question using the near native FarcastTM TruTumor histoculture platform. Fresh surgically resected Head and Neck squamous Cell Carcinoma (HNSCC) samples (n=8) along with matched blood were collected from consented patients. The tumor sample was processed to generate explants that were distributed into arms. These arms were treated in culture with P (32.9 µg/ml) or N (132 µg/ml) for 72 hours. The response was characterized using histopathology, cytokine release and flow cytometry. T-cell re-invigoration was assessed by evaluating Interferon gamma release while a decrease in tumor content and/or increase in cleaved Caspase expression was correlated with tumor cytotoxicity Pre-treatment cytokine levels across control and both treatment arms were equivalent (z-score &lt;1.5) across all samples. Additionally, when treated with the same drugs in duplicate arms similar tumor cytotoxic response was observed in the replicate arms (n=1). These data established arm equivalence. Post treatment with N or P, 6 out of 8 samples exhibited a T-cells reinvigoration phenotype. Of the remaining 2 samples, one exhibited tumor cytotoxicity with both treatments while the other showed tumor cytotoxicity only on N treatment. We evaluated the 6 samples that exhibited T-cell re-invigoration response further to understand the subtle differences in response to either N or P. While the response trends were similar for both drugs, the rate of response, as evaluated by significant increase in cleaved caspase-3 or decrease in tumor content, seem to be different in 3 samples. These 3 samples responded better with P compared to N.In this study, we broadly observed equivalent response to both the drugs with some patient samples responding slightly better to one over the other. Further studies are required to tease out the molecular reasons for these nuanced differences in response to these two anti-PD1 treatments. The FarcastTM TruTumor platform provides the unique opportunity to make personalized choice of the drug treatment that might provide best response in a patient.
Citation Format: Satish Sankaran, Biswajit Das, Kowshik Jaganathan, Gowri Shankar K, Jayaprakash C, Ganesh MS, Amritha Prabha, Vijay Pillai, Syamkumar V, Chandan Bhowal, Rajashekar M, Oliyarasi M, Ritu Malhotra, Govindraj K, Nandini Pal Basak. Simultaneous comparison of response to two different anti-PD1 drugs in the same patient using a human tumor histo-culture platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6632.