Abstract 4568: Evaluating response of renal cell carcinoma to tyrosine kinase inhibitor and immune checkpoint inhibitor using a human histo-culture platform
Authors: Sankaran Satish , Jaganathan Kowshik , K Gowri Shankar , Bhargav Saurabh , MS Ganesh , Prabha Amritha , BV Prakash , V Syamkumar , Das Biswajit , K Vasanth , A Manimaran , Bhowal Chandan , M Rajashekar , M Oliyarasi , Malhotra Ritu , K Govindraj , Basak Nandini Pal 
Published: April 2023

Abstract
Tyrosine Kinase Inhibitors (TKIs) and Immune checkpoint inhibitors (ICIs) are used in first line treatment of clear cell renal cell carcinoma (ccRCC). Identifying patients who truly benefit from these treatments remains a challenge. Developing newer and better therapy options that fail in the clinical phase is yet another unmet need. Both these limitations could be addressed by employing testing platforms that best capture the heterogeneity and complexity of the tumor within the patient. FarcastTM TruTumor is a near native human histo-culture platform which retains the tumor and stroma along with the intra-tumoral immune compartment post culture that holds promise to improve treatment outcomes in patients. In this study, we developed a ccRCC platform using surgical excess specimens from consented patients and compared its immune profile with the head and neck squamous cell carcinoma (HNSCC) platform. ccRCC samples (n=10) were processed to generate explants and cultured for 72h and interrogated for response to treatment with Sunitinib (TKI:27.7ng/ml) or Nivolumab (anti-PD1:132µg/ml). On comparison of immune profiles between HNSCC and ccRCC at baseline, we observed a significantly lower total immune content in ccRCC. ccRCC showed comparatively higher variation in myeloid (70%CV) and lymphoid compartments (30%CV) as compared to HNSCC. Live tumor and immune cell population was found to be well preserved post-culture in ccRCC. Presence of various T cell sub-populations, monocyte and macrophage population post culture were confirmed using flowcytometry. Sunitinib treatment significantly increased caspase-3 expression (8/10 samples, p value&lt;0.01), along with decrease in tumor content in 4/10 samples (average drop 23%). Two samples which did not respond to Sunitinib treatment showed an increase in Interferon gamma (IFNg) (Log2FC ± SD, 2.7± 0.7) and Granzyme B (Log2FC ± SD, 1.05± 0.85) secretion, in response to Nivolumab treatment. Of these, in one sample we observed an increase in CD8+ Granzyme B, CD8+ Ki67 and decrease in CD4+ FoxP3 population, with concomitant decrease in Pan CK+ population by flowcytometry. In this sample, we observed a decrease in tumor content indicating anti-tumor response to Nivolumab treatment. In summary, the TruTumor platform potentially offers personalized treatment choices to patients improving their chances of recovery. In addition, this platform could provide powerful insights into the mechanisms of a wide range of therapy molecules in development to predict their efficacy better than other simplistic and non-human testing models.
Citation Format: Satish Sankaran, Kowshik Jaganathan, Gowri Shankar K, Saurabh Bhargav, Ganesh MS, Amritha Prabha, Prakash BV, Syamkumar V, Biswajit Das, Vasanth K, Manimaran A, Chandan Bhowal, Rajashekar M, Oliyarasi M, Ritu Malhotra, Govindraj K, Nandini Pal Basak. Evaluating response of renal cell carcinoma to tyrosine kinase inhibitor and immune checkpoint inhibitor using a human 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 4568.