Abstract 5485: Clinical evaluation of a functional combinatorial precision medicine platform reveals combination-specific sub-populations in t-cell lymphoma

Abstract

Abstract T-cell lymphoma (TCL) is a heterogenous subgroup of non-Hodgkin’s lymphoma with poor prognosis. Approved targeted monotherapies have seen limited success due to lack of effective combinations or identification of sensitive patient populations. Hence, there is a need to develop alternative strategies to identify effective combinations for individual patients and specific TCL sub-populations. We interrogated the potential for an ex vivo combinatorial drug sensitivity platform, Quadratic Phenotypic Optimization Platform (QPOP), in a clinical study for relapsed/refractory Non-Hodgkin Lymphoma (RR-NHL) to identify effective subtype-specific combinations through a functional combinatorial precision medicine approach. We analyzed 37 primary samples from patients with RR-NHL of both T- and NK-cell origin in Singapore, with disease amenable to biopsy or blood/marrow aspiration. Single cell suspensions from tumor samples were treated with a panel of 12 drugs with known preclinical or clinical efficacy against TCL. Post-drug treatment cell viability was used as a phenotypic input for QPOP analysis, which maps experimental data points to a second-order quadratic function to predict cell killing efficacies for all possible permutations of drug combinations. Romidepsin-based combinations appeared among the top ranked QPOP-derived 2-drug combinations with predicted output cutoff < 0.55 in 91.8% of samples treated with similar QPOP drug panel. Among these combinations, combinations with copanlisib, ifosfamide and venetoclax were the most frequently occurring doublet, appearing in 24, 14 and 8 samples, respectively. A total of 10 patients received QPOP-derived romidepsin-based combinations at physicians’ discretion. We noted outcomes of stable disease or better in 7/10 (70%) patients, with clinical benefit seen in 2 complete responses and 2 partial responses (40%). Thus, romidepsin-based combinations showed improved outcomes for TCL patients compared to the prior reported overall response rate of 25% that led to romidepsin’s approval as monotherapy. This study showed the clinical utility of QPOP in identifying combination therapy-specific sub-populations in TCL. Targeted agents, such as romidepsin, copanlisib and venetoclax, that have previously been explored as single agents in TCL were predicted by QPOP to be more effective in the proper combination for the proper patient. This study demonstrates that functional combinatorial precision medicine platforms, such as QPOP, may improve clinical outcomes through identification of more appropriate combination therapies. This work, as well as additional studies in other cancer types, provide evidence towards the need for optimal combination therapy design and the potential of functional precision medicine to improve precision and personalized cancer treatment. Citation Format: Edward Kai-Hua Chow, Masturah Rashid, Sanjay Prasad De Mel, Jasmine Goh, Anand Jeyasekharan. Clinical evaluation of a functional combinatorial precision medicine platform reveals combination-specific sub-populations in t-cell lymphoma. [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 5485.