500 Assessing the efficacy of immunotherapies using Nilogen Oncosystems’ 3D-EXplore platform: a focus on PD-1/PD-L1 inhibitors in NSCLC tumors

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Background Despite the notable progress achieved by PD-1/PD-L1 immunotherapies in cancer treatment, their effectiveness in clinical trials often faces challenges. Models commonly used for pre-clinical evaluation of PD-1/PD-L1 immunotherapies often are biased due to their inability to mimic the intricate tumor microenvironment. Here we sought to compare the findings in concordance with drug responses observed in clinical trials with those generated by the ex-vivo Nilogen platform. By a rigorous evaluation the correlation between the platform’s outcomes and published clinical trial data, our objective was to deepen our understanding of its predictive capabilities and examine its potential implications for drug development and personalized medicine. Methods To assess the comparability of Nilogen Oncosystems’ 3D-EXplore platform with clinical trial outcomes, we investigated the immunotherapeutic efficacy and toxicity of pembrolizumab in NSCLC patients (n=45) across two independent study cohorts, selected based on clinical pathology. Following treatment, tumoroids were analyzed for changes in immune cell populations, tumor cell viability, transcriptomic profiling, and inflammatory cytokine profiles. Results A meta-analysis of two clinical trial studies (KEYNOTE 001 and 042) shows that the overall response rate (ORR) for NSCLC clinical trials using pembrolizumab monotherapy ranges from 19% to 29%. Using Nidogen’s 3D-EXpress platform tumoroids generated from patient derived NSCLC were treated with Pembrolizumab resulted in 20% responders. Pembrolizumab treatment showed increased expression of activation and proliferation markers in tumor infiltrating lymphocytes (TIL’s). Moreover, increased Granzyme B and perforin expression in TIL’s showed increased cytotoxic potential post-pembrolizumab treatment compared to control. Secretome analysis showed increased GM-CSF (granulocyte macrophage colony stimulating factor), IL-5, IFN-γ, and TNF-α in Pembrolizumab treated tumoroids. Transcriptomic profiling showed differential expression patterns in Myeloid and lymphoid activation markers when compared between Pembrolizumab treated responders and non-responders. Conclusions This study instills confidence in the tumoroid platform’s reliability for assessing efficacy of immunotherapies. Our findings align with Pembrolizumab monotherapy clinical trials in NSCLC, validating our tumoroid platform’s potential to bridge preclinical and clinical outcomes. By replicating clinical heterogeneity in a controlled setting, Nilogen’s platform facilitates the screening of precise immunotherapeutic agents, potentially reducing the bias, time and cost associated with other study models. Ethics Approval Ethics approval was obtained through Chesapeak IRB (Pro00014313) which determined ‘Using the Department of Health and Human Services regulations at 45 CFR 46, the IRB determined that this research project does not constitute human subject research and, therefore, does not require IRB oversight.’ Full informed consent was obtained for each tissue used in this study.

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