1085 Innate immune activation by microtubule destabilizing agents enhances their efficacy in vivo, as predicted by machine learning analyses of human PBMC treated with a large, bioactive compound library

• DOI: 10.1136/jitc-2023-sitc2023.1085
• Publication Date: 2023-10-31T14:31:22Z
• Authors: Hope O’Donnell; Matthew Booty; Ben Komalo; Sarah Headland; Lauren Nicolaisen; Brandon White; Christian Elabd
• Keywords: Rolipram

<h3>Background</h3> Chemotherapies are first-line cancer treatments, often preceding immunotherapies, but their impacts on immune responses poorly understood. Drug discovery pipelines typically must choose between large library screens with simple readouts or small, targeted compound sets for more complex mechanistic investigation. Spring's Immune Compass<b> uses machine learning (ML</b><b>) analyses of high-content cell paint images and secreted protein profiles to simultaneously screen full libraries while acquiring functional details each compound.</b> <h3>Methods</h3> 10,000+ bioactive compounds were screened in human PBMC using Compass platform. Compounds compared benchmark controls identified as potentiators further study vaccine adjuvants, innate agonists, among others.¹Microtubule destabilizing agents (MDAs) Taltobulin (oral) Verubulin (intravenous) explored MC38 EG7.OVA C57BL/6 mouse syngeneic tumor models at Charles River Labs. <h3>Results</h3> Here, we show that an established class chemotherapeutics, MDAs, our having immunostimulatory functions based similarity approved adjuvant AS03 pro-inflammatory cytokine profiles. Screening data, particularly IL-1b secretion, was used prioritize specific MDAs study. We confirmed vitro activate monocyte-derived dendritic cells, shown like Colchicine Vinblastine.^2–4 Further, these drugs, especially Taltobulin, reduce size prolong survival (figure 1). These effects not due exclusively cytotoxicity, benefits treatment continued without additional doses EG7 tumor-cleared mice upon rechallenge the opposite flank. In RAG2^-/- immunodeficient mice, initial clearance after administration similar wildtype C57BL/6, maintenance regression impaired, suggesting long term immune-mediated. <h3>Conclusions</h3> data demonstrate power coupling ML analysis high-throughput, high dimensional identify multiple classes novel drug candidates simultaneously. Using this approach, Spring potential MDA family, directly selected top candidates, designed vivo experiments demonstrated significance mediated stimulation. likely improved DC activation,^{3 4} future studies needed confirm. Our results support combination checkpoint inhibitors, require strong anti-tumor memory. particular, shows promise both cytotoxic durable memory generation minimal toxicity. <h3>Acknowledgements</h3> thank Ben Kamens Discovery, Inc. funding work, whole team work generating analyses. Special thanks Rachel Jacobson revisions. <h3>References</h3> Booty M, Komalo B, Hosny A, Headland S, Fernandez-Figueras Nguyen Cousin W, Heinrich J, Nicolaisen L, DeVay R, <i>et al.</i> Oral mTOR Inhibition Limits And Reduces Actinic Keratosis Cutaneous Squamous Cell Carcinoma A UVB-Induced Mouse Model. <i>Biorxiv</i>, 2022. 2022.11.03.513568. 10.1101/2022.11.03.513568. Mizumoto N, Gao Matsushima H, Ogawa Y, Tanaka Takashima A. Discovery immunostimulants by dendritic-cell-based screening. <i>Blood</i> 2005;<b>106</b>:3082–3089. 10.1182/blood-2005–03-1161. Classification Chemotherapeutic Agents Based Their Differential Effects Dendritic Cells. <i>Cancer Res</i>. 2009;<b>69</b>:6978–6986. 10.1158/0008–5472.can-09–1101. Kashyap AS, Fernandez-Rodriguez Zhao Monaco G, Trefny MP, Yoshida Martin K, Sharma Olieric Shah P, GEF-H1 Signaling Microtubule Destabilization Is Required Activation Specific Anti-tumor Responses. <i>Cell Rep</i>. 2019;<b>28</b>:3367–3380.e8. 10.1016/j.celrep.2019.08.057. <h3>Ethics Approval</h3> All procedures conducted accordance Institutional Animal Care Use Committee Labs, under IACUC No. I033.