1187 Enfortumab vedotin induces immunogenic cell death, elicits antitumor immune memory, and shows enhanced preclinical activity in combination with immune checkpoint inhibitors

• DOI: 10.1136/jitc-2022-sitc2022.1187
• Publication Date: 2022-11-08T01:19:49Z
• Authors: Devra Olson; Patrick Younan; Bernard Liu; Gabriele Blahnik-...; John Gosink; Katie Snead; Elena Tenn; Kelly Hensley; Disha Sahetya; Albina Nesterova; Margo Zaval; Anthony Cao; Christine O’Day; Ryan Heiser; Timothy Lewis; Shyra Gardai; Taisuke Nakazawa; Masashi Shimazaki; Christopher Carosino; Sharsti Sandall
• Keywords: Immune checkpoint

<h3>Background</h3> Enfortumab vedotin (EV) is a first-in-class Nectin-4-directed antibody-drug conjugate (ADC) with demonstrated improved overall survival in patients previously treated advanced-stage urothelial carcinoma.¹ EV comprised of fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) by protease cleavable maleimidocaproyl-valine-citrulline linker. has multifaceted mechanism action. Previously, we that induces antitumor activity vitro via direct cytotoxicity on Nectin-4-expressing malignant cells and indirect bystander neighboring Nectin-4­ negative cells, both which are mediated MMAE release within target cells. Here, expand upon action show tumor cell killing manner leading immunogenic death (ICD) improves responses when combined checkpoint inhibitors. <h3>Methods</h3> The ability induce hallmarks ICD was evaluated carcinoma lines. Immune activation associated assessed monocytes co-cultured EV-treated vivo immunohistochemistry, RNA-seq, flow cytometry, immune cytokine profiling. effects plus anti-PD-1 growth inhibition, microenvironment, memory were syngeneic mouse models engineered express Nectin-4. Antitumor also mice vaccinated <h3>Results</h3> In vitro, induced MMAE-mediated microtubule disruption concomitant endoplasmic reticulum (ER) stress, as evidenced increased phosphorylation JNK, extracellular inflammatory mediators ATP HMGB1, surface exposure calreticulin. Xenograft tumors upregulation MHC genes well involved ER autophagy, type I interferon response. Additionally, there noted increases macrophages dendritic along cytokines chemoattraction T-cell stimulation. Consistent induction, vaccination promoted immunity provided protection against rechallenge. Lastly, combination PD-1 inhibition durable vivo, consistent complementary modes these two anticancer agents. <h3>Conclusions</h3> These data provide insight into clinical observed bolster scientific rationale combine inhibitors, currently an area active investigation across multiple studies.^2-6 <h3>References</h3> Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Duran I, Lee JL, <i>et al</i>. Vedotin Previously Treated Advanced Urothelial Carcinoma. <i>N Engl J Med</i>. 2021;<b>384</b>(12):1125–35. Epub 2021/02/13. doi:10.1056/NEJMoa2035807. PubMed PMID: 33577729; Central PMCID: PMCPMC8450892. Friedlander TW, Milowsky MI, Bilen MA, Srinivas S, McKay RR, Flaig Study EV-103: Update durability results long term outcome enfortumab + pembrolizumab first line locally advanced or metastatic (la/mUC). <i>Journal Clinical Oncology</i> 2021;<b>39</b>(15_suppl):4528. doi: 10.1200/JCO.2021.39.15_suppl.4528. Galsky MD, Necchi A, Shore ND, Plimack ER, Jia C, Sbar E, KEYNOTE-905/EV-303: Perioperative cystectomy compared alone cisplatin-ineligible muscle-invasive bladder cancer (MIBC). <i>J Clin Oncol</i>. 2021;<b>39</b>(6_suppl):TPS507. 10.1200/JCO.2021.39.6_suppl.TPS507. Heijden MSVD, Gupta Derleth CL, Kataria RS, EV-302: A two-arm, open-label, randomized controlled phase 3 study versus chemotherapy untreated (aUC) (trial progress). Oncol</i> 2022;<b>40</b>(6_suppl):TPS589. 10.1200/JCO.2022.40.6_suppl.TPS589. Hoimes CJ, Bedke J, Nishiyama H, Fang X, KEYNOTE-B15/EV-304: Randomized perioperative cisplatin-eligible 2021;<b>39</b>(15_suppl):TPS4587. 10.1200/JCO.2021.39.15_suppl.TPS4587. ClinicalTrials.gov [Internet] Bethesda (MD): U.S. National Library Medicine. 2000 – . Identifier: NCT04960709. Treatment Combination Durvalumab, Tremelimumab Durvalumab Patients With Muscle Invasive Bladder Cancer Ineligible Cisplatin Who Refuse (VOLGA). 2021 Jul 14 [cited 2022 22]. Available from: https://clinicaltrials.gov/ct2/show/NCT04960709. <h3>Ethics Approval</h3> All animal studies conducted accordance protocols reviewed approved Institutional Animal Care Use Committee at Seagen, Astellas, external testing facilities studies.