Abstract CT191: A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1)

Abstract

Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, and atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint is CelTIL score [2], a metric for quantifying changes in tumor cellularity and the number of tumor infiltrating lymphocytes (TILs), where an increase in CelTIL score has been associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, changes to the TME by immunohistochemistry (IHC), PD-L1 expression by the Ventana SP142 assay used as the atezolizumab companion diagnostic, and T cell clonality by T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results: Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4]. Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer. References: [1] Bernstein, V., et al. Breast Cancer Res Treat, 2018. 167(2): p. 485-493. [2] Nuciforo, P., et al. Ann Oncol, 2018. 29(1): p. 170-177. [3] Mostafa, A.A., et al. Cancers (Basel), 2018. 10(6). [4] Lee, J., et al. Cancer Research, 2020. 80(16 Supplement): p. 2206-2206. Citation Format: Luis Manso, Fernando Salvador, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan M. Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose L. Alonso, Alejandro Martínez, Rafael Villanueva, Juan A. Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez-Farre, Grey A. Wilkinson, Thomas C. Heineman, Gerard Nuovo, Houra Loghmani, Matt Coffey, Azucena Gonzalez, Débora Martínez, Laia Paré, Tomás Pascual, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT191.

Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies

“…For this experiment, the clinical-grade formulation of Reo, named pelareorep (Pela in graphs), was used. Pelareorep is currently under investigation in multiple clinical trials as part of combinatorial approaches, including T cell–based immunotherapy, and has shown promising results ( 41, 42 ).…”

Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancements

“…Despite the early termination of phase II trial exploring pelareorep and pembrolizumab, the interim results from phase I/II trial evaluating the combination of pelareorep and anti-PD-L1 ICI atezolizumab (Eudra-CT Number: 2020-003996-16) for the treatment of advanced gastrointestinal cancers revealed that the combination therapy administered to 3 out of 3 patients with locally advanced/metastatic unresectable pancreatic ductal adenocarcinoma led to partial response at week 16 after the treatment with no safety signals. Similarly, interim results from the phase I trial evaluating the combination of pelareorep and atezolizumab in patients with early breast cancer (NCT04102618) that are hormone receptor-positive and HER2-negative were promising ( 107 ). The study evaluated CelTIL score, a metric that quantitates changes in tumor cellularity and TIL with higher score correlating to favorable therapeutic responses, and met the primary endpoint of the trial when greater than 30% increase in CelTIL score was achieved in 40% of the patients receiving pelareorep in absence of atezolizumab and 60% in the combination therapy arm.…”

New and Emerging Targeted Therapies for Advanced Breast Cancer

“…New emerging technologies are on the horizon for the treatment of breast cancer, including immuno-oncolytic virus drugs, histone deacetylase inhibitors, and novel combination therapies [9][10][11]. In this review, we will discuss the most novel breast cancer treatments for HER2-positive, HER2-negative, and triple-negative breast cancers, and the possibilities implicated in combinatorial therapy for the future of breast cancer medicine (Table 1).…”