A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

• Type of Material: Article
• Authors: Kai Sun, Houston Methodist Neal Cancer Center; Yitian Xu, Houston Methodist Research Institute; Licheng Zhang, Houston Methodist Research Institute; Polly Niravath, Houston Methodist Neal Cancer Center; Jorge Darcourt, Houston Methodist Neal Cancer Center; Tejal Patel, Houston Methodist Neal Cancer Center; Bin S Teh, Houston Methodist Neal Cancer Center; Andrew M Farach, Houston Methodist Neal Cancer Center; Carlo Guerrero, Houston Methodist Neal Cancer Center; Sunil Mathur, Houston Methodist Neal Cancer Center; Mark A Sultenfuss, Houston Methodist Hospital; Nakul Gupta, Houston Methodist Hospital; Mary R Schwartz, Houston Methodist Hospital; Susan L Haley, Houston Methodist Hospital; Sindhu Nair, Houston Methodist Neal Cancer Center; Xiaoxian Li, Emory University; Thi Truc Anh Nguyen, Emory University; Joseph D Butner, Houston Methodist Research Institute; Joe Ensor, Houston Methodist Neal Cancer Center; Jaime A Mejia, Merck Res Labs; Zhuyong Mei, Baylor College of Medicine; Brian E Butler, Houston Methodist Hosp; Shu-Hsia Chen, Houston Methodist Research Institute; Eric H Bernicker, Houston Methodist Neal Cancer Center; Jenny C Chang, Houston Methodist Neal Cancer Center
• Language: English
• Date: 2022-10-15
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: ©2022 The Authors; Published by the American Association for Cancer Research
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-22-0622
• Title of Journal or Parent Work: CLINICAL CANCER RESEARCH
• Volume: 28
• Issue: 20
• Start Page: 4392
• End Page: 4401
• Keywords: Life Sciences & Biomedicine; HEPATIC METASTASES; MOUSE MODEL; Science & Technology; IMMUNOTHERAPY; Oncology; PEMBROLIZUMAB; IRRADIATION; RADIOTHERAPY; RECURRENCE; SURVIVAL; II TRIAL; REGULATORY T-CELLS
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Purpose: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. Patients and Methods: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2CR(7.1%), 1PR(3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with medianDoTof 9.6 months andOSof 14.7 months.The medianOSwas 6.6 months in the total population. The combinationwas well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imagingmass cytometry (IMC) revealed a significant increase ofCD8T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.