Abstract P3-06-04: Treatment of Metastatic Breast Cancer with Multipotent Oncolytic/Helper Adenovirus CAdVEC

Abstract

Abstract Background: Metastatic breast cancer (MBC) which causes significant morbidity and mortality worldwide is in need of more effective treatment regimens. In combination with chemotherapy, anti-PD1 antibody pembrolizumab has been shown to prolong progression-free survival (PFS) of patients with triple-negative subtype MBC (TN-MBC), however, its efficacy remains low for the other 80% of patients with MBC. MBC’s heterogenous pattern of immune infiltration and expression make it challenging to treat with single immunotherapeutic agents such as pembrolizumab and successful immunotherapy must therefore target multiple pathways. To augment antitumor host immune responses during treatment, studies have examined adjunct agents such as “oncolytic” adenovirus (OAds), which are vectors that preferentially replicate in and lyse tumor cells leading to the activation of host immunity. OAds have been tested in a myriad of clinical trials with the hope to enhance host immune activation but those trials have shown limited successes. Methods: To overcome the multiple immunogenic barriers in solid tumors, our group developed a binary oncolytic/helper-dependent adeno-immunotherapy (CAdVEC). The first generation CAdVEC (CAdTrio) contains an OAd and a “helper-dependent” adenovirus (HDAd) that produces immunostimulant molecules including interleukin (IL)-12p70 and anti-PD-L1 antibody. Based on successful results using animal models, a first-in-human Phase 1 study with CAdTrio was conducted among patients with all solid tumors (NCT03740256). Four patients with MBC were enrolled in the virus dose-escalation phase of the trial and received an intra-tumor injection of CAdTrio. Given the novelty of this binary agent, starting dose of CAdTrio was more than 2-logs lower than that used in other OAd trials. Three patients received dose level (DL) 1 and one patient received DL2. All patients also received pembrolizumab 6 weeks after the virus injection. The primary endpoint for this phase I dose escalation was dose-limiting toxicities (DLT). Secondary outcomes included overall response rates (ORR), disease control rate (DCR), PFS, overall survival (OS), and treatment-related adverse events. Results: No patients developed DLT. The most common toxicities were fever, fatigue and pain around the injection site, but none were greater than grade 2. No significant elevation in liver enzymes were observed. Three of the four patients had partial response (PR). One patient progressed after ten weeks of stable disease and passed away. The three patients with PR received pembrolizumab within 7 weeks of CAdVEC injection. Analysis of injected tissues prior to pembrolizumab treatment showed that CAdTrio repolarized the tumor microenvironment toward immune activity by increasing the number of infiltrating Th1 immune cells, leading to responses in some treated tumors and even in one distant metastasis, demonstrating the potent systemic immune response to local CAdTrio treatment in patients with MBC. Conclusions: Our study demonstrated that intra-tumor injection with CAdTrio was safe and effective in patients with MBC but the significance of the results was limited by the small sample size. An MBC dedicated phase II trial is planned to be conducted to fully evaluate the efficacy and safety of CAdVEC treatment and to further elucidate mechanisms of resistance/sensitivity among patients with MBC. Citation Format: Natalie Chen, Daniel Wang, Caroline E. Porter, Amanda Rosewell Shaw, Catherine R. Robertson, Mae L. Woods, Ya Xu, Greyson Biegert, Alphi Kuriakose, Tao Wang, Bambi J. Grilley, Helen Heslop, Malcolm K. Brenner, Masataka Suzuki, Bora Lim. Treatment of Metastatic Breast Cancer with Multipotent Oncolytic/Helper Adenovirus CAdVEC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-04.