Binary oncolytic adenovirus in combination with HER2-specific autologous CAR VST for treatment of advanced HER2-positive solid tumors (VISTA).

TPS2679 Background: Urgent therapies are needed for patients with refractory Human Epidermal Growth Factor Receptor 2 (HER2) positive solid malignancies. Our group has previously shown potent antitumor effect of a binary oncolytic/helper-dependent adenovirus (CAdVEC) with dual expression of IL-12 and PD-L1 blocker. Initial preclinical and clinical studies with direct tumor injection of CAdVEC has shown it to be safe and result in increased infiltration of CD8 T cells into the tumor microenvironment, with antitumor effect on locoregional and distant metastatic sites. 1 Based on these results, we describe an ongoing study with addition of HER2-specific autologous chimeric antigen receptor (CAR)-T cell therapy to CAdVEC. Methods: This is a single arm, dose escalation phase I clinical trial guided by Bayesian Optimal Interval Design (BOIN) for patients with advanced HER2 positive solid tumors. Patients who are deemed unsuitable for curative treatments and progressed after at least one standard first line therapy are eligible. HER2 positivity is determined by IHC and defined as ≥2+. Patients are required to have at least one tumor site appropriate for intratumor injection and radiographically measurable disease per RECIST v1.1. Patients with autoimmune disease requiring systemic corticosteroids greater than 10mg/day and those with active/untreated CNS metastasis are excluded. Patients will receive increasing doses of CAdVEC intratumor injection alone (first two dose levels) or in combination with HER2 specific autologous CAR-T cells (dose levels 3-7). A total of 45 patients are planned. The primary endpoint of the study is to evaluate safety and maximum tolerated dose as assessed by incidence of dose limiting toxicities (DLT) of CAdVEC intratumor injection in combination with HER2-specific autologous CAR T cells. Secondary endpoints include anti-tumor activity of the combination measured by overall response rate (ORR), disease control rate (DCR), median progression free survival (PFS) and median overall survival (OS). Exploratory endpoints include assessing the immunogenicity of combination therapy by determining the impact of treatment on cellular and humoral immunity, as well as assessing long-term persistence and functional status of HER2 CAR T-cells. Correlative analysis of levels of adenovirus antibodies with clinical outcomes and immunological findings are also planned. This study is currently enrolling. 1. Wang D, Porter CE, Lim B, et al: Science Advances 9, 2023. Clinical trial information: NCT03740256 .