Synergistic immune response after EphrinB2 inhibition & PD-1 antibody therapy in urothelial carcinoma.

University Of Southern California, Los Angeles CA

Investigators

Abstract

ABSTRACT The best hope for cure for urothelial carcinoma is successful treatment of muscle invasive bladder cancer (MIBC). PD-1/PD-L1 antibodies produce modest response and synergistic combinations remain elusive. Emerging data in bladder cancer (BC) suggests that up to 40% of patients express no or low levels of Nectin4, and ephrinB2 expression seen in 60% of patients is associated with immunotherapy resistance. Sacituzumab govitecan, a once promising ADC in BC failed to meet its primary endpoint in a phase III trial against docetaxel. These data indicate a significant unmet need in BC. Several trials of immunotherapy and chemotherapy combinations thus far have not exceeded the 20+ year old pathologic complete response (pCR) rate of 38% for MVAC, suggesting an efficacy ceiling limit for the current approaches- See Table 3. We propose a phase II randomized trial of a synergistic combination of a novel agent- sEphB4-HSA, an EphrinB2 inhibitor, and pembrolizumab in EphrinB2 expressing and Nectin4 low/non expressing BC patients. This population does not benefit from enfortumab vedotin and is resistant to immunotherapy. In a single arm phase II trial (N=70, Sadeghi et al, JCO 2022), this combination more than doubled the expected overall survival, progression free survival, and objective response rate among EphrinB2 expressing tumors when compared to pembrolizumab alone results from Keynote-045. These data show synergy between EphrinB2 inhibition and PD- 1 blockade. Our preliminary data among 16 EphrinB2 positive MIBC patients show a pCR rate of 62.5%. sEphB4-HSA blocks bidirectional signaling between EphrinB2 and EphB4, both of which are transmembrane ligand-receptor proteins frequently expressed in BC but not normal bladder. EphB4 receptor tyrosine kinase promotes tumor initiation, migration, and cell survival. EphrinB2 expression in tumor vessels promotes angiogenesis and may function as a gatekeeper of immune cell traffic across tumor vasculature. sEphB4- HSA overcomes the barrier to immune cell traffic into the tumor and synergizes with pembrolizumab. Under aim 1, we investigate sEphB4-HSA and pembrolizumab combination in MIBC to determine clinical outcomes, pCR, and recurrence free survival. Aim 1 focuses on prospectively correlating clinical outcomes with EphrinB2, Nectin4, and PD-L1 expression, tumor DNA mutation profile and RNAseq, to determine mechanisms of induction of EphrinB2 and how it confers resistance to treatment. Under aim 2, we will investigate the immune cell number, type including antigen presenting cells and their phenotypes, and activation status in the context of their location in the tumor, perivascular, and stroma compartments of the tumors through spatial digital analysis for proteome using 500 markers and unbiased gene expression at single cell level in situ. We will further investigate whether this regimen enhances adaptive immune response by examining clonal and oligoclonal expansion of T cells by T cell receptor analysis.