Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors.

Abstract

734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.

The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity

“…Compared to CAR-T cells without an incorporated iMC domain, iMC-based CAR-T cells had better in vivo engraftment, proliferation, and stronger anti-tumor effects in various xenograft mouse models, including lung cancer, metastatic osteosarcoma, AML, and pancreatic adenocarcinoma [ 106 , 107 ]. In a phase 1/2 clinical trial, treatment with prostate stem cell antigen (PSCA)-targeting and iMC-containing CAR-T cells (named BPX-601) yielded a stable disease (SD) in three out of five advanced pancreatic cancer patients (NCT02744287) [ 110 ]. BPX-601 cells persisted, expanded in vivo, enhanced serum levels of key cytokines such as IFN-γ and GM-CSF, and infiltrated in metastatic lesions in patients.…”

Strategies to overcome the side effects of chimeric antigen receptor T cell therapy

“…86 For example, BPX-601 is a group of designed T cells the activation of which is dependent on the induction of MyD88/CD40. 87 The cells do not rely on antigen detection and only need a molecular switch. This type of switch is controlled using antibodies, such as rimiducid.…”

“…The cells remain inactive normally, so there is no need for using silencing methods 86 . For example, BPX‐601 is a group of designed T cells the activation of which is dependent on the induction of MyD88/CD40 87 . The cells do not rely on antigen detection and only need a molecular switch.…”