A phase I clinical trial using armored GPC3 CAR T cells for children with relapsed/refractory liver tumors.

Abstract

TPS2647 Background: CAR T therapies have been successful against hematologic malignancies, but have benefited only a handful of patients with solid cancers. Glypican 3 (GPC3) is an attractive immunotherapeutic target due to its preferential expression on multiple pediatric and adult solid cancers and lack of expression on non-malignant tissues. GPC3-CAR T cells were tested preclinically and inclusion of the 4-1BB costimulatory endodomain with IL-15 and IL-21 co-expression enabled CAR T cells to expand and persist the most in vitro and in vivo and led to robust antitumor activity in vivo. We are now testing GPC3-CAR T cells with IL15 and IL-21 for the first time in children with relapsed/refractory liver tumors. Methods: In this Phase 1 trial (GAP, NCT02932956), we are evaluating patients in 3 cohorts: 1) GPC3-CAR alone; 2) GPC3-CAR and IL-15; 3) GPC3-CAR with IL-15 and IL-21. We will 1) define the safety and establish the Recommended Phase 2 Dose (RP2D) of GPC3-CAR T cells co-expressing IL-15 and IL-21; 2) determine persistence and anti-tumor activity of GPC3-CAR T cells; 3) examine changes in gene and protein expression in the tumor microenvironment associated with potential immune escape mechanisms. Inclusion criteria are the following: age ≤18; histology proven, GPC3-positive tumor; life expectancy>12 weeks; Child-Pugh-Turcotte score<7; serum AST<5 times ULN; total bilirubin<3 times ULN for age; INR ≤1.7; absolute neutrophil count>500/μl; platelet count>20,000/μl; Hgb≥9.0 g/dl. Toxicity will be monitored using the Common Terminology Criteria of Adverse Events v4. The RP2D will be determined by the standard 3+3 dose escalation method using 5 dose levels. Persistence will be quantified using RT-PCR and flow cytometry. Antitumor activity will be defined by 3D imaging using RECIST 1.1 criteria and the immune-related response criteria. Immune-escape will be examined using single cell RNA sequencing and imaging of paraffin-embedded tissues using codetection by indexing to evaluate candidate proteins. Data will be analyzed via descriptive statistics. Cohort 1 of this study is now open for enrollment. Clinical trial information: NCT02932956.