Dose Escalation Study of GCC19CART CoupledCAR ® Technology for Patients with Relapsed or Refractory Colorectal Cancer

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in hematologic malignancies but limited success in solid tumors. GCC19CART, the first clinical candidate from the CoupledCAR ® solid tumor platform, targets guanylate cyclase-C (GCC) which is expressed in colorectal cancers. A Phase 1 investigator-initiated dose escalation trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer. Data presented here are from a single participating institution. Methods: Subjects with relapsed or refractory metastatic colorectal cancer are screened for GCC expression, with 70% to 80% of subjects expected to demonstrate GCC per historical data. Subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of three doses of 1x10 6, 2x10 6, or 3x10 6 cells/kg. Endpoints are safety and preliminary evidence of efficacy as determined by CT or PET/CT per RECIST1.1 or PERCIST 1.0. Results: 5 subjects have been enrolled to dose level 1 (1x10 6 cells/kg) and 5 subjects have been enrolled to dose level 2 (2x10 6 cells/kg) and have a 1-month post-infusion imaging study available for review. The most common adverse events were cytokine release syndrome (CRS) in 10/10 subjects (Grade 1 9/10 (90%) or Grade 2 1/10 (10%)) and diarrhea in 10/10 subjects (Grade 1 3/10 (30%) Grade 2 1/10 (10%) Grade 3 6/10 (60%)). Neurotoxicity was observed in 1/10 (10%) subjects at Grade 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 50% (5/10). For dose level 1, the overall response rate (ORR) per RECIST 1.1 was 40% (2/5). Two subjects demonstrated a partial response (PR) while an additional subject had partial metabolic response (PMR) on PET/CT with stable disease (SD) per RECIST 1.1. For dose level 2, The ORR per RECIST 1.1 was 60% (3/5). 3 subjects demonstrated a PR (2 at month 1, 1 at month 3 after being SD at month 1) and an additional subject had PMR on PET/CT with SD per RECIST 1.1. Conclusions: GCC19CART demonstrated meaningful clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A United States based Phase 1 trial of GCC19CART is anticipated for early 2022. Disclosures Pu: Innovative Cellular Therapeutics: Current Employment. Zhu: Innovative Cellular Therapeutics: Current Employment. Huang: https://www.accme.org/accreditation-rules/standards-for-integrity-independence-accredited-ce/eligibility: Current Employment. Tang: Innovative Cellular Therapeutics: Current Employment. Jia: Innovative Cellular Therapeutics: Current Employment. Chen: Innovative Cellular Therapeutics: Current Employment. Kennedy: Innovative Cellular Therapeutics: Current Employment. Wu: Innovative Cellular Therapeutics: Current Employment. Xiao: Innovative Cellular Therapeutics: Current Employment.

Process analysis of pluripotent stem cell differentiation to megakaryocytes to make platelets applying European GMP

Quality, traceability and reproducibility are crucial factors in the reliable manufacture of cellular therapeutics, as part of the overall framework of Good Manufacturing Practice (GMP). As more and more cellular therapeutics progress towards the clinic and research protocols are adapted to comply with GMP standards, guidelines for safe and efficient adaptation have become increasingly relevant. In this paper, we describe the process analysis of megakaryocyte manufacture from induced pluripotent stem cells with a view to manufacturing in vitro platelets to European GMP for transfusion. This process analysis has allowed us an overview of the entire manufacturing process, enabling us to pinpoint the cause and severity of critical risks. Risk mitigations were then proposed for each risk, designed to be GMP compliant. These mitigations will be key in advancing this iPS-derived therapy towards the clinic and have broad applicability to other iPS-derived cellular therapeutics, many of which are currently advancing towards GMP-compliance. Taking these factors into account during protocol design could potentially save time and money, expediting the advent of safe, novel therapeutics from stem cells.

A T-cell independent universal cellular therapy strategy through antigen depletion

CD19-targeting chimeric antigen receptor (CAR) T-cell therapeutics is a revolutionary, novel and successful treatment for B-cell malignancies. However, while CD19-CAR-T therapy can obtain high rates of complete responses in these patients, a significant fraction of patients may experience CD19-negative relapse. Moreover, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects such as cytokine-release syndrome (CRS). Whether CAR-T therapy can be substituted by a non-T-cell based universal cellular therapy is largely unknown. Surprisingly, we have demonstrated here that T-lymphocytic cells, as well as non-lymphocytic cells, can cause CD19 internalization and subsequent depletion when they are armed with a CD19-recognizing moiety. This CD19 antigen depletion can efficiently induce T-cell independent apoptosis in target cancer cells whose survival is dependent upon CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy. We therefore proposed a universal strategy for CRS-free cellular therapeutics, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and standardly as off-the-shelf mesenchymal stromal cells (MSCs) or other types of non-autologous cell expressing anergic CARs. Our results not only uncovered an unrecognized mechanism for CAR-T cytotoxicity and antigen loss, but also shed new insight into a shift in cellular therapeutics from unique patient-specific autologous therapeutics, to universal and standardized allogeneic treatment.