A Synthetic Receptor Enables Breakthrough Scale Manufacturing of iPSC-Derived CD19-CAR Cell Therapies for Hematologic and Autoimmune Diseases

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.148-148
• Main Authors: Jarrell, Dillon, Vereide, David, Arnold, Cassidy, Murphey, Max, Yingst, Ashley, Koning, Ryan, Perdue, Nikole, Romanov, Artem, Busch, Celeste, Slukvin, Igor, Crisman, Ryan, Larson, Ryan P., Scharenberg, Andrew M., Salinas, Branden, Ohara, Samantha
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-200130

Autologous CD19-CAR T cell therapies have revolutionized the treatment of hematologic malignancies; however, accessibility to CAR T cells continues to be hindered by manufacturing challenges that restrict the number of patients receiving therapy. The emerging application of CD19-CAR T cells across a range of autoimmune disease (AID) indications may further strain the commercial CD19 CAR T cell supply chain, underscoring the urgent need for scalable cell therapy solutions. To address these limitations, we are developing Synthetic Receptor Enabled Differentiation (ShRED), a scalable manufacturing process that produces unprecedented quantities of immune effector cells derived from induced pluripotent stem cells (iPSCs). In ShRED, we introduce the Rapamycin Activated Cytokine Receptor (RACR) into iPSCs to provide controlled growth and survival signals. Rapamycin activates the RACR, inducing a consistent JAK/STAT signal. This signal directs RACR-expressing iPSCs to differentiate into hematopoietic progenitors and subsequently into immune effector cells, termed induced Cytotoxic Innate Lymphoid cells (iCILs). Based on the dose levels currently in use in the clinic, our 50L scale ShRED manufacturing process can produce hundreds to thousands of iCIL doses per batch. The high yield and scalability provided by ShRED is a promising solution to meet the increasing demand for ‘off-the-shelf’ cell therapies. The final drug product produced in ShRED is RACR-expressing iCILs, a highly functional innate lymphocyte that includes both native and engineered features to enable engraftment, expansion, and effector function in allogeneic recipients. Specifically, iCILs lack MHC class I and MHC class II expression, express high levels of CD47, and are equipped with a suite of potency enhancing receptors as well as gene edits to protect against allogeneic rejection. iCILs can further be armed with either CD19-CAR or CD20-CARs to enable specific targeting of B cells and have demonstrated robust in vitro B cell depletion in peripheral blood across many healthy and disease-specific donors without evidence of allogeneic responses against the iCIL drug product. The ShRED manufacturing process has been scaled up to the 50L industrial scale in stirred tank bioreactors. The first step in the ShRED process is production of iCIL-progenitors and an intermediate cell bank (iCB). The iCB process produces more than 100 billion iCIL progenitors, which can support over 25 manufacturing runs of th