Abstract ND02: CTX112 and CTX131: Next-generation CRISPR/Cas9-engineered allogeneic (allo) CAR T cells incorporating novel edits that increase potency and efficacy in the treatment of lymphoid and solid tumors

• DOI: 10.1158/1538-7445.am2023-nd02
• Publication Date: 2023-05-30T19:07:18Z
• Authors: Jonathan A. Terrett; Demetrios Kalaitz...; Mary-Lee Dequeant; Sushant Karnik; Mohammed Ghonime; Changan Guo; Robert Chain; Heidi Heath; Nivedita Jaishankar; Rachel Yuen; Davis Settipane; Zinkal Padalia; Lauren Zakas; Meghna Kuppuraju; Paul Tetteh; Chandirasegaran M...; Brigid McEwan; Glenn Leary; Henia Dar; Daniel Ferulo; Melanie Allen; Kimberley Tipton; Laura Serwer; Thao Nguyen; Melanie Butler-Ga...; Parin Sripakdeevong; Shashwat D. Nagar; Yin Tang; Hemangi Chaudhari; Nicole Flanagan; Elaine Huang; Shashwant Phuyal; Elizabeth Koch; Andrew Dunn; Erisa Sula; Jacob Waldman; Cristian Loaiza; Maria Lei Zhang; Erin Thorstensen; Keith Steiger; Katie Schum; Kayla Urbaez; Mark Benton; Anna Ma; Sarah Cohen; Annie Weaver; Christopher Finch; Phuong Khanh Morrow
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Abstract Allo CAR T cells represent an “off-the-shelf” treatment option that addresses the unmet need for immediately available, potentially curative therapies. CRISPR Therapeutics’ first generation allo cell products, CTX110® (CD19-directed) and CTX130TM (CD70-directed), have shown encouraging efficacy in ongoing clinical trials (NCT04035434, NCT04502446, NCT04438083), including complete durable responses B- T-cell lymphoma renal carcinoma (RCC). However, exhaustion, occurring even prior to clearance by immune system, can result diminished loss of response, especially patients with high tumor burden. To address this challenge, we performed a screen discover potency edits incorporate into next-generation programs. Herein, describe two novel therapies, CTX112TM CTX131TM, synergistic Regnase-1 TGFBR2. CTX112 CTX131 (CD70-directed) are produced from healthy donor modified ex vivo using CRISPR/Cas9 gene editing. TGFBR2 been added our first-generation programs: TRAC (T-cell receptor prevent GvHD), B2M (MHC class I reduce mediated rejection), CD70 (to eliminate fratricide increase potency), site-specific insertion at locus AAV template. These modifications CAR-T therapies demonstrated increased potency, prolonged persistence, sustained antitumor activity. Disruption improves functional persistence increasing cellular expansion potential, correlating central memory phenotype. disruption allows avoid microenvironment suppression. In combination, these least 10-fold. addition, long-term maintenance CM phenotype enables efficient manufacturing. expansion, resistance elevated effector cytokine release when tested vitro models. survival regression CD19+ Nalm6-Luciferase leukemia Jeko-1 models relative control only or disruption. Similarly, “rechallenge model” which xenografts were serially implanted following single dose cells, caused NCI-H1975 lung, A498 RCC, Caki-2 RCC tumors. No evidence clonal nor independent growth occurred, suggesting multiplex edited safe use. summary, programs edits, potential may translate clinically deeper, more responses. will be developed B malignancies, advanced solid tumors, RCC. Citation Format: Jonathan A. Terrett, Demetrios Kalaitzidis, Mary-Lee Dequeant, Sushant Karnik, Mohammed Ghonime, Changan Guo, Robert Chain, Heidi Heath, Nivedita Jaishankar, Rachel Yuen, Davis Settipane, Zinkal Padalia, Lauren Zakas, Meghna Kuppuraju, Paul Tetteh, Chandirasegaran Massilamany, Brigid McEwan, Glenn Leary, Henia Dar, Daniel Ferulo, Melanie Allen, Kimberley Tipton, Laura Serwer, Thao Nguyen, Butler-Gauthier, Parin Sripakdeevong, Shashwat D. Nagar, Yin Tang, Hemangi Chaudhari, Nicole Flanagan, Elaine Huang, Shashwant Phuyal, Elizabeth Koch, Andrew Dunn, Erisa Sula, Jacob Waldman, Cristian Loaiza, Maria Lei Zhang, Erin Thorstensen, Keith Steiger, Katie Schum, Kayla Urbaez, Mark Benton, Anna Ma, Sarah Cohen, Annie Weaver, Christopher Finch, Phuong Khanh Morrow. CTX131: Next-generation CRISPR/Cas9-engineered allogeneic (allo) incorporating lymphoid tumors [abstract]. In: Proceedings American Association Cancer Research Annual Meeting 2023; Part 1 (Regular Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Res 2023;83(7_Suppl):Abstract nr ND02.