Perutelli, Francesca

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Institutional Research Information System University of Turin

Blood 142 (2023) 6827–6828The 65th ASH Annual Meeting AbstractsONLINE PUBLICATION ONLY703.CELLULAR IMMUNOTHERAPIES: BASIC AND TRANSLATIONALTargeting B-Cell Malignancies with Anti-ROR1 CAR T-Cell TherapyJinsheng Weng, MD PhD 1, Cao Cuong Le 2, Yong Pan 3, Francesca Perutelli 3, Xiaoyun Cheng, MDMS 4, Jingjing Cao, BSc 5,Owhofasa Agbedia 3, Shao-Qing Kuang 5, Jingwei Liu, MD 6, Fuliang Chu, PhD 5, Sridevi Patchva 5, Neeraj Y. Saini, MD 7,Sattva S. Neelapu, MD 81Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX2The Texas university of MD.Anderson cancer center, houston, TX3The Texas University of MD.Anderson cancer center, houston, TX4The Texas University of MD.Anderson cancer center, Houston, TX5The University of Texas MD Anderson Cancer Center, Houston, TX6Department of Lymphoma and Myeloma, The Texas University of MD.Anderson cancer center, houston, TX7Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center,Houston, TX8Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TXAnti-CD19 chimeric antigen receptor (CAR) T cell therapy has been shown to induce highcomplete response rates in the majority of B-cell lymphoma patients. However, over 50% ofpatients relapse within one year. A major cause of failure appears to be due to loss of CD19expression on the tumor cell surface. This indicates that novel therapeutic strategies are stillneeded in clinic. Receptor tyrosine kinase like orphan receptor 1(ROR1) is an oncofetal receptorfor Wnt5α that is expressed in multiple embryotic tissues but absent in virtually all adult tissues.However, ROR1 is expressed at high levels in chronic lymphocytic leukemia (CLL), mantle celllymphoma (MCL), diffuse Large B-Cell Lymphoma (DLBCL), and several solid tumors. The highexpression level of ROR1 in tumor cells is associated with adverse clinical prognosis. Inaddition, a small percentage of cancer cells with characteristics of undifferentiated leukemiacells or cancer stem cells were found to overexpress ROR1. Using hybridoma technology, wegenerated an anti-ROR1 monoclonal antibody that speci cally recognized ROR1 protein. Theantibody bound to ROR1-expressing MCL cell lines but not to normal donor T cells, B cells, ormonocytes, indicating the speci city of the antibody. Lentiviral transduction of a CAR moleculederived from the anti-ROR1 antibody into primary human T cells redirected their speci cityagainst B-cell lymphoma cell lines. We found the anti-ROR1 CAR T cells speci cally lysed B-cell lymphoma tumor cells at high ef ciency but not normal B cells. At an effector: target ratio of1:1, the anti-ROR1 CAR T cells lysed over 95% of B-cell lymphoma tumor cells during 3-days ofcoculture. To determine the optimal CAR construct, we evaluated various hingetransmembrane, and costimulatory domains in the CAR molecule. We found that incorporationof the CD28 hinge and transmembrane domain in the CAR construct dramatically enhanced thein vitro lysis ef ciency of anti-ROR1 CAR-T cells. In conclusion, we developed a novel andpotent anti-ROR1 CAR T-cell therapy product that may be used for treatment of various B-cellmalignancies and ROR1-expressing solid tumors.Disclosures Liu: N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property).Patchva: N/A: Patents & Royalties: Related to the safety switch described (intellectual property). Saini: Panbela Theraputics:Research Funding;GSK:Research Funding.Neelapu: Longbow Immunotherapy:Current holder of stock options in a privately-held company; Chimagen: Consultancy, Other: Advisory board member; Caribou: Consultancy, Other: Advisory board mem-ber; Astellas Pharma: Consultancy, Other: Advisory board member; Synthekine: Consultancy, Other: Advisory board member;Takeda:Consultancy, Other: Advisory boardmember; Fosun Kite:Consultancy, Other: Advisory boardmember; Janssen:Con-© 2023 by The American Society of Hematology 2 NOVEMBER 2023 | VOLUME 142, NUMBER Supplement 1 6827ONLINE PUBLICATION ONLY Session 703sultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Sana Biotechnology:Consultancy, Other: Advisory board member, Research Funding; Adicet Bio: Consultancy, Other: Advisory board member,Research Funding; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Athenex: Consul-tancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; Sellas LifeSciences: Consultancy, Other: Advisory board member; Merck: Consultancy, Other: Advisory Board Member; Orna Thera-peutics: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other:Scienti c Advisory Board;N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual prop-erty);Morphosys: Consultancy, Other: Advisory board member; Kite, A Gilead Company: Consultancy, Other: Advisory BoardMember, Research Funding; Carsgen: Consultancy; Precision Biosciences: Research Funding; Incyte: Consultancy, Other: Ad-visory board member.https://doi.org/10.1182/blood-2023-1800286828 2 NOVEMBER 2023 | VOLUME 142, NUMBER Supplement 1 ABSTRACTS

Targeting B-Cell Malignancies with Anti-ROR1 CAR T-Cell Therapy

https://iris.unito.it/bitstream/2318/2046316/1/argeting%20B-Cell%20Malignancies%20with%20Anti-ROR1%20CAR%20T-Cell%20Therapy%20_%20Blood%20_%20American%20Society%20of%20Hematology.pdf

Targeting B-Cell Malignancies with Anti-ROR1 CAR T-Cell Therapy

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