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741 CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Cellular Therapies for Low and High Grade Lymphomas
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Adults, Translational Research, Lymphomas, Non-Hodgkin Lymphoma, Clinical Research, B Cell Lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Aggressive Lymphoma, Therapies, Lymphoid Malignancies, Study Population
Monday, December 13, 2021: 3:15 PM

Matthew J. Frank, MD, PhD1,2*, John H. Baird, MD1,2, Shabnum Patel, PhD3*, Juliana Craig, BA1,2*, Jay Y. Spiegel, MD, FRCPC1,2, Zachary Ehlinger, MS3*, Harshini Chinnasamy, MS2*, Sheren F. Younes, MD, PhD4*, Jean S. Oak, MD, PhD5*, Yasodha Natkunam, MD, PhD4, Warren D. Reynolds, BS3*, Maria Iglesias, BS1,2*, Emma Crawford, BS2,6*, Hrishikesh K. Srinagesh, MD1, Emily L. Egeler, PhD2*, Sally Arai, MD, MS1, Laura J. Johnston, MD1, Robert Lowsky, MD1, Robert S. Negrin, MD1, Andrew R. Rezvani, MD1, Parveen Shiraz, MD7, Surbhi Sidana, MD1,2, Wen-Kai Weng, MD, PhD1, Liora M. Schultz, MD8, Sneha Ramakrishna, MD8, Kara L. Davis, DO9, Bita Sahaf, PhD2*, Steven A. Feldman, PhD2*, Crystal L. Mackall, MD10,11, David B. Miklos, MD, PhD1,2 and Lori Muffly, MD2,12

1Division of BMT and Cellular Therapy, Stanford University School of Medicine, Stanford, CA
2Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA
3Center for Cancer Cell Therapy, Stanford University, Stanford, CA
4Department of Pathology, Stanford University School of Medicine, Stanford, CA
5Department of Pathology, Stanford University Medical Center, Stanford, CA
6Division of BMT and Cellular Therapy, Stanford University Hospital, Stanford, CA
7Division of BMT and Cellular Therapy, Stanford University, Stanford, CA
8Department of Pediatrics, Division of Hematology and Oncology, Stanford University School of Medicine, Palo Alto, CA
9Department of Pediatrics, Division of Hematology, Oncology and Stem Cell Transplant, Stanford University School of Medicine, Stanford, CA
10Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
11Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
12Division of BMT and Cellular Therapy, Assistant Professor of Medicine Bone & Marrow Transplantation Stanford University Medical Center, Stanford, CA

BACKGROUND: Patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after failure of CD19-directed CAR T-cell therapy (CAR19) have a dire prognosis, with an overall response rate (ORR) of 29% to conventional salvage therapies, and a median overall survival (OS) of 6 months. CD22 is expressed on the majority of B-cell malignancies. Autologous CAR T-cells targeting CD22 (CAR22) have yielded an ORR of 70-90% in pediatric patients with R/R B-cell acute lymphoblastic leukemia (B-ALL), including those who had previously failed CAR19 therapy. Based on these encouraging results, we evaluated CAR22 in adult patients with R/R LBCL, focusing on those with CAR19-refractory disease.

METHODS: This ongoing single-institution phase I dose escalation clinical trial (NCT04088890) is evaluating a CAR construct incorporating the m971 CD22 single chain variable fragments and 41BB/CD3z endodomains integrated within autologous T-cells via lentiviral transduction. After lymphodepletion (LD) with fludarabine and cyclophosphamide, patients are infused with cryopreserved CAR T-cells after a 7- to 11-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). Primary objectives assess the ability to successfully manufacture CAR22 and safety. Secondary objectives include efficacy and durability of responses.

RESULTS: Twenty-one patients with LBCL [n=12 at dose level 1 (DL1), 1x106 CAR+ cells/kg; n=9 at dose level 2 (DL2), 3x106 CAR+ cells/kg] have been enrolled with a median age of 64 years (range, 36-79) and a median of 4 (range, 3-8) prior lines of therapy. All patients had at least one high risk feature, including failure of prior CAR19 therapy (n=20); refractory disease to second-line or later therapy (n=17); elevated lactate dehydrogenase (LDH) pre-LD (n=17); high tumor burden (n=9); a history of primary refractory disease (n=7); failure of prior autologous hematopoietic stem cell transplantation (HSCT) (n=6); never achieving CR to any therapy (n=5); or LBCL with MYC gene rearrangements (n=5). Successful manufacturing of cells was achieved in all patients. All patients reached day 28 post-infusion and are included in the safety and efficacy analysis presented here; updated results will be presented at the meeting. Every patient experienced cytokine release syndrome (CRS); 20/21 (95%) were Grade 1-2, 1/21 (5%) were Grade 3. Four patients (19%) experienced immune effector cell-associated neurotoxicity syndrome (ICANS); all cases were Grade 1-2 and resolved within 2 days. Five patients (24%) experienced a hyperinflammatory macrophage activation syndrome (MAS), manifested in all cases by pancytopenia and consumptive coagulopathy (DIC) requiring transfusion and/or growth factor support. One patient who received DL2 had a Grade 5 infectious event in the setting of ongoing MAS and pancytopenia. Relative to DL1, higher prevalence of Grade ≥3 cytopenias beyond D28 (89% vs. 50%) and MAS (33% vs. 17%) were observed at DL2; thus, DL1 was selected as the maximally tolerated dose (MTD). ORR at D28 was 86% (CR, n=11; PR, n=7), and was similar between DL1 and DL2 (92% vs. 78%; p=ns). 3/7 (43%) initial PR improved to CR at a median of 3 months post-infusion. All 14 patients (67% of cohort) who achieved CR remain in remission, with a mean follow-up of 7.3 months (range, 1.2-21.3); median progression free survival (PFS) and OS have not yet been reached. Five patients died from disease progression, and one patient died from septic shock in CR. CD22 expression by flow was downregulated or absent in 1/3 (33%) patients evaluated after relapse. Peak CAR-T expansion as detected by peripheral blood flow cytometry occurred at a median of 14 days, with a trend towards earlier and higher peak levels in DL2 patients. Significantly higher mean CAR-T levels occurred at peak expansion in patients who developed MAS (1070±915 vs. 196±209 CAR+ cells/μL; p=0.001).

CONCLUSIONS: Infusion of CAR22 in R/R LBCL is safe and well tolerated at DL1. Manufacturing of CAR22 was uniformly successful. With a mean follow-up of 7.3 months, the ORR and CR rates are 18/21 (86%) and 14/21 (67%), respectively. These data demonstrate CAR22 to be an effective salvage therapy for CAR19-refractory or CD19-negative LBCL.

Disclosures: Frank: Allogene Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees. Oak: Kite Pharma-Gilead: Research Funding. Arai: Magenta Therapeutics: Research Funding. Rezvani: Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; US Department of Justice: Consultancy. Shiraz: Kite Pharma-Gilead: Research Funding. Sidana: Janssen: Consultancy, Research Funding; Allogene: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Weng: Kite Pharma: Research Funding. Davis: Novartis Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Research Funding. Feldman: Samsara Biocapital: Consultancy; Obsidian: Consultancy; Lonza PerMed: Consultancy; Gradalis: Consultancy. Mackall: Syncopation Life Sciences: Consultancy, Current holder of individual stocks in a privately-held company, Other: Founder; Neoimmune Tech: Consultancy; Lyell: Consultancy, Current equity holder in publicly-traded company, Other: Founder; Nektar: Consultancy, Research Funding; Apricity: Consultancy, Current equity holder in publicly-traded company. Miklos: Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Muffly: Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy.

OffLabel Disclosure: CD22-directed CAR-T therapy for the treatment of adults with relapsed/refractory large B-cell lymphoma

*signifies non-member of ASH