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983 CD22-Targeted CAR-Modified T-Cells Safely Induce Remissions in Children and Young Adults with Relapsed, CD19-Negative B-ALL after Treatment with CD19-Targeted CAR T-Cells

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Acute Leukemia and Hodgkin Lymphoma
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Biological therapies, Chimeric Antigen Receptor (CAR)-T Cell Therapies, pediatric, Diseases, Therapies, Lymphoid Malignancies, young adult , Study Population, Human
Monday, December 12, 2022: 5:30 PM

Regina M. Myers, MD1, Amanda M. DiNofia, MD, MSCE1*, Yimei Li, PhD2*, Caroline Diorio, MD1, Richard Aplenc, MD, PhD1, Diane Baniewicz, MSN, CRNP1*, Jennifer L Brogdon, PhD3, Colleen Callahan, MSN, CRNP1*, Boris Engels, PhD3*, Joseph A. Fraietta, PhD4*, Vanessa Gonzalez, MBA4*, Emma Iannone, BS1*, Allison Barz Leahy, MD, MSCE1*, Hongyan Liu, PhD2*, Susan E. McClory, MD, PhD5, Susan R. Rheingold, MD1, Laura Shinehouse, BA1*, Gerald Wertheim, MD, PhD6, Lisa Wray, MD1*, Noelle V. Frey, MD, MS7, Shannon L. Maude, MD1 and Stephan A. Grupp, MD, PhD1

1Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA
3Novartis Institutes for BioMedical Research, Cambridge, MA
4Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
5Division of Oncology, Children's Hospital of Philadelphia, Havertown, PA
6Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA
7Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA

Introduction: Children and young adults with B-lymphoblastic leukemia (B-ALL) who relapse with CD19 antigen loss after CD19-targeted CAR T-cell therapy have a dismal prognosis, with a median overall survival of 9.7 months. Novel immunotherapies are urgently needed for this population. CD22 can serve as a potential alternative target. In our initial pilot trial of CD22-targeted/4-1BB CAR T cells, clinical activity was unexpectedly poor. Based on additional preclinical work demonstrating that shorter scFv linkers improve T-cell effector function, a novel CD22/4-1BB CAR construct with a short scFv linker (CART22-65s) was developed and investigated in a phase 1 study (NCT02650414).

Methods: After fludarabine/cyclophosphamide lymphodepletion, patients (pts) were infused with CART22-65s using a 3-day fractionated dosing scheme with the 2nd/3rd doses held for early signs of cytokine release syndrome (CRS). The primary endpoint was safety. Key secondary endpoints were feasibility, efficacy, and CAR T cell expansion and persistence.

Results: Nineteen pts were enrolled and had a product successfully manufactured. Of 17 pts infused (median age, 16 years; range 3-28 years), all had CD19-negative, relapsed disease after prior CD19-directed therapy (CART19, n=16; blinatumomab, n=1); 8 had prior inotuzumab; 9 had prior stem cell transplant (SCT); and 3 had multiple prior SCTs. Median bone marrow blasts immediately pre-infusion was 31% (range, 0-99%); 8 patients had >75% blasts. The median cell dose infused was 4x106 CART22-65s cells/kg (range, 0.8 to 10 x 106).

In vivo cellular kinetics by qPCR demonstrated robust initial CAR T cell proliferation peaking at a median of 20 days post-infusion, and persistence that correlated with clinical response (Figure A). At day 28, 13/17 (77%) pts achieved a complete remission (CR) of which 10 (77%) had undetectable minimal residual disease (uMRD) by flow cytometry. One additional pt cleared MRD at month 2 without intervention. Notably, 4/5 (80%) pts refractory to prior inotuzumab achieved a CR with CART22-65s. Of 11 pts with a best response of uMRD CR, 5 proceeded to consolidative SCT, including 3 with prior SCT: 2 remain in CR post-SCT, 2 are in CR after a brief course of alternative therapy for emergence of MRD, and 1 had a CD22+ relapse post-SCT. Of 6 pts with uMRD CR who did not proceed to SCT (5 had a prior SCT), 5 experienced relapsed disease with a range of CD22 expression and 1 remains in CR 30 months after infusion with ongoing CAR T persistence. Of 2 pts with MRD+ CR (1 CD22+, 1 CD22-), both progressed to morphologic relapse; one received alternative therapy prior to progression. Of 4 pts with non-response, all died of disease within 9 months. Thus, with a median follow-up of 29 months, median relapse-free, event-free, and overall survival were 5.3 (95% CI, 1.9-NR), 5.8 (95% CI, 2.1-NR), and 16.5 (95% CI, 9.3-NR) months, respectively (Figure B). In addition, 2 patients received CART22-65s retreatment for CD22+ relapsed disease after initial infusion. Both engrafted, but only 1 achieved uMRD CR.

CRS was observed in 15 pts (grade 1, n=10; grade 2, n=5), and mild neurotoxicity in 6 pts (grade 1, n=5; grade 2, n=1). In the retreatment setting, 1 pt developed grade 3 CRS, which resolved, and grade 3 encephalopathy/hypotonia, but died of progressive disease prior to resolution. Autopsy findings were consistent with leukomyelopathy of the spinal cord, which was inconclusive in its relation to CART22-65s. Other SAEs included: (1) platelet refractoriness and recurrent, severe inflammatory reactions to platelet transfusions in 1 pt that improved with corticosteroids and anakinra; and (2) delayed hemophagocytic lymphohistiocytosis in 1 pt after CART22-65s retreatment that resolved without intervention.

Conclusion: CART22-65s induced remissions in 77% of children and young adults with highly refractory, CD19-negative B-ALL, including in 4/5 pts refractory to prior CD22-directed therapy. Manufacturing was successful, and the overall toxicity profile was favorable even in pts with high disease burden. Several uncommon toxicities were observed, but the only grade 3 CRS and neurotoxicity events occurred in the retreatment setting. Our observation of high initial response rates, but later recurrences, highlights the need to use CART22-65s as part of combination therapy. These promising preliminary data provide support for a combined CD19/22 approach using the CART22-65s construct.

Disclosures: Brogdon: Novartis: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Engels: Miltenyi Biotec: Current Employment; Novartis: Ended employment in the past 24 months, Other: Holds stocks and patents. Rheingold: Pfizer: Consultancy. Frey: Sana Biotechnology, Kite Pharma, and Syndax Pharmaceuticals: Consultancy; Novartis: Research Funding. Maude: Wugen: Research Funding; Novartis Pharmaceuticals: Consultancy, Other: study steering committee, Patents & Royalties: Patent pending and licensed to Novartis Pharmaceuticals for PCT/US2017/044425: Combination Therapies of Car and PD-1 Inhibitors , Research Funding. Grupp: Carisma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Research Funding; Vertex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Roche: Consultancy; GSK: Consultancy; CBMG: Consultancy; Eureka: Consultancy; Amerisource: Consultancy; Janssen: Consultancy; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Alogene: Membership on an entity's Board of Directors or advisory committees; Cabaletta: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH