-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4862 Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, adult, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies, Study Population, Human, Minimal Residual Disease
Monday, December 11, 2023, 6:00 PM-8:00 PM

Nirali N. Shah, M.D.1, Jacques Azzi2, Brenda W Cooper, MD3, Abhinav Deol, MD4*, John DiPersio5, Divya Koura, MD6, Brian McClune, DO7, Lori S. Muffly, MD8, Muhammad Umair Mushtaq, MD9, Rupa Narayan, MD10, Hyung Chan Suh, MD, PhD11, Gregory Yanik, MD12*, Sritama Nath, PhD13*, Jennifer Whangbo, MD, PhD13 and Guenther Koehne, MD, PhD14

1Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD
2Division of Hematology & Medical Oncology, Cellular Therapy and Bone Marrow Transplant, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
3University Hospitals Seidman Cancer Center, Cleveland, OH
4Karmanos Cancer Institute/ Department of Oncology, Wayne State University, Detroit, MI
5Department of Internal Medicine, Division of Oncology, School of Medicine, Washington University, Saint Louis, MO
6UCSD Moores Cancer Center, La Jolla, CA
7Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
8Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University School of Medicine, Stanford, CA
9Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Westwood, KS
10Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA
11Hackensack University Medical Center, Hackensack, NJ
12Rogel Cancer Center, University of Michigan, Ann Arbor, MI
13Vor Biopharma, Cambridge, MA
14Baptist Health South Florida, Miami Cancer Institute, Miami, FL

Background and Significance:

Although allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with high-risk acute myeloid leukemia (AML), relapse occurs in 30% to 40% of alloHCT recipients and is associated with a 2-year post-relapse survival rate of less than 20%. Chimeric antigen receptor (CAR) T cells targeting tumor-associated antigens have demonstrated efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia and other hematologic malignancies, but there is limited clinical experience with CAR T cell therapies for AML. Current challenges for autologous AML CAR T cell therapy include the inability to harvest adequate numbers of functional, undifferentiated T cells as CAR T cell starting material. In addition, the potential presence of AML blasts in an autologous cell collection can interfere with T cell proliferation and function during the manufacturing process. To circumvent these impediments in patients with R/R AML after alloHCT, VCAR33 represents a CD33-directed CAR T cell product generated from lymphocytes from each patient’s prior allogeneic stem cell donor. CAR T cell manufacture from HLA-matched donors will likely not only eliminate delays and failures in production due to lymphopenia but also improve T cell function by using healthy starting material.

CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts and because prior clinical experience with gemtuzumab ozogamicin (GO; tradename: MylotargTM) has demonstrated the safety and efficacy of targeting CD33.

Study Design and Methods:

Study NCTxxxxxxxx* is a multi-center phase 1/2 study evaluating the safety and preliminary efficacy of VCAR33, donor-derived allogeneic CAR T cells targeting CD33 (Figure 1). The CAR construct used for the manufacture of VCAR33 contains a lintuzumab-derived binding domain and a CD28 co-stimulatory domain. Key inclusion criteria include adult patients with relapsed or measurable residual disease positive (MRD+) AML after undergoing alloHCT with an 8/8 HLA-matched related or unrelated donor. Patients who have undergone alloHCT with trem-cel, a CD33-deleted allogeneic stem cell product intended to facilitate the post-HCT treatment with CD33-directed therapies by reducing on-target off-tumor hematotoxicity, may also participate. Patients will be assigned to one of two study arms based on their AML disease burden: Arm A for morphologic disease with ≥ 5% blasts in the bone marrow, or Arm B for MRD+ defined as < 5% blasts in the bone marrow with ≥ 0.1% CD33+ leukemia cells by flow cytometry. The patient’s prior stem cell donor undergoes apheresis for collection of mononuclear cells, which are used as starting material for VCAR33 manufacturing. Patients will receive lymphodepletion on days -5 to -2 with fludarabine (total 120 mg/m2) and cyclophosphamide (total 1000 mg/m2) followed by infusion of VCAR33 on Day 0. Each study arm will enroll and escalate independently according to a standard 3+3 trial design, starting at 1 x 106 CAR T cells/kg for Dose Level 1. The dose limiting toxicity monitoring period is 28 days, at which time patients will undergo evaluation of disease response. Secondary endpoints include incidence of cytokine release syndrome, graft-vs-host disease, and clinical response. Exploratory endpoints aim to correlate VCAR33 properties with clinical response by characterizing T cell phenotypes within the VCAR33 product and by examining VCAR33 expansion and persistence after infusion. Follow up on trial will continue for up to 2 years after infusion followed by long term monitoring for up to 15 years. Patients may undergo second alloHCT for consolidation of remission or for rescue of prolonged cytopenia due to on-target off-tumor effects of VCAR33.

*NCT number pending. Clinical trial information submitted to CT.gov on July 19, 2023.

Disclosures: Shah: Lentigen: Research Funding; CARGO: Consultancy; VOR: Consultancy, Research Funding; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board. DiPersio: Rivervest: Consultancy; Vertex: Consultancy; Magenta: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties; Bioline: Consultancy; Macrogenics: Research Funding; WUGEN: Current holder of stock options in a privately-held company, Other: Ownership Investment, Patents & Royalties, Research Funding. Koura: BMS: Consultancy, Research Funding. Muffly: adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; orca bio: Research Funding; bms: Research Funding; jasper: Research Funding; amgen: Consultancy; pfizer: Consultancy; kite: Consultancy, Honoraria, Research Funding; autolus: Consultancy; astellas: Consultancy, Research Funding. Narayan: Novartis: Other: Research funding to institution; Sanofi: Other: Spouse employment . Nath: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH