A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT
Abstract
Abstract VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)–positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts ≥5%) at dose level 1 (DL1; 1 × 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 × 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 × 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell–associated neurotoxicity syndrome (1 ≥grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in arm A and 1 arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary antileukemic activity. This trial was registered at www.clinicaltrials.gov as #NCT05984199.
Article Details
Authors (35)
Muhammad Umair Mushtaq
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS
John F. DiPersio
Department of Medicine, Washington University School of Medicine, St. Louis
Jacques Azzi
3Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
Brenda W. Cooper
4Adult Hematologic Malignancies and Stem Cell Transplant, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH
Guenther Koehne
5Miami Cancer Institute, Baptist Health South Florida, Miami, FL
Divya Koura
6University of California San Diego Moores Cancer Center, San Diego, CA
Joseph Maakaron
7Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
John Magenau
University of Michigan
Brian McClune
9Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT
Joseph C. Rimando
10Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
Nirali N. Shah
Hyung C. Suh
12Division of Hematology Oncology, Department of Medicine, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Kelly Beuka
13Vor Biopharma, Cambridge, MA
John Sturrock
13Vor Biopharma, Cambridge, MA
Mugdha Nikam
13Vor Biopharma, Cambridge, MA
Eric Berglund
13Vor Biopharma, Cambridge, MA
Jianxin Hu
Yonina Keschner
13Vor Biopharma, Cambridge, MA
Julia Etchin
13Vor Biopharma, Cambridge, MA
John R. Lydeard
13Vor Biopharma, Cambridge, MA
Michele Vasquez
13Vor Biopharma, Cambridge, MA
David O’Donnell
13Vor Biopharma, Cambridge, MA
Guy Mundelboim
13Vor Biopharma, Cambridge, MA
Sanjana Thosar
13Vor Biopharma, Cambridge, MA
Giacomo Canesin
13Vor Biopharma, Cambridge, MA
Juliana Xavier-Ferrucio
13Vor Biopharma, Cambridge, MA
Sharon L. Hyzy
13Vor Biopharma, Cambridge, MA
Deborah M. Lloyd
13Vor Biopharma, Cambridge, MA
Kristin Spink
13Vor Biopharma, Cambridge, MA
Diana Hummel
13Vor Biopharma, Cambridge, MA
Melissa M. Lee-Sundlov
Julian Scherer
13Vor Biopharma, Cambridge, MA
Michelle I. Lin
13Vor Biopharma, Cambridge, MA
Jennifer S. Whangbo
13Vor Biopharma, Cambridge, MA
Lori S. Muffly
Stanford University School of Medicine