A new therapy for relapsing or persistent leukemia and myeloid malignancies harnesses the genetic differences between donor versus recipient stem cells to treat patients! Leukemia or myeloid neoplasms are cancers that affect blood cells produced in the bone marrow. Radiation- or chemotherapy-based elimination of the patient’s bone marrow and transplantation of donor stem cells—termed allogeneic hematopoietic stem cell transplantation (HCT)—cures disease in about 70% of patients with blood cancers. However, the remaining 30% of these patients relapse relatively quickly . Particularly aggressive disease occurs following early relapse within the first 100 days after HCT, which is associated with only 3% of patients surviving past 2 years shared Dr. Michelle Brault, a Staff Scientist in the Bleakley lab at Fred Hutchinson Cancer Center. Patients that relapse have genetically healthy donor blood cells and malignant self-blood cells that can be recognized as different by immune cells. To capitalize on this difference Dr. Marie Bleakley, a Professor in the Translational Science and Therapeutics Division and Director of Cellular Therapy and Transplantation for Pediatric Leukemia at Fred Hutch, her lab, and Dr. Elizabeth Krakow, an Associate Professor in the Clinical Research Division, devised a cleaver strategy. They hypothesized that immune cells trained to recognize unique proteins on self-blood cells that are cancerous could be used to specifically target relapse after HCT. Dr. Krakow led a preliminary feasibility and safety trial and found that this form of T cell therapy for patients with blood cancers was logistically feasible and well tolerated. These findings were published in Blood.
Minor histocompatibility (H) antigens are peptides or small protein fragments that come from proteins naturally made by cells , not from foreign pathogens like viruses or bacteria. A subset of these minor H antigens that include the HA-1 antigen “are tissue restricted to hematopoietic cells, which make them excellent candidates for targeting blood malignancies,” shared Dr. Brault. Additionally, these small differences in minor H antigen between donor and recipient in the case of HCT can be distinguished by T cells, thus this idea to target the HA-1 antigen on the cancer cells of some patients using T cell therapy was formed. Prior to a clinical trial of therapy efficacy, preliminary feasibility and safety studies were required. To do this, Dr. Krakow recruited nine ‘HA-1 positive’ patients with relapsing leukemia following HCT. This cohort mostly included patients with rapid relapsing cancer occurring less than 100 days following HCT therapy shared Dr. Brault. The researchers then engineered T cells to target HA on the patients’ cancer cells. Herein, they found that T cell manufacturing at several doses was feasible, and that patients treated had no dose limiting toxicities. Furthermore, the T cell therapy was able to recognize a patient’s cancer cells and persist and expand in the patient’s blood and bone marrow for more than a year following initial infusion. Excitingly, although this study was not an efficacy trial, four of the nine patients in this study either entered remission or remained in remission. These findings support the manufacturing feasibility and treatment safety of this T cell therapy and hint at its potential efficacy to treat aggressive relapsing blood malignancies.
“This work is a key step in the clinical translation of a novel T cell therapy developed by our lab at Fred Hutch,” shared Dr. Bleakley. “It enables subsequent clinical trials, and potentially ultimate FDA approval of a new cell therapy for patients who develop recurrent leukemia after hematopoietic stem cell transplantation, who currently have a very poor prognosis. Primary endpoints of feasibility and tolerability were met. This is also, as far as we are aware, the first published trial to use a class I-restricted TCR and a CD8 co-receptor to enable antigen-specific CD4+ T cell function, so provides important information for the development of other TCR-T for other cancers.”
The Bleakley lab continues to hold high research goals for their future work, “We plan to reopen the clinical trial and enroll another cohort of patients later in the year, after we complete some modifications of the cell manufacturing,” shared Dr. Bleakley. “If that [study] is also successful, we hope to go on to perform phase 2 trials.” Dr. Bleakley concluded by recognizing the core facilities at Fred Hutchinson Cancer Center, “The Cancer Consortium supports the Therapeutic Manufacturing Facility and Flow Cytometry Core Facility, both of which were crucially important to this research.”
The spotlighted research was funded by ElevateBio, National Institutes of Health, Damon Runyon Foundation, Alex’s Lemonade Stand Foundation, Hyundai Hope on Wheels, Leukemia and Lymphoma Society Translational Research Program, the Gerdin Family Foundation, the Bezos Family, and Richard Lumsden Foundations.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Elizabeth Krakow, Corinne Summers, Ryan Cassaday, Ann Dahlberg, Brian Till, Cecilia Yeung, Ted Gooley, David Maloney, Stanley Riddell, Philip Greenberg, Aude Chapuis, Evan Newell, Scott Furlan, and Marie Bleakley contributed to this work.
Krakow EF, Brault M, Summers C, Cunningham TM, Biernacki MA, Black RG, Woodward KB, Vartanian N, Kanaan SB, Yeh AC, Dossa RG, Bar M, Cassaday RD, Dahlberg A, Till BG, Denker AE, Yeung CCS, Gooley TA, Maloney DG, Riddell SR, Greenberg PD, Chapuis AG, Newell EW, Furlan SN, Bleakley M. 2024. HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation. Blood. blood.2024024105.