Acute myeloid leukemia (AML) is commonly treated with allogeneic hematopoietic cell transplantation (HCT). Donor T cells arising from the graft can prevent relapse by targeting leukemia cells. These T cells can bind to antigens expressed by the leukemia cells presented on the cell surface by a major histocompatibility complex (MHC) and eliminate the cancer cells. However, many antigens presented by cancer cells are also present in normal tissue. As such, T cells with T cell receptors (TCRs) specific for those normal tissue antigens can damage the patient in what is known as graft-versus-host disease (GVHD). The Greenberg and Chapuis labs (Clinical Research Division) collaborated on a study treating patients with T cells transduced to express a TCR specific for WT1, a protein involved in proliferation which is expressed highly on leukemic cells compared to other cells. The results were published in the journal Nature Medicine.
In order to avoid GVHD that could be caused by T cells against off-target antigens, the authors expanded donor T cells with TCRs specific for an Epstein-Barr virus antigen. They then transduced these expanded cells with the WT1 TCR, which they called TTCR-C4 cells. They found that TTCR-C4 effectively lysed leukemia cells and expressed effector cytokines after being stimulated with WT1 peptide.
The authors then tested the effectiveness of TTCR-C4 cells in preventing AML relapse. They infused TTCR-C4 into 12 poor-risk patients—people with a high likelihood of relapse—and monitored them for signs of AML relapse. Seven of the patients received a second infusion to maintain high levels of TTCR-C4. When the patients were assessed approximately four years after infusion, all had no evaluable disease (NED). As a comparison, the authors looked at a group of 88 other AML patients with similar risk and found 40 of them had relapsed or died.
Next, the authors tested whether TTCR-C4 might cause toxicity to normal tissues. Nine patients experienced low level and one patient experienced an intermediate GVHD; however, this could have been due to donor T cells arising from the prior transplant and may not be caused by the infused TTCR-C4. Analysis of the tissues with toxicity revealed that TTCR-C4 were found in lesser frequencies in the tissue than in the blood. The GVHD arose long after TTCR-C4 infusion. Both of these findings suggest that TTCR-C4 were not the cause of GVHD.
Many of the patients maintained high levels of TTCR-C4. Of the twelve infused patients, nine had >3% of total CD8 T cells that were TTCR-C4, and TTCR-C4 were found at >10% in four patients for more than a year. These persisting TTCR-C4 were mainly effector memory cells.
This research shows great promise for the future of TCR transduced T cells. WT1 specific T cells were involved in preventing relapse in AML patients and did not cause toxicity to normal tissues. Not only is there potential to treat more AML patients with TTCR-C4, this study shows that there could be many more TCRs effective at treating other types of cancer when transduced into donor T cells.
This work was supported by the National Institutes of Health, the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center, Damon Runyon, the Guillot Family ZachAttacksLeukemia Foundation, and Juno Therapeutics.
Fred Hutch/UW Cancer Consortium members Aude Chapuis, Daniel Egan, Merav Bar, Raphael Gottardo, Marie Bleakley, Cecilia Yeung, M. Juliana McElrath, Ted Gooley, and Philip Greenberg contributed to this research.
Chapuis AG, Egan DN, Bar M, Schmitt TM, McAfee MS, Paulson KG, Voillet V, Gottardo R, Ragnarsson GB, Bleakley M, Yeung CC, Muhlhauser P, Nguyen HN, Kropp LA, Castelli L, Wagener F, Hunter D, Lindberg M, Cohen K, Seese A, McElrath MJ, Duerkopp N, Gooley TA, Greenberg PD. 2019. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat Med. 2019 Jul;25(7):1064-1072. doi: 10.1038/s41591-019-0472-9.