Challenges With TCRs, CAR T Cells, and Other Cell Therapies

Aude G. Chapuis, MD
Physician, Seattle Cancer Care Alliance; Assistant Professor, Division of Medical Oncology, University of Washington School of Medicine; Assistant Professor, Clinical Research Division, Fred Hutchinson Cancer Research Center
John F. DiPersio, MD, PhD
Professor, Department of Medicine, Oncology Division, Bone Marrow Transplantation & Leukemia and Stem Cell Biology, Washington University School of Medicine in St. Louis

As indications for allogeneic hematopoietic cell transplantation (HCT) and adoptive cellular therapies are expanding, more patients are benefiting from these approaches. However, clinicians are still confronted with two major challenges: disease relapse despite these therapies, and the toxicities that accompany them.

As part of this year’s Scientific Program, transplant and cellular immunotherapy specialists will present advances in the understanding of the basic biology of relapse and adverse events following cell therapies, as well as insights from clinical trials and patient samples about how to confront these challenges. Here, John F. DiPersio, MD, PhD, from Washington University School of Medicine in St. Louis, and Aude G. Chapuis, MD, from Fred Hutchinson Cancer Research Center in Seattle, preview the topics they will be discussing during the session, “Challenges in Cell Therapy: Relapse and Toxicities.”

Allogeneic HCT is the best chance for a “cure” for many patients with hematologic malignancies, but how often does relapse occur?

Dr. DiPersio: Unfortunately, relapse occurs frequently and, along with graft-versus-host disease (GVHD)–related complications, is a leading cause of allogeneic HCT failure. The patients who are at highest risk of relapse are those who come to transplant with either active disease or measurable residual disease (MRD). Other factors that increase risk of relapse have to do with the inherent biology of the disease, including certain chromosomal abnormalities and mutations.

What are the challenges in balancing sufficient graft-versus-leukemia effects against the potential for graft-versus-host effects?

Dr. DiPersio: There is a dogma in the field that GVHD is associated with a lower relapse incidence. But, looking at the data, the situation is more complicated. In a T-cell–depleted transplant, the relapse rate goes up, so T cells are important for clearing leukemic cells and preventing relapse. Having acute or chronic GVHD is not necessarily protective from relapse, but the benefit of adding T cells has been clearly established. This means that, in theory, we could modulate the graft-versus-host process without altering the graft-versus-leukemia effects by reducing severe GVHD to tolerable or negligible levels without changing relapse rates. However, this would need to be evaluated in prospective and retrospective studies.

What are the unanswered questions about the mechanisms of relapse?

Dr. DiPersio: The mechanisms of relapse after allogeneic transplant are incompletely understood. There are at least four, and the most common and impactful mechanism is the presence or absence of active or MRD-positive disease at the time of transplant. How frequently the other mechanisms occur or whether there are additional mechanisms by which patients relapse following transplant is not clear.

Dr. Chapuis: With T-cell receptor (TCR) therapy, we need to better understand whether relapse of disease under immunologic pressures is due to the infused T cells. The biology of T-cell therapy with transgenic TCRs is different from that of chimeric antigen receptor (CAR) T-cell therapy. The TCR is the natural receptor used by the immune system to survey cytoplasmic antigens; TCRs bind to peptide epitopes that are associated with major histocompatibility complex molecules. These antigens are processed inside the tumor cell, then presented on the surface for T cells to recognize.

The cornerstone of TCR therapy is to make sure that the target of the TCRs is a peptide that is actually present on the surface of tumor cells. Tumors, under pressure from the presence of the T cells, can undergo immunologic escape, either by down-regulating human leukocyte antigen or protein expression, or by changing how they process peptides internally, such that the tumor no longer presents the TCR target.

We have been exploring some of these mechanisms from the T-cell side, asking whether the infused T-cell product persists in the patient and whether it gets to its tumor cell targets, as well as whether the cells are proliferating well when they recognize their target.
There also are issues with the T cells themselves, which can become exhausted. We need to improve our ability to distinguish among these T-cell–based and tumor-based relapse mechanisms to inform the next iteration of the therapy for patients. TCR therapy has remarkable potential, both for solid tumors and for hematologic malignancies; the field is moving quickly and diligently to harness the potential of this modality.

Challenges in Cell Therapy: Relapse and Toxicities

Live Q&A: Saturday, December 5, 2020
9:30 a.m. – 10:15 a.m., Pacific time