Everett Meyer, MD, PhD, Associate Professor, Division of Blood and Marrow Transplantation, Stanford University, California, discusses the combined results of a single center phase 2 and a multicenter phase 1b study on how Orca-T, an investigational cell therapy, led to high graft-versus-host-disease (GVHD)-free and relapse-free survival following myeloablative conditioning for hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), lymphoma, or myelofibrosis (MF). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

My name is Everett Meyer. I'm an associate professor at Stanford University in the division of Blood and Marrow Transplantation.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

(In) the early 2000s, a number of investigators showed in preclinical models that enriching T regulatory cells (TRegs) and donor grafts could prevent GVHD. One of these investigators was Robert Negrin, our former Chief at Stanford and my collaborator. Based on this key-initiated translation at Stanford, which I then picked up in 2015.

OLN: Please briefly describe your study and its findings.

The study is a combined result of a phase 2 single-center trial—the phase would be multicenter trial—testing the idea of enriching TRegs in a donor graft, and also giving a time infusion of the graft where the stem cells are given with the TReg of day 0. The Tregs create an immune environment to help the donor T-cells then come into day 2.

The idea was to see if this approach would reduce the incidence of acute (aGVHD) and chronic (cGVHD) GVHD, which it appears to have done.

In general, we saw that the incidence of aGVHD grade 3 or 4 dropped considerably from a control cohort or from the literature by about 75%. Also, interestingly, the incidence of cGVHD, which can affect the long-term survival and quality of life for transplant survivors.

The cGVHD also looked like it was reduced by about 80% compared to a standard of care control cohort or just the literature. The control cohort was not randomized just to try to get a sense on the phase 2 trial of how we're doing. In general, when treating the patients, it did feel like it was an easier course for most of them.

OLN: Were any of the outcomes particularly surprising?

One of the things we do in the clinical trial is we use the Tregs with single-agent tacrolimus. In general, on standard care, we use tacrolimus and methotrexate. We were able to eliminate the methotrexate, which is a nasty drug to give after transplantation. Early after transplantation, many of the patients didn't have a lot of the side effects of the methotrexate—bad mucositis, nausea, other issues. That was nice to see with the trial participants.

OLN: What are the possible real-world applications of these findings in clinical practice?

What's very exciting about these studies is the idea that was generated by Dr Negrin at Stanford preclinically was translated to the clinic at a single center. That's always where you worry, "OK, is this just special sauce from a single center?"

The multicenter data now recapitulated across the United States shows the approach appears scalable. In addition, our partnership with the company that's doing the manufacturing also shows that an idea that could be started could be scaled. In terms of affordability, it's possible this could be provided to more patients in the future.

There is a phase 3 trial plan, and so that's also very exciting because it means that preliminarily the FDA has looked and said, "This is interesting enough to consider moving forward."

OLN: Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

Not only do we look forward to a phase 3 trial, but also, we're testing the approach in different transplant settings, for example, by reducing the intensity of conditioning going from fully what's known as model ablative to reduced-intensity conditioning where there are many patients who could be served is one area.

Also, thinking about TRegs as a living drug platform and how we might modify the T reg cells in the future to improve their efficacy or for specific sub indications.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

It's been a lot of fun to work with colleagues across the country, and push forward something that looks like it's helping patients.