Orca-T Reduces GVHD, Improves GVHD-Free RFS in Posttransplant Setting Across Hematologic Cancers

Arpita Gandhi, MD

The impressive clinical activity demonstrated with Orca-T, a high-precision allogeneic cellular therapy, has been mirrored in both single-institution and multicenter trials, highlighting the void that this type of treatment could fill for patients with hematologic cancers in the posttransplant setting.

In data presented at the 2021 ASH Annual Meeting, Orca-T graft was found to significantly improve graft-vs-host disease (GVHD)–free relapse-free survival (GRFS) when compared with patients treated with standard-of-care grafts at Stanford University with serious hematologic malignancies.¹

The data were seen in both a single-center phase 2 trial (NCT04013685) and a multicenter phase 1b trial (NCT01660607).

“I think it is remarkable and worth noting that the data remains generally equal, despite after the study going to a multicenter design,” study author Arpita Gandhi, MD, an assistant professor in the Division of Hematology Oncology at Oregon Health & Science University (OHSU), said in an interview with OncLive^®.

In the interview, Gandhi discussed the background of Orca-T in further detail and how this type of treatment could revolutionize outcomes for patients with serious hematologic malignancies.

OncLive^®: Could you please share some of the background of Orca-T? Why could this high precision allogeneic cellular therapy fill an unmet need for patients with hematologic cancers?

Gandhi: As transplanters, we struggle on a daily basis to find this fine balance that we're looking for in post–allogeneic stem cell transplant outcomes, between GVHD and graft-vs-leukemia or graft-vs-disease. Different graft manipulation techniques and prophylactic medications have been evaluated or are in ongoing clinical trials.

This one really hits the point with reduction in GVHD for a couple of reasons. One, it significantly reduces acute GVHD—which is often debilitating for our patients in the long run—without increasing relapse and an acceptable relapse free survival of 73% at 1 year.

Orca-T graft is a highly purified, high-precision, cell therapy product. You are taking freshly collected donor cells, peripheral blood stem cells, that [go through a manufacturing process]. This trial uses a single-agent immunosuppressive therapy with tacrolimus, skipping our standard combination of tacrolimus and methotrexate for GVHD prophylaxis. Omitting methotrexate results in less mucositis, potentially contributing to earlier engraftment and overall less complications in the posttransplant setting.

The GVHD reduction is significant for Orca-T recipients. When you look at the data and at the graphs presented by Everett Meyer, MD, at the 2021 ASH Annual Meeting, you can clearly see a big difference in Orca-T recipients and Stanford’s standard-of-care patients when comparing the GVHD-free RFS for these patients. The big picture is that the GVHD incidence was reduced in Orca-T recipients; relapse did not increase or it remained consistent with what one would expect in standard-of-care transplants. These patients had comparable, or maybe even improved, immune reconstitution based on the low incidence of high-grade infections noted in these patients.

Let's expand on some of the details you previously mentioned about Orca-T. What data presented prior to the 2021 ASH Annual Meeting demonstrated the promise of this agent in this patient population?

Dr Everett Meyer, Dr Robert Negrin, and others at Stanford University Medical Center have published [in the Journal of Clinical Oncology in 2019] in the initial trial that was conducted, which included about 12 patients with high-risk hematologic malignancies, some with relapsed/refractory disease and some with active disease. This is when they showed that the fresh product was better when compared to the cryo-preserved product after cell selection. This was then expanded to a large, single-institution trial. I was a fellow at Stanford when I had the opportunity to be a part of taking care of these patients, later to lead the trial as a site principal investigator at OHSU for the multicenter trial. The level at which we have expanded the knowledge of the Orca-T graft from a single-institution trial to a multicenter trial, allowing a novel graft manipulation method of GVHD prevention to go from single institution to a large multi-institutional trial, and therefore making it more accessible to patients, has been really, really remarkable. It is truly impressive.

What is very important is when you do single-center trial, and then expand to multicenter trial, you want to see equivalent results. That is exactly what we are seeing with Orca-T graft, going from a Phase 2 single-institution trial at Stanford University to a Phase 1b multicenter trial.

What is most interesting to note from the patient's baseline characteristics that were enrolled on the studies?

This study is designed for patients who are eligible for myeloablative transplant to include patients with myeloid and lymphoid malignancies, specifically acute leukemias [including those who have not achieved a complete remission], myelodysplastic syndrome, and myelofibrosis. This is just to give you an idea of the high-risk patient population that was included in the multicenter trial.

Based on my personal experiences and the data presented at the 2021 ASH Annual Meeting, what is really interesting and also important in patient care is that our patients receiving Orca-T graft are not getting the toxicities that we generally see in patients who are getting methotrexate as part of their standard-of-care regimen. Right off the bat posttransplant, there is less mucositis and people are generally tolerating Orca-T quite well.

As far as engraftment goes, engraftment is occurring somewhat faster, as noted by Dr Meyer in his presentation. I have also seen a reduced number of days of hospitalization. All in all, I think patients are tolerating this well; engraftment was achieved rapidly and their performance status is good. At day +30, day +60, and day +100, people are returning to work (virtually) because they feel good. From a transplant-physician standpoint, there is nothing more gratifying then to know that our patients are actually going back to life. That is telling of the [reduction in] GVHD and [improvement] in relapse-free survival.

What else is there to note about the clinical activity with Orca-T?

There are other methods of preventing GVHD, which may achieve that goal but they may potentially carry a risk for increase in relapse, especially for patients who are going through transplant with active disease status. In this case, RFS at 1 year was acceptable in the range of approximately 73% on the multicenter trial, which is quite good. Future publications and more data at [future meetings] will be telling when we compare [these data with] larger datasets with [Center for International Blood and Marrow Transplant Research], and the planned randomized study will be critical for its true efficacy in preventing posttransplant relapse, while reducing GVHD, so that will be important.

What are some next steps with Orca-T that you think might be important to mention?

I look forward to future studies with Orca-T graft for mismatched and reduced intensity stem cell transplants. Something else I'm really looking forward to for Orca-T data in the future is going to be its cost effectiveness. There is a lot of cost attached with the diagnosis of GVHD. One is the cost of medications, 2 is the hospitalizations, 3 is the poor quality of life, and some patients may never return to work, resulting in economic burden to families and our society. It will be really good to look at cost analysis of standard-of-care transplant vs Orca-T transplants. That's something I really look forward to at future meetings.

Reference

Hoeg RT, Pavlova A, Gandhi A, et al. Orca-T results in high GVHD-Free and Relapse-Free Survival following myeloablative conditioning for hematological malignancies: results of a single center phase 2 and a multicenter phase 1b study. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 98.