Orca-T Offers an Alternative to HSCT With Improved Patient Experience

Mehrdad Abedi, MD

Advances in the treatment of patients with leukemias and lymphomas have led to a significant improvement in survival, which has increased the need for bone marrow transplant as a later-line therapy, said Mehrdad Abedi, MD, who added that Orca-T, a high precision cell therapy, confers significant antitumor activity, minimizes the incidence of acute and chronic graft-vs-host disease (GVHD), and causes less adverse effects (AEs) compared with standard bone marrow transplant among these patients.

“There is a lot of research [ongoing]; the ‘holy grail’ of research is trying to figure out whether we can separate the graft-vs-leukemia or graft-vs-lymphoma effect from GVHD,” said Abedi. “[The Orca-T trial] is basically looking at the past 10 years of research in this area to try to identify the cells that are good from those that are bad.”

During the 2021 Transplantation and Cellular Therapy (TCT) Meetings, findings from an analysis of 2 studies demonstrated a significant reduction in cases of GVHD, a higher GVHD relapse-free survival rate, and a lack of treatment-related mortalities with Orca-T when historically compared with hematopoietic stem cell transplant (HSCT).

Additionally, the median time to neutrophil engraftment, median time to platelet engraftment, and median time from day 0 to hospital discharge was shortened with Orca-T compared with HSCT.

In an interview with OncLive^® during the 2021 TCT Meetings, Abedi, a professor of cancer, hematology/oncology, and internal medicine in the Department of Internal Medicine, Division of Hematology and Oncology at the UC Davis Comprehensive Cancer Center, discussed the challenges of standard transplant, how Orca-T could overcome some of those limitations, and the potential future of transplant in hematologic malignancies.

OncLive^®: What are some of the limitations of standard hemopoietic stem cell transplant in patients with hematologic malignancies?

Abedi: HSCT has been around for more than 50 years in one form or another. It has been used mostly for patients with blood cancers, [such as] leukemia and lymphoma. Allogeneic bone marrow transplants, where we use cells from a donor, are very effective. [They are associated with] a very high response rate for patients who have no other options and whose disease is going to [recur] without transplant.

The problem [with allogeneic bone marrow transplant] is that it [is associated with] AEs. When we give donor cells to patients after high-dose chemotherapy, [which is given] so that the patient’s body doesn’t reject [the cells], even though the cells are a match for the patient, they can still [develop] severe GVHD.

The acute form of GVHD can be life threatening, whereas the chronic form can become a nuisance for the rest of a patient’s life. A lot of patients suffer [from GVHD] to the point where they regret going through transplant. Fortunately, that is not everybody, but it is still a problem that needs to be solved and an unmet need for the field.

This research has been focused on [the question of]: Are there specific cells in the graft we give to the patient’s immune cells that can cause GVHD? Can we separate those cells from those that are responsible for causing graft-vs-leukemia effects?

How was Orca-T designed to prevent acute and chronic GVHD, and how did UC Davis get involved with evaluating the product?

Basically, Orca Bio approached UC Davis a few years ago to [start] collaborative research with our Good Manufacturing Practice [GMP] facility and to produce these products.

Each graft of [the Orca-T] product has stem cells and immune cells in it. The stem cells are what we need to maintain the graft and [allow the product to] stay in the patient for a long time. The immune cells are the ones that can cause graft-vs-leukemia [effects], which is what we want.

From the work that Robert Negrin, [MD] at Stanford University and many other investigators [did], it is very clear that there is a population of T cells called T-regulatory cells that can prevent GVHD. There are other populations, such as the naïve T cells or conventional T cells that can cause GVHD. It looks like a smaller number of [those cells] may actually be helpful; they can cause graft-vs-leukemia, but not GVHD.

The graft is basically designed so that we can give stem cells, but they get rid of a lot of conventional T cells that can cause rapid GVHD. [The graft provides] a small amount of conventional T cells that can cause graft-vs-leukemia effects, as well as the regulatory T cells that can prevent GVHD. UC Davis got involved [with this work] because we have a very robust GMP facility. We helped Orca Bio design these protocols and manufacture the cells. Now, [Orca Bio] has moved on to their own facility. I have been involved [with this research] for the past few years.

How is Orca-T tolerated among patients compared with standard transplant? Have any quality-of-life (QOL) data read out with this approach?

[We] haven’t looked at the QOL data, but there have been several short-term and long-term benefits so far that we have seen.

We give high-dose chemotherapy that can get rid of all [the patient’s] stem cells and leukemia or lymphoma cells. Then, we give the graft; however, after the graft is given, it takes a couple of weeks usually to engraft [before] new cells [develop]. In between, the patients are sick because of the effects of the chemotherapy; patients also have low blood counts.

[With Orca-T] we have seen that the engrafting [occurs] a little bit earlier. For everyday [sooner] the engraftment [occurs], there is less risk of complication and suffering for the patient. That has been a major difference [with Orca-T].

Also, we have noticed that patients in general are doing better [with Orca-T compared with traditional transplant]. When we give high-dose chemotherapy, it is the same whether the patient is on a clinical trial or not. They may still get sick [with Orca-T] because of the effects of chemotherapy.

However, there is also inflammation [that can occur] as the donor cells are trying to establish themselves in the body because some of them attack the body. That inflammation also adds to the problems with chemotherapy. We haven’t seen that inflammation [with Orca-T]. We have seen some effects from the chemotherapy, but because we don’t have the inflammation, other AEs that we see with the standard of care aren’t seen with Orca-T.

In general, patients do better [with Orca-T vs standard of care], and that has been a universal experience with all of our patients who have gone through the trial so far.

[Patients] just look and feel better. When they are discharged, they are not as sick compared with patients [receiving] the standard of care.

Are patients receiving Orca-T required to receive immunosuppressive agents as well?

With the standard of care, after we give the graft, we have to give patients a new medication to prevent GVHD because it is such a lethal problem. If we don’t put patients on immunosuppressive medications to prevent GVHD, there is a very high chance that they get and die from GVHD. Those immunosuppressive medications are critical.

The way the Orca-T graft is designed is that we don’t need as many of those [immunosuppressive] medications. For example, there is a medication called methotrexate that we give on days 1, 3, 6, and 11 after [standard] transplant. That medication can cause a lot of other AEs, such as mouth sores, delayed engraftment, and kidney [problems], that can make the patient miserable. With Orca-T, we don’t have to [give methotrexate], which by itself is a huge improvement.

We do give immunosuppressive medications, such as tacrolimus [Envarsus XR] or sirolimus [Rapamune] to these patients, but we don’t give 2 or 3 medications as we usually do with the standard of care. Less immunosuppressive medications mean probably less infection, but more importantly, less AEs. That’s [a factor that has made] a big difference in patient experience.

What does the future of HSCT look like in your opinion?

That is a very loaded question. There are a lot of new drugs coming, some of which are very targeted to treat leukemia or lymphoma. Thus far, we haven’t seen any curative [benefit] with those drugs, so in most situations, we will still need an allogeneic stem cell transplant for patients.

The exceptions [to that] were rare diseases, such as chronic myeloid leukemia [CML], where [an oral medication was approved] and we don’t need to transplant patients. That is an example of a targeted treatment that may exclude [the need to] transplant patients. That would be great because transplant is not a trivial procedure and it has a lot of AEs.

However, [CML] is a very specific disease with 1 gene that causes the disease. In most leukemias and lymphomas, multiple genes are involved, so we don’t think single-target treatments will get rid of the disease. We still think that allogeneic transplant will be around for a long time.

In fact, if you look at any center in the country, the volume of transplant has substantially increased over time because patients are living longer. Patients end up being able to go to a transplant vs before when many were dying in the middle of their treatment and not getting to transplant.

That being said, there are 2 directions [we can go in]. One is to try to decrease the AEs associated with transplant. This [Orca-T cell therapy] is very effective [in doing this] by targeting the graft-vs-leukemia effect and preventing GVHD. The second direction is to use these allogeneic cells to specifically target the tumor cells. That is why gene modifications, CAR T-cell therapies, and other approaches are coming. They still use allogeneic cells from a donor, but now they are directing them to specifically go after tumor cells.

Reference

1. Meyer EH, Hoeg R, Moroz A, et al. Orca-T, a precision Treg-engineered donor product, in myeloablative HLA-matched transplantation prevents acute gvhd with less immunosuppression in an early multicenter experience. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 88. https://tct.confex.com/tct/2021/meetingapp.cgi/Paper/17670.