Novel Treatments Give Hope for a Transformed Transplant Community

Lori Muffly, MD

Improvements in graft-vs-host disease (GVHD) and transplant-related mortality have created a wave of hope for clinicians treating their patients with hematologic malignancies, stemming from the encouraging data seen with Orca-T and other novel therapeutics in the pipeline.

For example, at the 2023 Transplantation and Cellular Therapy Meetings, data from a single-center phase 2 trial showed that Orca-T, which is a high precision cell therapy, produced a 100% overall survival rate in 8 patients with acute leukemia, myeloproliferative neoplasms, chronic myeloid leukemia, and other hematologic cancers who underwent an allogeneic hematopoietic stem cell transplant with 7/8 non-permissive haploidentical mismatched donors.¹

The immune reconstitution of Orca-T in 100 patients from an ongoing, multicenter phase 1b trial (NCT04013685) was also examined in findings presented at the 2022 ASH Annual Meeting. Investigators performed longitudinal measurements of immune reconstitution, showcasing the peripheral blood counts of platelets, white blood cells, neutrophils, lymphocytes, monocytes, T cells, B cells, and natural killer (NK) cells. Results showed that patients on Orca-T exhibited early immune reconstitution in each of the key leukocyte and lymphocyte subsets believed to manage relapse and infection.² Researchers also observed elevated Treg frequencies. Overall, these immune reconstitution data may be correlated to the reduced occurrence and severity of acute and chronic GVHD.

In an interview with OncLive^®, Lori Muffly, MD, an associate professor of medicine at Stanford University, discussed the updated findings with Orca-T in hematologic malignancies, spoke to the product's immune reconstitution profile, and the next steps she hopes to see taken with this type of treatment and others in the pipeline.

OncLive: Orca-T has been an agent to watch for over the last few years. Updated findings were presented at the 2022 ASH Annual Meeting, as well as some at the 2023 Transplantation and Cellular Therapy Meetings. Could you highlight the topline data reported at both meetings?

Muffly: We are really excited about Orca-T in the transplant community. The data have been presented a few times now from the single-center phase 2 and multicenter phase 1b studies . In the matched setting, which has been presented multiple times, what has been shown is low rates of both acute and chronic GVHD, and incredibly low rates of transplant-related mortality.

For someone like me, who treats patients with typically adverse risk of acute leukemia, I think the most exciting part is seeing that the relapse rates appear to be not increased in any way compared with our historical tacrolimus/methotrexate GVHD prophylaxis. That is very exciting because having overall survival rates that are phenomenal, low relapse rates, and then particularly low GVHD and transplant-related mortality rates, is exactly what we're looking for in the field of transplant.

There were some immune reconstitution data with Orca-T that were presented at the 2022 ASH Annual Meeting. What were the key takeaways from that?

One of the other nice things about the Orca-T platform, which is really a reduced T-cell dose, along with an administration of regulatory T cells, is that the infection rates are quite low, relative to historical control. One of the problems with more of a traditional T-cell depleted graft, either ex vivo or in vivo, is higher rates of infection, particularly viral infections. We have not seen that with Orca-T.

At this past year's ASH Annual Meeting, there was a poster demonstrating in about 90 patients, at least with day 28 data, and then around 50 patients with 1 year of follow-up, the immune cell subset reconstitution. What we could see is that these patients reconstituted B cells, T cells, regulatory T cells and NK cells by 1 year, quite effectively. That probably has something to do with why we're seeing lower rates of infection than as predicted in a T-cell deplete graft.

Putting it into context for the practicing clinician, why is immune reconstitution important and how do we use it to guide treatment decisions for patients?

With transplant, there are so many different factors that we think about—of course, a focus on the disease itself that we're transplanting for. For example, if a patient has acute myeloid leukemia, trying to get a transplant that has the most potential for graft vs leukemia is important. We think about GVHD, because that is the adverse flip side of graft vs leukemia and identifying mechanisms of transplant that are associated with lower GVHD is important.

Then finally, the ability of the new graft to protect patients from infection and particularly opportunistic infection and viral reactivations [are what we think about]. Any 1 of those 3 components that's missing is a big problem for our patients. If you have a transplant approach that really can take care of all 3 [components], that is really the holy grail of transplant: low relapse, low GVHD, and low infection.

Taking these data into context, what next steps would you like to see taken with this type of therapy?

I am really excited about the possibilities with Orca-T. Currently, as you probably know, there is a randomized phase 3 study, a registration trial, ongoing comparing Orca-T with historical control tacrolimus and methotrexate [and alloHSCT]. We have been very actively participating in that study. Obviously, we are hopeful to see the results and that this may lead to commercialization of this product.

We're also really excited about Orca-T in the mismatched myeloablative setting. There was an oral abstract at the [2023 Transplantation and Cellular Therapy Meetings] presented with just under 10 patients with mismatched, unrelated donors. Those data look exciting, as well. There is a lot of opportunity for this program in the clinical space.

Now, the other thing that's happening in the transplant community, which is very difficult to miss, is the evolution and uptake of posttransplant cyclophosphamide as GVHD prevention. We are really blessed right now that we have 2 exciting approaches going on at the same time: posttransplant cyclophosphamide and Orca-T. The field eventually will want to look at the 2 of them side by side, because they both seem to lead to low GVHD rates without an increase in disease relapse. As someone who offers these treatments to my patients, I have never been more excited about what we have going on in this field. I look forward to future studies as well.

Is there anything else that you think would be important for the practicing oncologist to know about these or any other therapies in the pipeline?

It is important for the practicing oncologist to know that as our therapeutics for blood cancers are improving, so are our approaches to bone marrow transplant. I no longer think about transplant-related mortalities of 20% to 30% when I'm talking to patients, and that's how things started, at least when I started. I'm now hopeful that that sort of topline number is going to be more like a 5% risk [as more options become available]. While that's still too high, it's at least a bit more acceptable.

Also, the likelihood of developing GVHD with these newer approaches has substantially gone down. That is important for referring physicians to know because the darker days, scarier days, of transplant are behind us. This is a therapeutic that has curative potential for many, many adults out there. Many patients just are not referred. These data are important to get out there so that people in the community can realize transplant data are looking different than they used to look.

References

1. Pavlova A, Lowsky R, Muffly L, et al. Orca-T, a high-precision cell therapy, for the treatment of hematologic malignancies in patients with 7/8 mismatch donors. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 30.
2. Meyer EH, Killian MS, Pavlova A, et al. Rapid immune reconstitution and elevated regulatory T cell frequencies in patients treated with Orca-T. Blood. 2022;140(suppl 1):7656-7657. doi:10.1182/blood-2022-164468