Updated Orca-T Data Continues to Show Reduced GVHD, Non-Relapse Mortality Rates in Hematologic Cancers

Caspian Oliai, MD

Treatment with Orca-T, a high-precision cell therapy, demonstrated a reduction in graft-vs-host disease (GVHD) and non-relapse mortality (NRM) rates, while also producing higher than expected graft-vs-leukemia and graft-vs-infection effects, in patients with hematologic cancers at more than 1 year of follow-up, according to updated findings presented at the 2022 ASH Annual Meeting.

Results, which comprised patients with acute myeloid leukemia (AML; n = 62), acute lymphocytic leukemia (ALL; n = 42), mixed phenotype acute leukemia (n = 4), chronic myeloid leukemia (CML) with prior blast crisis (n = 4), or high-risk myelodysplastic syndrome (n =15), showed that the benefits were upheld from previous findings with Orca-T.

Patients had received Orca-T either as part of a single-center phase 2 study (n = 32; NCT01660607) or a multicenter phase 1b study (n = 95; NCT04013685).

At a median follow-up of 413 days, the 1-year relapse-free survival (RFS) rate with Orca-T was 87% and the NRM rate was 0%. When stratified by minimal residual disease (MRD) status, the relapse free survival (RFS) rates in patients with MRD-negative acute leukemia, MRD-positive acute leukemia, and MDS was 93%, 68%, and 100%, respectively.

Additionally, the incidence of acute and chronic GVHD at 1 year was 1.5% and 5%. GVHD RFS (GRFS) was 81% and overall survival was 94%.

Investigators hope these data will be confirmed in the ongoing, phase 3 Orca Precision-T trial (NCT05316701), which compares Orca-T plus single-agent tacrolimus with standard unmanipulated allograft plus dual-agent prophylaxis with tacrolimus and methotrexate.

In an interview with OncLive^®, lead study author Caspian Oliai, MD, an assistant clinical professor of medicine at University of California, Los Angeles, discussed these data from the 2022 ASH Annual Meeting in more detail and the potential implications of the ongoing phase 3 trial.

OncLive^®: There are a couple of different treatment strategies being explored in GVHD. Could you discuss the recent data with each of them?

Oliai: The most compelling studies in allogeneic transplant that could potentially change clinical practice in the near future use 2 very different strategies; they make allogeneic transplant more tolerable while maintaining the curative intent.

The first is using Orca-T with myeloablative conditioning, and the other alternative strategy is using posttransplant cyclophosphamide, also with myeloablative conditioning.Orca-T is a cellular immunotherapy from an allogeneic donor that contains a highly purified polyclonal T-reg population that's infused on the same day as the hematopoietic stem cells, followed by conventional T cells, which are typically infused 2 days later. In general, the major difference in patients who receive Orca-T is that they only receive single-agent GVHD prophylaxis in the form of tacrolimus as compared with standard allogeneic HSCT that typically uses multiple agents.

The data presented at the 2022 ASH Annual Meeting reported on the efficacy outcomes of the phase 1b/2 trial. This complemented the data that I presented at the European Hematology Association Congress [EHA] in Vienna the previous summer, which demonstrated that Orca-T was associated with a large reduction in rates of GVHD. The efficacy outcomes at [ASH 2022] included 126 patients who had AML, ALL, or MDS who underwent a myeloablative allogeneic transplant using Orca-T, and it demonstrated an impressive relapse-free survival [rate] of approximately 80% in 1 year. Most importantly, patients who are in remission but had MRD positivity had a substantially better RFS rate of 71% as compared with the historical control, which was estimated by a [Center for International Blood and Marrow Transplant Research] cohort of 48%—so 71% vs 48% in patients who were MRD positive.

Orca-T was also well tolerated, with a 1-year non-relapse mortality [rate] of 0% in patients who received the most common conditioning regimen, which was myeloablative busulfan, fludarabine, and thiotepa. That excellent tolerability, also with low rates of GVHD, and promising efficacy, led to the FDA supporting a phase 3 trial that's currently accruing patients across the country.

If you compare that with the emerging alternative approach, which is to mitigate GVHD by adding posttransplant cyclophosphamide, there's a trial that was presented at the 2022 ASH Annual Meeting that can help put things into perspective. Results from a single-center, phase 2 trial use posttransplant cyclophosphamide in 125 patients, and those patients receive GVHD prophylaxis with posttransplant cyclophosphamide, tacrolimus, and mycophenolate.

Finally, this achieved the low rate of both acute GVHD, and also a low rate of chronic GVHD requiring treatment of only 4%. This 4% was basically the same rate as the GVHD rate in the Orca-T outcomes that I presented at EHA this past summer. The 2-year relapse rate on this single-center trial at ASH was 25%, and the non-relapse mortality rate was approximately 10%.

Overall, the outcomes of these 2 strategies are both very promising. The major difference though, is that the posttransplant cyclophosphamide uses multi-agent GVHD prophylaxis.

For example, in this trial at ASH that regimen uses triple-agent GVHD prophylaxis in comparison to the Orca-T approach, which uses single-agent GVHD prophylaxis with tacrolimus only. Based on the lower amount of immunosuppression used with Orca-T, I expect that the relapse rate and infectious complications rate may be lower with Orca-T, but we're going to have to wait until the phase 3 trial results come out to see if my assumption is true, and see if it's statistically significant.

If you have a patient who comes into clinic, what factors do you consider when determining which of these 2 treatment strategies to go for?

This is a question that hopefully the phase 3 trial will answer. Do you think that the patient is going to tolerate the addition of mycophenolate and cyclophosphamide to the [prophylaxis] regimen? Are [the patients] robust enough to tolerate those additional medications? That is the most important aspect. With Orca-T, we are seeing that even the single-agent tacrolimus trough is only 5 to 10. Most patients will be able to tolerate that. The question is: Can they tolerate the addition of 2 other agents? Because when you look at the outcomes [between the 2 regimens], they're similar. Is [more medication] something that can be tolerated?

Specific to Orca-T, what is unique about this agent's mechanism of action?

With Orca-T, the infusion of cells is separated into 3 distinct components in comparison to a standard allogeneic stem cell transplantation, in which you get an infusion of a cellular product all at once. When you separate out the conventional T cells, T regulatory cells, and hematopoietic stem cells, what you get is the T regulatory cells going to the sites of the solid organs first, so that by the time several days later, when the conventional T cells have the opportunity to get to the solid organ sites, they're already met with T regulatory cells.

This can potentially reduce them from doing any damage; it basically is a timing aspect. The T-regulatory infusion is a highly precise population—in the very high 90 percentile of polyclonal, highly purified, T regulatory cells. That is something that's able to be delivered consistently, and with a very high level of purity.

What else is there to note regarding the tolerability of Orca-T, and what is the optimal management of any related adverse events?

That is one of the most important questions of this; it has a lot to do with immune reconstitution. If we're able to show that immune reconstitution is similar to a standard allogeneic transplant, then we wouldn't expect a higher risk of infectious complications. However, we need both immune reconstitution data and infectious rates to make that determination. With the data presented at EHA this past summer and at ASH in December, it was suggested that the immune reconstitution is very good. As expected, the rates of severe infection are around 9%, which is what you would expect for a standard allogeneic transplant.

You mentioned the phase 3 trial with Orca-T. Could you discuss this study in more detail?

The phase 3 trial is currently up and running; it is enrolling in my center and many centers across the country. This includes patients who are between the ages of 18 and 65, who are candidates for myeloablative conditioning and, also have either an 8/8 match from either a sibling or an unrelated donor. These patients have to get myeloablative conditioning; the most common conditioning regimen is busulfan, fludarabine, and thiotepa regimen. For patients with lymphoblastic disease, it's total body irradiation and cyclophosphamide. We want to be able to show, in that specific population, is this strategy better than standard allogeneic transplant in patients who get the same conditioning regimen but GVHD prophylaxis with both tacrolimus and methotrexate, in comparison with Orca-T plus single-agent tacrolimus?

Could either of these treatment strategies potentially provide any kind of relief regarding cost burden to these patients?

It's such an important question. We're going to have to look at the finances on how both approaches pan out. If you compare it with standard allogeneic transplant, the reduction in cost that you can achieve with preventing GVHD is going to be far superior to saving money on a potentially logistical process that requires a cell product to be delivered. GVHD subsequently is associated with hospitalization, additional medications, and then the out-of-pocket expense for patients who have to pay for [multi-agent prophylaxis].

We expect that to offset the costs when you compare it with the emerging approach with posttransplant cyclophosphamide. Again, right now for the myeloablative patient population, we don't have good data for just double-agent prophylaxis. Right now, the data for triple-agent prophylaxis, you would assume that, that other outpatient cost might be something substantial when they have to pay for 2 expensive immunosuppressive medications.

Is there anything else about either treatment that is important to mention?

The logistics are going to be something that's going to be important to look at when you're dealing with a cell therapy product. You are going to have to have a delivery of an actual product, compared with administering a couple other medications. Obviously, there's a difference in logistics there.

However, it's important to take into consideration what future logistics look like. If there is a superior approach, or an approach that is not compared head-to-head yet, but if there's approach that looks like it could potentially benefit by reducing the rate of GVHD [and RFS], that's something that we need to prioritize as the most important, both for quality of life and long-term cost.

Reference

Oliai C, Hoeg RT, Pavlova A, et al. Precision-engineered cell therapy Orca-T demonstrates high relapse-free survival at 1 year while reducing graft-versus-host disease and toxicity. Blood. 2022;140(supp 1):654-656. doi:10.1182/blood-2022-165654