Orca-T Shows Feasibility as a Reduced-Intensity Transplant Strategy in Hematologic Malignancies

Robert S. Negrin, MD

Early findings from a phase 1 study indicate that the high-precision cell therapy Orca-T is both a safe and feasible transplant strategy for patients with advanced hematologic malignancies undergoing reduced-intensity hematopoietic stem cell transplantation (HCT), according to Robert S. Negrin, MD. He added that further study of graft-vs-host-disease (GVHD)–free and relapse-free survival with Orca-T in large, multicenter studies is needed to validate these findings and expand the limited body of research on donor graft-engineered products in the reduced-intensity setting.

According to data presented at the 2023 ASH Annual Meeting, the use of Orca-T at a 1:1 ratio infusion of regulatory T cells and conventional T cells was shown to engender early and robust myeloid and T-cell engraftment in this patient population (n = 15). Furthermore, there was a low incidence of both acute GVHD (7%) and chronic GVHD (7%), and disease relapse was not reported in any patients, suggesting that graft-vs-Leukemia effect was not compromised. Regarding safety, the incidence of grade 2/3 infections (27%) in the first 90 days after transplant was comparable to that of using post-cyclophosphamide GVHD prophylaxis.

“This study highlighted that the [Orca-T] strategy is robust and allows us to theoretically treat most patients who go through a bone marrow transplant, hopefully with a reduced risk of GVHD,” said Negrin, who is a professor of medicine (blood and marrow transplantation), and former chief of the Division of Blood and Marrow Transplantation at Stanford University, in California.

In an interview with OncLive®, Negrin outlined the advantages of the Orca-T strategy for potentially mitigating GVHD while preserving the graft-vs-tumor effect in patients undergoing HCT, highlighted the product’s viability and potential to improve outcomes in hematologic malignancies based on preclinical and clinical data, and emphasized the necessity of confirming its efficacy vs current standard approaches to transplant through randomized trials.

OncLive: What is unique about the Orca-T strategy compared with other approaches to allogeneic transplant in hematologic malignancies?

Negrin: The Orca T approach goes back many years. What sets it apart is that it is a biologically based strategy that tries to reduce the major complication of allogeneic transplantation, namely the fact that the donor cells can react with the recipient and cause GVHD. In our field, we’ve recognized that GVHD has been a major limitation to the success of transplant. We and many other groups looked at animal models to try to understand the biology of GVHD and distinguish it from the major benefit of the transplant: that the donor cells can react with the patient’s cancer and exert a biological effect that cures their underlying disease. This strategy is one of many that are aimed at trying to reduce the risk of GVHD yet maintain the graft-vs-tumor response through more natural mechanisms in the immune system.

What preclinical and early clinical data led to the development of Orca-T and its subsequent investigation in patients undergoing reduced-intensity HCT?

It’s an interesting story that goes back over 20 years, to when a colleague and I established this concept of what we call bioluminescent imaging. The question was, when you transplant the cells into a recipient, in this case a preclinical animal model, what happens to the cells and where do they go? We developed a system where we put a light source into the cells from a firefly. The gene called luciferase was inserted into the T cells that induce this immune reaction. We saw that when the T cells enter the recipient, they immediately become activated and go through rapid expansion, eventually causing the symptoms that we call GVHD. That took several weeks [to develop], but it was really the events within days that were critical. What it represented to us was a dysregulated immune reaction.

When we explored various mechanisms of how the immune system is regulated and built upon work from Shimon Sakaguchi, MD, PhD, [a distinguished professor at Osaka University] in Japan, and Samuel Strober, MD, [a professor of immunology and rheumatology] at Stanford University, who were studying these suppressor cells or regulatory cells, what was observed was that these regulatory T cells can rebalance an immune reaction, sort of like what happens when we get sick. We get exposed to the flu, we get sick, and then we get better. In GVHD you don’t get better; it just keeps going and going. We did some studies in 2003, where we added not just conventional T cells, but also regulatory T cells. That paper highlighted that this strategy could have benefit. It took many years to move [the strategy] forward from preclinical models into the clinic. That’s where Orca comes into the story because they were able to develop the technology and turn an idea into a workable clinical strategy. They brought together resources and the ability to do this on a clinical scale; that was critical to move this concept forward.

The data look strong. The abstract presented at last year’s ASH Annual Meeting was on [Orca-T] with reduced-intensity transplants, which is one way we do transplants these days. There’s also a large, randomized trial that is comparing outcomes with Orca-T with a standard transplant in the ablative transplant setting and a more aggressive treatment setting. We’re excited about these results, but at the end of the day, it depends on how [these approaches] perform in a larger multi-institutional trial as compared with the current standard. That’s what’s ongoing, and we’ll wait with much anticipation for those results.

Please detail the design, methodology, and enrollment criteria used in the phase 1 study presented at the 2023 ASH Annual Meeting.

This trial presented at the meeting was built upon a prior trial, which explored whether this strategy would be effective in patients receiving high doses, or so-called myeloablative conditioning; that’s the standard approach to an allogeneic bone marrow transplant. However, many patients who are older or have other medical conditions can’t tolerate these very high doses of chemotherapy, so the strategy of reduced-intensity conditioning has been developed in our field. This has been a significant advance because it allows us to treat patients who are in their 60s, 70s, and sometimes even early 80s, which is where these diseases that can benefit from transplant are largely observed. However, GVHD is a persistent problem for these patients.

This study explored the use of Orca-T in reduced-intensity conditioning. There are some reasons why that may be more complicated, having to do with how T cells impact not only GVHD but also the potential for graft rejection. However, this study showed that the [use of Orca-T] in the reduced-intensity conditioning setting was feasible, as we had previously shown in the myeloablative conditioning setting. What we’ve observed is that many patients who go through this therapy go through it in a simpler way, they tend to have fewer problems, they tend to get out of the hospital faster, and have a more favorable experience.

Please describe the Orca-T strategy in greater detail. What are the steps of this procedure?

The [Orca-T] strategy [involves] the collection of cells from a donor from anywhere in North America. These cells are then shipped to a processing center, which is located in Sacramento, California. Then the cells go through the selection of 3 different populations: stem cells, regulatory cells, and conventional cells. All those products are shipped back to the center that’s performing the transplant, so it’s complicated. There’s a lot of logistical pieces that must work. What we observed in the preclinical model is that if you give the stem cells and regulatory cells [to patients] first, and then wait 48 hours before giving the conventional cells, the regulatory cells can expand in the recipient and are more effective. That strategy was taken forward in this and other trials done by Orca [Bio].

How are the results from this study significant for patients with advanced hematologic malignancies?

This study showed [that this approach] was feasible. There were no manufacturing failures, the patients received their cells, and the patients engrafted promptly. That’s a big question, because one of the benefits of more intensive conditioning is that it can enhance engraftment from the donor. If we reduce the intensity of conditioning and reduce the number of T cells, the worry was that we would see more graft rejection, but we did not see that. It was important to find that this [Orca-T approach] was feasible to do with relatively low toxicity risk. Patients went through the treatment reasonably well, [although] it’s an intensive treatment.

At the end of the day, what one needs to show is that not only do patients engraft and have low risk of GVHD, but that they also have reduced relapse risk. [To confirm that,] you have to follow patients for a longer period. What was not shown in this study yet is that the overall outcome remains positive. We just have to follow patients longer, treat more patients, and ultimately compare [their outcomes] with the standard approach. That’s what’s being done in a more intensive conditioning study. A precursor to this could be done in reduced-intensity conditioning, as well. This study was very important because it highlighted that the [Orca-T] strategy can be extended throughout the continuum of the way that we treat patients who will go through these treatments.

What could be done to potentially reduce the incidence of infections that were seen on this study?

First, it’s important to recognize that allogeneic bone marrow transplantation is risky. There’s inherent risk to going through this procedure, mainly due to the risk of infection. [This is] because we have to do something very unnatural: we actually have to immunosuppress the recipient so that they won’t reject the donor, and [ensure that] the donor has engrafted in the recipient. The infections that were observed were the typical types of infections that we see in bone marrow transplant recipients. We’ve made a lot of progress over the years in managing those infections, and that’s been a major advance in our field. We have much better antiviral, antifungal, and antibacterial drugs that allow us to manage these complications. However, one of the unmet needs in our field that the Orca strategy does not necessarily address is [figuring out] how to accelerate immune recovery to avoid some of these infections that our patients experience.

In this trial, the patients experienced some infections, but they were largely manageable. It is very difficult to tell from a small study like this if the infections are more or less than what you would typically see. That’s why randomized trials are critically important to compare Orca-T with a standard [approach] and [determine] whether the infections that we observe are more or less what we would typically observe with this type of treatment. Bone marrow transplantation is still complex and risky, but the infections that were observed were manageable, and most patients got through them.

What are the next steps for this research?

The next steps are clear. What we’ve established with these various studies is that this approach has merit. It’s technically feasible, patients get through it quite well, and the outcomes look good. All that must ultimately be validated in a phase 3 randomized trial. That’s the only way to say whether this [approach is] better than our current strategy. We have to conduct those studies, and they’re difficult to do. Patients don’t like to be randomly assigned [to treatment], as they like to choose what treatments they receive. These studies also take time, money, and effort. Orca [Bio] has sponsored an ongoing randomized phase 3 trial that is [using] the more standard, intensive conditioning approach to bone marrow transplantation. That trial is now being performed in many centers throughout the United States and North America. It will be the ultimate test of any therapy, including this one.

One of the challenges of randomized clinical trials is [figuring out] the comparison. [Identifying the standard for comparison] is something that our field struggles with. We chose to use a calcineurin inhibitor combined with methotrexate, which is a standard that’s been used for many decades. That’s what [the regimen in] this study is being compared with. One of the other real advantages of our field is that we collect data on what happens to our patients. It goes through a central repository called the Center for International Blood Marrow Transplant Research. That’s an enormous resource. We can now go back into that registry in addition to these randomized trials and do other analyses of the data that we obtained. That’s where we are right now. The trial is almost finished as far as enrollment, and then we have to follow patients for some time to see what their outcomes are. One of the questions is: What will happen to the risk of disease relapse? Will that be impacted either favorably, unfavorably, or not [at all] by this strategy? For better or worse, we must wait many months, sometimes a year or 2 before we can determine that the relapse risk has been altered. There’s no other strategy besides just following patients.

These studies take a long time and require a big commitment, a lot of resources, and many patients and their families to participate. I give Orca [Bio] a tremendous amount of credit for taking this concept forward, although I have no financial relationship, as I’m required through my conflict-of-interest requirements. We’re thankful that they moved this concept forward because many ideas sometimes stall if we just can’t get the resources or the support that’s needed to move them forward.

What is your take-home message for your colleagues regarding this study?

I appreciate all our colleagues who support these ideas. This idea is based upon a lot of underlying biology that goes back many years, and it’s taken a long time to move forward. We’re excited about trying to make progress in our field to the benefit of our patients. This requires a lot of collaboration amongst our colleagues, our partners in industry, and our patients and their families. It’s that network and the commitment to collecting data and asking critical questions in as unbiased a way as possible [that makes this research possible.] All those things are a sign of a robust field, so I’m proud to be part of this field that is setting many standards and moving the science forward. To me, that’s what’s most exciting.

Reference

Villar-Pradosi A, Sutherland K, Negrin RS, et al. Phase 1 trial results for patients with advanced hematologic malignancies undergoing reduced intensity allogeneic HCT with Orca-T donor cell therapy product and single agent tacrolimus. Blood. 2023;142(suppl 1):3560. doi:10.1182/blood-2023-188162