Orca-Q Demonstrates Encouraging GRFS, Tolerability, and Low GVHD Incidence in Hematologic Cancers

Amandeep Salhotra, MD

Orca-Q, a next-generation investigational cell therapy, showed reduced rates of acute and chronic graft-vs-host disease (GVHD) and improvements in GVHD relapse-free survival (GRFS) with single-agent tacrolimus, without the use of posttransplant cyclophosphamide (PTCy) or mycophenolate mofetil, in patients undergoing haploidentical allogeneic hematopoietic stem cell transplantation (HSCT).¹

The findings, which were from the haploidentical arm of a 3-arm, phase 1 trial (NCT03802695) presented at the 2022 ASH Annual Meeting, showed that the 1-year GRFS rate was 75% with Orca-Q. In comparison, this rate was 46% in patients who underwent allogeneic HSCT with PTCy.²

“If you can get a haploidentical graft in without the use of cyclophosphamide, that would be a great thing,” lead study author Amandeep Salhotra, MD, said in an interview with OncLive^®. “This study has shown that this can be done successfully. You can get a haploidentical graft and get normal engraftment and eliminate posttransplant cyclophosphamide.”

In the interview, Salhotra, an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, provided insight on the data with Orca-Q shared during the meeting.

OncLive^®: The Orca-T data presented a couple of years ago were very interesting. Now, we have results on Orca-Q, which demonstrated favorable GVHD and RFS in haploidentical transplants without posttransplant cyclophosphamide. Could you provide some background on this product? What are the differences between Orca-T and Orca-Q?

Salhotra: We are one of the lead centers for this multicenter clinical trial, which is sponsored by Orca Bio. There are 2 products made by this company. One is called Orca-T, and the phase 1/2 data look good. Now, [the product is] being studied in a randomized [trial] of standard of care vs Orca-T. That study is ongoing, and we are participating in that. That product essentially is a regulatory T [T-reg], conventional T [T-con] kind of approach where after receiving a myeloablative transplant, patients receive a dose of CD34-positive cells—more than 3 million cells per kilo—in combination with T-reg cells. Two or 3 days later, they get an infusion of T-con cells.

Typically, in a stem cell transplant, the dose of T cells is higher than the total nucleated cell dose, but on the T-con dose, they reduce the dose to around 3 million cells per kilo. There is a 2-log reduction in the conventional T cells. Therefore, the strategy of giving the CD34-positive stem cells with regulatory T cells and giving a lower dose of conventional T cells a couple of doses later has been effective in terms of controlling disease and controlling GVHD. Additionally, the fact that the T regs are given prior to conventional T cells gives them 2 to 3 days to expand and inhibit the unreactive T cells.

The precursor to this study was a BMT CTN study, which was a 3-arm, calcineurin-free inhibitor study between standard methotrexate, posttransplant cyclophosphamide, and CD34-selected graft.Patients who got a pure CD34-selected graft tended to have less GVHD, but they had more non-relapse mortality, so it’s a decrease in the survival of those patients. Although the 1-year GRFS was equivalent, the overall survival was a little bit lower. Clearly, CD34-selected graft is not the answer because of the non-relapse mortality. That [sums up the background and rationale to develop Orca-T].

The Orca-Q product is fundamentally different from Orca-T, and it’s somewhat of a proprietary product. I cannot disclose exactly what the components are, but essentially, they deplete certain T-cell subsets from the graft. Therefore, these are naïve T cells, which are depleted and then some T-cell subsets are added back. This has helped in terms of reduction of the acute and chronic GVHD, while preventing the relapses from occurring. The Orca-Q trial has 3 arms: one is for the matched donor arm, then there’s a haploidentical arm, and an arm in which no [prophylaxis is given]. At the 2022 ASH Annual Meeting, data were reported on the haploidentical arm of the study.

Please expand on the patient population that is being evaluated on this trial.

We reported on outcomes of 26 patients on the study. These patients must receive a myeloablative conditioning therapy. The median age of the patients was 46 years or so; however, patients up to the age of 65 years are allowed to enroll on the study. The majority of these 26 patients were all in complete remission. There were 3 patients who had minimal residual disease [MRD]–positive disease, and most of the patients had either acute myeloid leukemia [AML] or acute lymphoblastic leukemia [ALL]; I think 15 patients had ALL and 9 had AML. We had 2 patients with chronic myeloid leukemia and blast crisis.

We use the Disease Risk Index [DRI] to stratify how aggressive the disease is, and most of the patients had an intermediate DRI. That was the baseline demographics of these patients, and in terms of the myeloablative conditioning regimen, there was the combination of busulfan and fludarabine.

Here, at City of Hope, we use radiation-based conditioning regimens, so we have used total body irradiation and VP-16, or a cyclophosphamide-based conditioning regimen. Tacrolimus is also allowed to help facilitate engraftment.

Is this considered a difficult-to-treat population?

In terms of the patient population, it’s pretty standard for those patients who go onto stem cell transplant. The only point I’ll make is, with myeloablative conditioning, how we’ve been able to do a haploidentical stem cell transplant is by using posttransplant cyclophosphamide, which is a good approach to get the graft to facilitate engraftment and hematopoiesis and eliminate leukemia. However, with myeloablative conditioning, adding a high dose of cyclophosphamide posttransplant gets a little bit challenging. Patients have longer hospital stays. There are [also] concerns with enriching cystitis, BK virus, mucositis, recovery from heavy doses of chemotherapy, and cardiotoxicity. These are certainly things that we worry about with high doses of cyclophosphamide.

Any transplant study would have this mix of patients, although I would say that we do not have any active disease patients. For this phase 1 study, we tended to be a little bit conservative. However, I think as the study matures, perhaps active disease patients could be included.

Something that has been emphasized with Orca-T is its manufacturing process, and how the treatment helps to alleviate the cost burden that many patients face posttransplant. Is there a similar benefit with Orca-Q?

Typically, we identify patients during the workup process who are eligible for myeloablative therapy. If they have a haploidentical matched donor, we must [consider] both the donor and the recipient. They go through apheresis, and the apheresis product is very similar to what we will do for a normal donor. What happens is the product is shipped from our site to the Orca Bio manufacturing site. Being in the same state [of California] helps a bit, so the timelines are a little bit compressed for us.

Typically, most of our grafts have been manufactured with 1 day of release collection. You want to ensure that the donor mobilizes well, that they have a good, preferably CD34, counts. We collect as close to 10 million cells as we can, ship the product over, and then within 24 hours or so the product is back here. Of 19 or 20 patients that we have treated on both Orca Bio studies, we have never had any instance where the graft could not be manufactured, or there was a failure, or the patient could not get the graft within 72 hours. That has been very reassuring that if you enroll the patient, we know that the graft is going to be made and the patient will get it.

In terms of cost saving and such, if you do a myeloablative transplant with the haploidentical donor, [data from the Center for International Blood and Marrow Transplant Research] suggest that the incidence of chronic moderate to severe GVHD would be anywhere between 30% and 40% or so. These patients will develop chronic GVHD; studies have shown that they have poor quality of life [QOL]. Fortunately, we have medications available to treat patients with GVHD. The 3 approved medications are ruxolitinib [Jakafi], belumosudil, and ibrutinib [Imbruvica] was the first one that was approved. However, all 3 drugs come with adverse effects and there is a cost associated with use of these medications.

Therefore, if you can avoid an increased incidence of chronic GVHD, and patients do not need to be on immunosuppression posttransplant, then that up-front investment in that cost and getting a better graft may be justified. That’s how I would think about it, although you probably spend a little bit more money up front in terms of generating the graft at the back end. Patients have good QOL, you’re not seeing them that often, and you’re avoiding these TKI therapies; that’s the cost-benefit analysis that health economists would have to do. From a patient standpoint, it’s a bit of transplant experience for them to get to the transplant much easier; the engraftment is quick. You do not see a lot of acute GVHD. All in all, it’s a better way to do a stem cell transplant.

What is important to highlight from the efficacy data from this study?

In this study, there were 2 patients who had engraftment failures, and 1 of them we were able to salvage with a subsequent transplant. Before the other patient could get to a second transplant, he unfortunately developed a fungal pneumonia and passed away. It’s important to point out, but for the remaining patients, the engraftment for neutrophils was around 12 days, and platelet engraftment was around 16 days.

The other important thing I touched upon a little bit was cytokine release syndrome [CRS]. Sometimes that can be a big problem post infusion, where patients can have fevers, [so they get] antibiotics, more workup, sometimes fluid resuscitation, intensive care units transfers, and such. However, greater than grade 2 CRS was very infrequently seen, and most patients can be managed with antidiuretic medications, such as Tylenol.

The next thing was the acute and chronic GVHD rates. [The rate of] grade 2 or higher acute GVHD was around 8% or so, and [the rate of] grade 3/4 acute GVHD was less than 5%. The way this graft is manufactured, because it does have depletion of specific T-cell subsets, a few patients do develop GVHD. There’s no PTCy; there is just a single-agent prophylaxis with tacrolimus. For patients who do develop some GVHD, typically a 3- to 5- day course of systemic steroids is able to take care of those acute GVHD rates.

Importantly, and surprisingly, with the median duration of follow-up of approximately 200 days, and 9 patients with more than 1 year of follow-up, there are no patients with moderate to severe chronic GVHD. That is impressive. It’s a composite outcome of many patients who have absence of chronic GVHD, and who are in remission 1 year posttransplant. In this case, [the GRFS rate is] around 75% of patients who were enrolled.

When they look at [the GRFS rate] comparatively with [myeloablative therapy with cyclophosphamide posttransplant], it is around 45%; therefore, you get a 30% bump in the composite outcome. That is because this type of graft is effective in terms of reducing acute and chronic GVHD, and relapse rates are not any higher than what you typically see with other graft types. We see an improvement in this composite outcome.

Since we are eliminating PTCy, [severe] infection rates were around 20% or so. Therefore, the non-relapse mortality due to infections with GVHD is low, so that helps patients, as well. Eliminating the PTCy is an important way to think about the benefit of this graft.

Following these data, what are the next steps for Orca-Q?

These were the data on the haploidentical arm, and this is a 3-arm study. We are anxiously awaiting data on the match-donor setting. The match related and unrelated donor [arm] has around 30 or so patients, so hopefully those data will be presented at upcoming meetings. Then, finally, there is an arm which is immunosuppression free, so patients get their match related or unrelated donor, and that has no posttransplant immunosuppression.

I’ve put a few patients on this study. I have been very impressed by how good the graft is and how effective it is in terms of preventing GVHD, but again, that’s anecdotal, and we need to look at the aggregated data. Looking forward, data on the matched donor arm and the immunosuppression-free arm are going to be important, and 1-, 2- and 3-year follow-up data on the haploidentical arm are also going to be important.

Looking ahead, how could Orca-Q and Orca-T complement one another in the field of hematologic cancers?

The inclusion criteria so far are for patients in complete remission. However, it will be important to see how patients with active disease or those who cannot get into remission with current available regimens, would deal with this type of graft. There is the fact that you’re able to get the graft in with minimal immunosuppression. The disease-free survival in those patients with active disease, or MRD-positive disease, may be slightly better than what we have traditionally seen.

At our own center, we have an interest in intensified conditioning regimens, where we use higher doses of radiation through a technique called total lymph node irradiation. With that, you can go to higher doses in the bone marrow. If you could escalate radiation in those active disease patients, follow it up with an Orca-Q or Orca-T graft, and see how those active disease patients do, that is going to be important.

At the 2022 ASH Annual Meeting, there were some data in the late-breaking abstract on the ETAL3-ASAP trial [NCT02461537], which looked at patients with active AML going onto transplant, with or without disease control. They showed good responses. However, maybe substituting this type of graft may also be a way to kind of improve on what German investigators had found out in their study.

Disclosures: Dr. Salhotra has received support from Bristol Myers Squibb and consultancy for Sanofi Kadmon.

References

1. Salhotra A, Srour SA, Hoeg RT, et al. Orca-Q demonstrates favorable GvHD-and-relapse-free survival in haploidentical transplants without post-transplant cyclophosphamide. Blood. 2022;140(supp 1):1865-1866. doi:10.1182/blood-2022-170459
2. Sanz J, Galimard J-E, Labopin M, et al. Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT. J Hematol Oncol. 2021;14(1):84. doi:10.1186/s13045-021-01094-2