Orca-T Continues to Break New Ground in Hematologic Cancers

Samer Srour, MD

Orca-T, a cell therapy product that has demonstrated encouraging efficacy in patients with hematologic cancers as it relates to graft-vs-host disease (GVHD), relapse-free survival (RFS) and overall survival (OS) in phase 1/2 studies, has just opened a phase 3 randomized trial that is comparing the product with standard-of-care hematopoietic stem cell transplantation (HSCT).

The experiences with Orca-T from patients and investigators alike, has showcased the product’s improvement of patients’ quality of life, as well, according to Samer Srour, MD, who is a principle investigator on the multicenter, single-arm trial.

Most recently, updated results of Orca-T were presented at the 2022 Transplantation & Cellular Therapy (TCT) ASTCT and CIBMTR Tandem Meetings. The data, which included new findings from 137 patients with hematologic cancers, continued to show a significant reduction in acute and chronic GVHD compared with standard of care (SOC), without an increase in relapse or infections. Further results showed that there were positive outcomes in a subset of patients with myelofibrosis who received Orca-T, and additional analyses highlighted the reliability and scalability linked with the Orca-T manufacturing platform.

Orca-T is also expected to have data presented at the 2022 European Hematology Association (EHA) Congress in June.

In an interview with OncLive^®, Srour, who is also an assistant professor in the Department of Stem Cell Transplantation, in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed his experiences with the Orca-T and Orca-Q programs, and highlighted how this type of treatment is shifting the field of hematologic malignancies.

OncLive^®: How would you describe your overall experience with the Orca-T program?

Srour: My Orca-T experience started over 2 years ago. One of my mentors spoke to me over the phone that we are invited to be part of this study. He talked about the science behind it in maybe 1 or 2 minutes. When I listened to the brief scientific background, I told my mentor, ‘If there is a study, I want to open it in the allogeneic stem cell transplant setting for hematologic malignancies, this will be that kind of study.’ The most attractive part of the Orca studies, in my opinion, is the idea ‘to harmonize graft composition to improve outcomes, rather than taking a pharmacologic approach which frequently encompasses additional immunosuppression and toxicities and adds to the burden of the patients by taking extra medicines.’ This approach seems one of the best approaches toward safer transplants without compromising efficacy.

Finally, we started treating patients over a 1 year ago, and with the first patient we treated, the experience was just amazing compared with other ‘conventional’ transplants we do using the standard conditioning and graft platforms.

These patients in the Orca-T got the same chemotherapy just as any other transplant patient would get, but the composition of that Treg graft made a big difference; we treated these patients with a minimal amount of immunosuppression after transplant. We don't give methotrexate, cyclophosphamide, we don't give even [mycophenolate mofetil], we only give them single-agent tacrolimus. Within 9 or 10 days, you start seeing signs of engraftment. They get discharged from the hospital within 12 to 14 days, which is something that I'm not used to seeing in the transplant setting with the conventional or traditional way of doing the transplant. With most subsequent patients we treated, it just was the same exact good experience [as it was] with the first patient.

Since then, Orca-T has become a preferred way for me [to] treat patients with high-risk hematologic malignancies if [they] were eligible to [participate on] the study, because I can see a difference without compromising the efficacy of the transplant itself.

How does the Orca-Q program differ from that of Orca-T?

Orca-Q was the second Orca Bio study that was activated more recently at our institution. We have been collaborating very closely with Orca Bio, and given the great experience we have with the Orca-T study, we wanted to explore the Orca-Q. Regarding the graft composition, the Orca-Q is a bit different from the Orca-T. Although the Orca-T consists mainly of regulatory T-cells and conventional T cells in addition to the progenitor CD34 stem cells, the Orca-Q is more of a proprietary mix of donor cells in which high-dose T memory cells are targeted to enhance antitumor activity and antiinfection activity.

From a clinical standpoint, the goal of Orca-Q is to improve outcomes of patients who receive their transplants from mismatched and haploidentical donors [compared to matched donors in the Orca-T]. Patients with mismatched transplants are known to have worse outcomes and higher risk of complications compared [with] matched transplants.

What can you share about how the patient experience has been with these products? What adverse events are they experiencing and how are they being managed?

As an investigator on these studies, when I bring up [these trials] to discuss with my patients, although the overall intent from the transplant is cure, I tell my patients, ‘I'm not really presenting this study for you to improve your cure rates. If you have a 70% chance to be living at 1 or 2 years, I'm not presenting this study to make it 80% although this is possible. However, my first goal is improving your QOL without compromising the cure rate. As such, even if you have same 70% chance of survival, you will have much safer transplant with less complications, etc.’

Therefore, this is really what attracted me the most about this study: an excellent quality of life without compromising efficacy. Almost every patient, by 3 or 4 weeks after transplant, they are just close to getting back to normal. Maybe in 40 or 50 days, they are pretty much feeling normal. I do have a lot of patients ask me about going back to work even before day 60.

Rarely, we see severe GVHD cases (≤ 5% each for severe cases acute and chronic GVHD), serious infections or recurrent hospital admissions when compared with conventional transplants. Most of the encountered adverse effects are manageable with low risk of non-relapse mortality (4% at 1 year).

Is there anything that you find important to note about the manufacturing or reliability of Orca-T as a product?

One of the concerns when we opened this study was how to figure out the logistics and getting a fresh and highly purified graft with a goal to deliver the cells to our patients within 48-72 hours from stem cell collection. At the 2021 ASH Annual Meeting, we presented updated data about Orca-T. Orca Bio has indeed successfully manufactured and delivered grafts for all treated patients. The reliability was so high with no manufacture failures, all grafts were delivered within the 72-hour window (all were within <60). From my personal experience at my institution, it was the same pleasant experience and the Orca-T graft consisted of high Treg purity and adequate Treg dose.

What other data with Orca-T demonstrate its impact on the field of hematologic cancers?

I would like to highlight again the [data presented at the 2021 ASH Annual Meeting]. The study included 80 patients with high-risk hematological malignancies who received the Orca-T graft, up to age 65 and all received myeloablative conditioning. Patients were compared to a control group of 95 patients who received SOC transplant at Stanford University (unmanipulated grafts with methotrexate and tacrolimus GVHD prophylaxis). This study showed significant improvement in transplant outcomes in favor for the Orca-T. If you look at the primary end points of GVHD, we saw 17% grade ≥2 acute GVHD in the Orca-T (only 5% with ≥3) compared with 33% on the standard-of-care arm (20% with ≥3) and significantly less moderate to severe chronic GHVD (4% in the Orca-T vs 42% in the SOC arm).

Then, when we look at the combined GVHD-free and relapse-free survival (GRFS) end point, a frequent important end point we look at in more recent years, the 1-year GRFS was only 34% in the standard-of-care arm compared with 76% on the Orca-T arm. This is a huge difference. We are talking about 76% of the patients at 1 year who don't have GVHD in a severe form, and they don't have relapse, meaning survived and with an excellent quality of life. This is again, what attracts me more to these types of studies.

Then, the survival rate was also numerically better at 91% in the Orca-T compared to 78% for SOC arm. There was a recent update of the data at the 2022 TCT meeting with larger sample size for patients who received the Orca-T graft (n=101) and the results were overall consistent confirming better GVHD and GRFS rates compared to SOC arm. We are also updating data with a larger sample size and will be presented at the 2022 EHA Congress in June.

Where do you see Orca-T going in the future?

Orca-T has previously received Regenerative Medicine Advanced Therapy designation from the FDA, and Orca Bio is now conducting a large phase III randomized clinical trial in patients with acute leukemias and myelodysplastic syndromes comparing Orca-T with single agent tacrolimus to SOC transplant with dual agent GVHD-based prophylaxis. That's really what we need to confirm the very encouraging results we have seen in the prospective phase I/II studies. Pivotal phase 3 clinical trials will give us the confirmatory answer whether this is superior in terms of GVHD, GRFS, as well as relapse and OS. Based on the data from the phase I/II studies and assuming these results will hold true with longer follow up, I think the Orca-T might be a new standard or preferred approach for our patients in the coming few years.

References

1. Hoeg RT, Pavlova A, Gandhi A, et al. Orca-T results in high GVHD-Free and Relapse-Free Survival following myeloablative conditioning for hematological malignancies: results of a single center phase 2 and a multicenter phase 1b study. Blood. 2021;138(suppl 1):98. doi:10.1182/blood-2021-15491
2. Orca Bio presents positive data reinforcing clinical profile and manufacturing reliability of Orca-T at 2022 Transplantation & Cellular Therapy ASTCT and CIBMTR Tandem Meetings. News release. Orca Bio. April 25, 2022. Accessed May 10, 2022. https://bwnews.pr/3wjo4mF