Vice President of ASH Will Focus on Gene Therapies, ASH’s Global Impact

Robert S. Negrin, MD

Concepts that originated from basic research have kept the hematology field on its toes as they turn into significant advancements, and promising new therapies to treat malignancies and graft-vshost disease (GVHD) continue to emerge. The high-precision cell therapy Orca-T is one that has surfaced in clinical trials for patients who received allogeneic hematopoietic stem cell transplant (HSCT), as is axatilimab, which stood out at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition as a potential future option for patients with GVHD.

“It’s extraordinary to see the breadth of scientific inquiry and how that is now impacting patients,” Robert S. Negrin, MD, vice president of ASH and a professor of medicine at Stanford University in California, said in an interview with OncologyLive. “My own research endeavors are interesting. Some of the work that we did in murine models 20 years ago, we’ve [just] published the first papers on.”

Negrin explained that he’s excited about further development of gene therapy applications. When considering all that has been learned about sickle cell disease—ranging from etiology to the discovery that enhancing fetal hemoglobin can help correct it—the therapies developed from these concepts are nothing short of amazing to Negrin. “It is incredible stuff,” he said.

A New Agent for GVHD in Development

Exciting endeavors investigators are exploring include those focused on the treatment of patients with GVHD. Because chronic GVHD significantly impacts quality of life and is a main cause of late morbidity in approximately 30% to 50% of patients, there is a need for well-tolerated, efficacious treatments. Data on the CSF-1R targeted investigational monoclonal antibody axatilimab presented at 2023 ASH demonstrated promise as patients receiving the agent at 0.3 mg/kg every 2 weeks had durable and rapid responses.¹

Findings from the phase 2 AGAVE-201 trial (NCT04710576) revealed that patients experienced an overall response rate of 74% (95% CI, 63%-83%) in the 0.3 mg/ kg every 2 weeks cohort (n = 80), 67% (95% CI, 55%-77%) at 1.0 mg/kg every 2 weeks (n = 81), and 50% (95% CI, 39%-61%) in the 3.0-mg/ kg every-4-weeks cohort (n = 80). Additionally, 60% (95% CI, 43%-74%) of patients maintained a response for at least 12 months in the 0.3-mg/kg cohort.

“Axatilimab is a new drug to treat chronic GVHD that’s being developed. It came from basic research to now clinical application, and hopefully a drug approval [will occur]. We will see how we use cellular-based therapeutics to improve outcomes for our patients who are undergoing transplant— [that] is an area of extraordinary growth with lots of activity right now,” Negrin said.

Findings from the safety population of the 0.3-mg/kg cohort (n = 79) revealed that the most common any-grade adverse events (AEs) associated with axatilimab treatment were fatigue (22.8%), headache (19.0%), and COVID- 19 (16.5%), and 17.7% of patients experienced at least 1 grade 3 or higher AE. One patient in the 0.3-mg/kg cohort, 7 patients in the 1.0-mg/kg cohort, and 6 patients in the 3.0-mg/kg cohort (n = 79) died from an AE. Notably, rates of periorbital edema were 2.5% vs 23.5% vs 29.1%, respectively. The rates of laboratory abnormalities were also lower in the 0.3-mg/kg arm, and the most common events included increased levels of aspartate aminotransferase (13.9%), lactate dehydrogenase (13.9%), alanine aminotransferase (12.7%), creatine phosphokinase (11.4%), lipase (11.4%), and amylase (3.8%).¹

“Our field is extraordinarily rich,” Negrin said of the findings presented at 2023 ASH. “What’s most extraordinary to me is that it’s no longer just the laboratory-based scientists and the clinicians working in parallel universes—now these 2 worlds have come together in truly profound ways.”

High-Precision Cell Therapy Gains Traction

Orca-T has also sparked promise with previous data from a phase 1/2 trial (NCT01660607) demonstrating that the high-precision cell therapy produced a 100% overall survival rate in 8 patients with hematologic malignancies who received an allogeneic HSCT with 7/8 nonpermissive human leukocyte antigen mismatched donors.²

“This concept of using a ‘precision graft’ instead of just isolating cells from the donor, but now purifying different cell populations that may bring out some of the positive impacts of an allogeneic transplant, [can] limit some of the challenges like GVHD and perhaps improve immune recovery,” Negrin said.

Investigators who presented data at 2023 ASH on Orca-T noted that there’s an opportunity to improve clinical outcomes from allogeneic HSCT; as current transplants are an uncontrolled mix of more than 50 cell types typically administered together in a single infusion, cellular selection may allow for greater benefit.³

Orca-T therapy has 3 separate components: hematopoietic stem cells infused on day 0, highly purified regulatory T cells given in a separate infusion on day 0, and conventional T cells infused on day plus 2 (Figure).

Presenting author Caspian Oliai, MD, MS, medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center at UCLA Health in Los Angeles, California, said, “This separation allows for the regulatory T cells to travel to the solid organs first so that by the time the conventional T cells arrive, an immune barrier is in place that can potentially mitigate GVHD while maintaining an optimal graft vs leukemia effect through natural immune reconstitution. This has been demonstrated preclinically.”³

Negrin noted, “To me, this Orca-T trial represents a combined effort to try to move these concepts forward from promising preclinical studies to initial studies in patients and now, finally, a phase 3 registration trial. I hope the trial is successful, but it represents a little bit more than just the success of that individual product. [It represents] this cooperative reliance of academia and pharmaceutical companies that is critical to move concepts forward to the success and benefit of our patients.”

The phase 3 Precision-T trial (NCT05316701) is currently enrolling approximately 174 patients with advanced hematologic malignancies undergoing allogeneic HSCT to receive Orca-T or standard-of-care allogeneic graft.⁴

Negrin Looks to Leave a Global Mark on ASH

With the conclusion of 2023 ASH, Negrin has assumed his 1-year role as vice president; his terms as president-elect and president will follow. A member of ASH since 1998, Negrin was the chief of the Division of Blood and Marrow Transplantation at Stanford University from 2000 to 2020 and was founding editor in chief of the peer-reviewed journal Blood Advances from 2016 to 2021.^5,6

“I’ve been involved with ASH for several decades now so I’m excited and incredibly honored to be able to take on a leadership role,” Negrin said. “I’m particularly interested in ASH’s international role. How do we more effectively utilize the success that ASH has achieved in being the leading voice in the field of hematology to impact our more global community? How do we utilize the science that is being developed to [usher in] new therapies and do whatever we can to make sure they’re available to our patients, especially those in greatest need and who are most vulnerable? That’s an area that we have a lot of work to do in.”

One of several ASH programs designed for hematologists practicing outside of the US, Mexico, and Canada is the Translational Research Training in Hematology joint program with the European Hematology Association; the yearlong training and mentoring experience is for junior researchers.⁷

Additionally, regarding research in the transplant field, Negrin noted he’s interested in ways to “solve or make inroads on challenges and extend transplant into other areas. There’s a lot of work being done, for example, to treat [diseases] other than hematologic malignancies such as autoimmune disorders or induction of solid organ tolerance as we learn how to manage the complications of transplant,” Negrin said.

He noted that funding is an area he also hopes to home in on during these next few years with ASH. “The funding environment that we’re in is still very challenging not only for academic researchers but also for investment in a lot of these concepts,” Negrin noted.

"I’ve seen several companies that have very successful ideas [and are] not able to find funding, so I hope that we’ll be able to advocate for improved financial support, not only for academia but also for the development of these concepts,” he said. “Ultimately, how do we export them to our patients? How do we meet the patients in greatest need from the most challenging environments, both in our country and abroad? How do we provide these benefits to those individuals as well? [These] are areas that are incredibly important and areas that I hope to work on in my roles in the ASH leadership.”

References

1. Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). Blood. 2023;142(suppl 1):1. doi:10.1182/blood-2023-186963
2. Pavlova A, Lowsky R, Muffly LS, 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 ASTCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 30.
3. Oliai CH, Pantin JM, Hoeg RT, et al. Optimizing outcomes with myeloablative conditioning in older patients: efficacy and safety of precision engineered Orca-T in patients > 55 years old with hematologic malignancies. Blood. 2023;142(suppl 1):230. doi:10.1182/blood-2023-186749
4. Precision-T: a randomized phase III study of Orca-T in recipients undergoing allogeneic transplantation for hematologic malignancies (Orca-T). ClinicalTrials.gov. Updated September 26, 2023. Accessed December 20, 2023. bit.ly/3RFmGFQ
5. New leadership elected to the American Society of Hematology. News release. American Society of Hematology. October 26, 2023. Accessed December 20, 2023. bit.ly/3RRcafN
6. Robert Negrin. Stanford Medicine CAP Profiles. Stanford Medicine. Accessed December 20, 2023. bit.ly/48pp6Px
7. Global initiatives. American Society of Hematology. Accessed December 20, 2023. bit.ly/3GTNHjA