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JCO Spotlight on Advances, Limitations of Immunotherapy for Hematologic Malignancies

Mar 09, 2021

By Geraldine Carroll, ASCO Publishing

Remarkable advances in recent years in pharmacologic and cellular approaches that can potentially deliver effective antitumor immune responses for patients with hematologic malignancies are highlighted in a Special Series published in the Journal of Clinical Oncology. The series, “Immunotherapy for Hematologic Malignancies,” explores themes including improving allogeneic stem cell transplantation through increased donor availability and innovative transplant technology, novel cellular therapies such as chimeric antibody receptor T cell (CAR-T), the application of checkpoint inhibition, and other insights into the impact of distinct immunotherapeutic strategies in disease specific settings.

The development and refinement of CAR-T cell therapy has shown great promise for immunotherapy in hematologic malignancies. The series provides an update on the outcomes of CAR-T and addresses the management of toxicities as well as new CAR-T strategies. Like other novel therapies and agents explored in the innovative series, it was crucial that the data be sufficiently mature.

“We believe that now is the right time to publish this series because we have certain treatments like bispecific antibody treatments and CAR-T treatments that are sufficiently mature, so we can really start to see where they are fitting in the treatment paradigm,” said Jonathan Friedberg, MD, MMSC, co-editor of the Special Series and editor-in-chief designate of JCO.

In the series, O’Neill and Chakraverty1 highlight the central role that allogeneic stem cell transplantation currently plays in the management of hematologic malignancies, and complications caused by graft-versus-host disease (GVHD), which is still a major cause of transplant-related toxicity.

The Emergence of Donor Registries

Holtan et al2 explore the recent expansion in potential stem cell sources through the development of adult unrelated donor registries, resulting in the registration of more than 30 million volunteers as potential unrelated donors. They cite the emergence of allelic typing of major histocompatibility which has led to an effective donor selection algorithm and improvements in transplant outcomes.

Dr. Friedberg noted that the improvement in donor options will help accelerate progress across the field.

“It’s remarkable to me… I don’t do a tremendous amount of transplant anymore, but I covered around Thanksgiving, and about half of the patients on the floor were either getting a haploidentical transplant or a core blood transplant, and those are alternative donor sources that just didn’t exist a few years ago,” Dr. Friedberg said. “I think what we need to do is leverage these types of experiences in international registries, and that will only accelerate the progress in those diseases.”

Cytokine release syndrome and neurologic toxicity continue to be limitations of CAR-T cell therapy targeting CD19, and Reagan and Neepalu3 provide a summary on pathophysiology and expert management advice on how to deal with these toxicities, including the use of novel cytokine-directed therapies.

New CAR-T Cell Approaches

Looking at new CAR-T cell approaches, Grover and Heslop4,5 look beyond CD19 by including new antigens such as CD30 and the Epstein-Barr virus, respectively.

“I will just say that in my own practice, for example, I will look for a CD30 CAR as a treatment for refractory Hodgkin lymphoma if I am confronted with that in the context of a clinical trial, just because of the promise of these treatments,” Dr. Friedberg said.

The emergence of checkpoint blockade has transformed the management of multiple solid tumors, and Ansell6 evaluates the evolving role of checkpoint blockade across several B-cell lymphoma types.  

Dr. Friedberg noted that although checkpoint blockade is most active in Hodgkin lymphoma compared to any other cancer, many in the field think of melanoma or lung cancer in this context, but the response rates to single-agent therapy are far higher for Hodgkin lymphoma than any other cancer.

“We know that there is a genetic underpinning to that,” Dr. Friedberg said. “What has been disappointing is the fact that checkpoint blockade as a single agent has really not been particularly active in non-Hodgkin lymphoma like follicular lymphoma, despite immune responses to other treatments.”

He added that this still opens the door to combinations such as checkpoint blockade and CAR-T cell therapy to see if there may be a way forward with those drugs.

Clinical trial reform is addressed in the final manuscript by Devine and Horowitz7 who established the U.S. Bone and Marrow Clinical Trials Network. The manuscript describes an innovative model of how to reform the clinical trial infrastructure to accelerate the assessment of novel hematopoietic cell transplantation strategies, which could potentially impact the future assessment of novel immunotherapeutic agents.

Dr. Friedberg hopes that oncologists caring for patients who are in the scenarios described in this series will try to seek out a clinical trial involving some of these highly promising agents if these agents are not yet approved.

References

  1. O’Neill AT, Chakraverty R. Graft-versus-leukemia: Current status and future perspectives. J Clin Oncol. Epub Jan 12 2021. doi:10.1200/JCO.20.01801.
  2. Holtan SG, Versluis J, Weisdorf DJ, et al. Optimizing donor choice and GVDH prophylaxis in allogenic hematopoietic cell transplantation. J Clin Oncol. Epub Jan 12 2021. doi: 10.1200/JCO.20.01771.
  3. Reagan PM, Neelapu SS. How I manage: Pathophysiology and management of toxicity of chimeric antigen receptor T-cell therapies. J Clin Oncol. Epub Jan 12 2021. doi:10.1200/JCO.20.01616.
  4. Grover NS, Tschernia N, Dotti G, et al. Extending the promise of chimeric antigen receptor T-cell therapy beyond targeting CD191 tumors. J Clin Oncol. Epub Jan 12 2021. doi: 10.1200/JCO.20.01738.
  5. Heslop HE, Sharma S, Rooney CM. Adoptive T-cell therapy for Epstein-Barr virus–related lymphomas. J Clin Oncol. Epub Jan 12 2021. doi:10.1200/JCO.20.01709.
  6. Ansell SM. Checkpoint blockade in lymphoma. J Clin Oncol. Epub Jan 12 2021. doi:10.1200/JCO.20.01522.
  7. Devine SM, Horowitz MM. Building a fit for purpose clinical trials infrastructure to accelerate the assessment of novel hematopoietic cell transplantation strategies and cellular immunotherapies. J Clin Oncol. Epub Jan 12 2021. doi:10.1200/JCO.20.01623.

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