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Immunotherapy's Growing Impact on the Treatment of Hematologic Malignancies

Nalley, Catlin

doi: 10.1097/01.COT.0000549543.89788.0b
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Immunotherapy has revolutionized the field of oncology and continues to gain momentum. With ongoing research and a number of promising therapies, this approach has shifted how oncologists treat a variety of solid tumors.

How has the growth of immunologic therapies impacted the world of hematologic malignancies? Those working in this field have actually been utilizing one of the oldest forms of cancer immunotherapy for decades, allogeneic hematopoietic stem cell transplantation (HCT), which continues to help shape the treatment approaches in this patient population.

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Stem Cell Transplantation

Since its conception, utilization of allogeneic HCT continues to increase with widening clinical indications and the use of alternative donors, according to Im, et al (J Hematol Oncol 2017; doi:10.1186/s13045-017-0453-8). Additionally, overall survival after stem cell transplantation has seen significant improvement.

“Allogeneic HCT has provided a model of immunotherapy in hematologic malignancies, offering invaluable information that can be used as the field moves forward. For example, we have learned about the sensitivity of hematologic malignancies to the ‘graft-versus-leukemia’ or ‘graft-versus-tumor’ effect, and thus, we know these are appropriate targets for immunotherapy” (J Hematol Oncol 2017; doi:10.1186/s13045-017-0453-8).

Building upon the success of allogeneic HCT, researchers continue to seek out new ways to enhance its benefits while overcoming associated challenges. For instance, a recent study, led by Benjamin Vincent, MD, and Paul Armistead, MD, PhD, both members of University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, lays the groundwork for the development of immune-based treatments tailored to individual leukemia patients who are undergoing stem cell transplantation (Blood Adv 2018;2(16):2052-2062).

“A key problem in transplant and in affecting cures from transplants is: how do you maximize the graft-versus-leukemia effect without causing graft-versus-host disease (GVHD),” noted Vincent, Assistant Professor in the UNC School of Medicine Division of Hematology/Oncology. “Decoupling the graft-versus-leukemia effect from GVHD is critical.”

In an effort to combat this issue, the researchers conducted a retrospective analysis that included 101 myeloid leukemia patients who had undergone stem cell transplant. “To discover the minor histocompatibility antigens that are present in any donor recipient pair in the context of allogeneic stem cell transplant, we first used genetic analysis along with gene expression analysis of donors, recipients, and leukemias,” Vincent explained. “We developed a computational method to predict which antigens would be expressed by the leukemias, but not expressed by the normal, healthy cells that would otherwise be targets of GVHD.”

The team then tested whether their software could predict antigenic targets in the cohort of leukemia patients who had undergone stem cell transplant. “Using our software package we were able to predict 102 new minor histocompatibility antigens that could be good immunotherapy targets,” said Vincent. “Next, we picked one [minor histocompatibility antigen] and conducted detailed biological studies to confirm that it is presented by leukemia cells and patients who received allogeneic stem cell transplant could mount immune response to that particular antigen.”

This research is an important step in efforts to maximize the impact of stem cell transplantation among patients with hematologic malignancies. Moving forward, Vincent and his team plan to repeat the process for additional antigens. “The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”

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CAR T-Cell Therapy

In recent years, one of the most significant immunotherapy advances has been the development of CAR T-cell therapy; the tremendous potential of this approach was first demonstrated in patients with hematologic malignancies. “[CAR T-cell therapy] had its first curative successes with acute lymphoblastic leukemia (ALL) and that has spurred a revolution in therapy for this disease,” noted Vincent.

Tisagenlecleucel was the first CAR T-cell therapy approved by the FDA in 2017 for patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. The safety and efficacy were demonstrated in a multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83 percent.

“We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, MD, at the time of approval. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”

The same year, another CAR T-cell therapy, axicabtagene ciloleucel, was approved for adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

And the momentum of this innovative approach continues today. In May 2018, the approval of tisagenlecleucel was expanded to include the treatment of adult patients with relapsed or refractory DLBCL as well as high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

The success of CAR T-cell therapies has sparked a plethora of new research to optimize this approach, including efforts to better understand and combat negative side effects, specifically severe cytokine release syndrome (CRS), which usually occurs within days of T-cell infusion.

In an effort to improve therapeutic and preventative treatments, Giavridis, et al, sought a better understanding of CRS (Nat Med 2018;24(6):731-738). In the recent study, researchers reported “a murine model of CRS that develops within 2-3 days of CAR T-cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. [They] show that its severity is mediated not by CAR T-cell-derived cytokines, but by IL-6, IL-1, and nitric oxide produced by recipient macrophages, which enables new therapeutic interventions.”

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Immune Checkpoint Inhibitors

While immune checkpoint inhibitors have shown to be effective in a number of solid tumors, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, the same level of success has not be seen in hematologic malignancies and requires further study.

“The major advance in immunotherapy over the past 10 years has been the rise of immune checkpoint inhibition with drugs that target CTLA-4 or the PD-1 axis,” Vincent explained. “Those drugs have had less documented activity in hematologic malignancies with the exception of PD-1 blockade in Hodgkin lymphoma, where it has been very successful.”

Significant responses have been seen for pembrolizumab and nivolumab in Hodgkin lymphoma. Two single-arm, multicenter trials in adults with classical Hodgkin lymphoma led to the FDA approval of nivolumab for the treatment of relapsed/refractory Hodgkin lymphoma after autologous stem cell transplant and brentuximab.

Evidence supports the responsiveness of Hodgkin lymphoma to immune checkpoint blockade and studies in this area are ongoing to determine ideal combination approaches and timing of immunotherapeutic agents for these patients.

Why have other hematologic malignancies not seen the same response? “[These diseases] often have a lower number of mutations and lower degree of overall immune reactivity against the tumor at baseline compared to tumors such as melanoma or lung cancer, so immune checkpoint inhibition may be less effective,” Vincent noted. “They are not ineffective and as a field we need to understand how to use those agents for hematologic malignancies.

“However, in the world of cell therapy the great advances have actually been made in hematological malignancies and I think will continue to be over the next 5-10 years,” he concluded.

Catlin Nalley is associate editor.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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