Researchers at John Theurer Cancer Center First in US to Initiate Groundbreaking New Studies

Published Online: Thursday, Aug 31, 2017

Two related trials that may greatly expand the role of immunotherapy in hematologic malignancies are being led by researchers at one of the most active hematopoietic stem cell transplant (HSCT) centers in the United States—the John Theurer Cancer Center at Hackensack University Medical Center, which is part of Hackensack Meridian Health.

The trials are testing the hypothesis that combined checkpoint inhibitors administered after HSCT will prevent or substantially reduce the risk for relapse in several blood and bone marrow malignancies. “To our knowledge, we are the first to initiate a formal trial to evaluate combined immunotherapy in combination with stem cell transplant in hematologic cancers, to prevent relapse” reported Andrew L. Pecora, MD, Chief Innovations Officer, who is principal investigator of one of the trials and a co-investigator of the other. Dr. Pecora is also a professor of medicine and oncology at Georgetown University.

“If we can demonstrate safety and efficacy from this approach, it will be an important therapeutic advance for patients, and it will move the field forward,” Dr. Pecora said. Investigators at the Georgetown Lombardi Comprehensive Cancer Center, in Washington, D.C., are also participating in both studies.

Though early, the studies are potentially groundbreaking because they are pursuing a strategy that tries to consolidate the already substantial benefits of HSCT. Hematopoietic transplantation, which follows destruction of malignant cells with chemotherapy and radiation, can be curative in some patients with hematologic malignancies. In other patients, the engraftment of nonmalignant cells to reconstitute normal blood and marrow function provides an extended disease-free remission before an eventual relapse. These relapses are thought to occur as a result of small numbers of residual cancer cells that eventually multiply.

Engaging the immune system early on in the stem cell transplant process to recognize and attack these residual cancer cells is exceptionally promising. Several approaches are possible, but both of these studies will evaluate combined checkpoint inhibitors, which are monoclonal antibodies targeting signals that block the activity of effector T cell lymphocytes, which routinely kill malignant cells in a functioning immune system.

“We already have evidence that those patients with an early recovery of lymphocytes after HSCT have a better long-term outcome, but we have had no way of increasing the likelihood of this recovery,” Dr. Pecora explained. With early introduction of combined checkpoint inhibitors, which are already licensed for use in several solid tumors, such as melanoma and lung cancer, the anticancer function of the immune system can be boosted, an activity that may be more feasible when the tumor burden is still low.

One important aspect of the design of both studies is that two different checkpoint inhibitors will be evaluated. In both studies, they will be combined. Ipilimumab (Yervoy, Bristol-Myers Squibb) is an inhibitor of the CTLA-4 checkpoint, and nivolumab (Opdivo, Bristol-Myers Squibb) inhibits the PD-1 checkpoint. There are modest but potentially important differences in how inhibition of these checkpoints affects immune function, which will be explored in these studies. When combined, there is a potential for additive or even synergistic benefits. One reason is that following HSCT, which generates an inflammatory response, the activity of the effector T immune cells that attack the tumor can be impaired by suppressor cell activity.

“There is some research to support the premise that early inhibition of CTLA-4 and PD-1 will skew the immune response away from tolerance to greater activity of effector T cells,” Dr. Pecora reported.

Autologous and Allogeneic Approaches

The specific studies, CPIT001a and CPIT002,b have several important distinctions. CPIT001 is evaluating combined checkpoint inhibitors after an autologous HSCT in patients with recurrent or relapsed non-Hodgkin lymphoma or multiple myeloma. CPIT002 is evaluating checkpoint inhibitors after an allogeneic HSCT in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome.

Both studies are largely focused on safety, as these are early-phase investigations setting the stage for larger trials with a greater focus on clinical end points, such as progression-free survival (PFS) or overall survival. Due to the differences between autologous and allogeneic HSCT, the relative benefits of checkpoint inhibition may differ. Autologous HSCT involves reintroducing the patient’s own stem cells harvested prior to the ablation employed to treat the malignancy. In allogeneic HSCT, stem cells are engrafted from tissue-matched donors. Immunotherapy could enhance the efficacy of both.

“In general, the risk of relapse is greater after autologous than allogeneic HSCT, so one of the goals of this research will be to determine whether combined checkpoint inhibition can improve the efficacy of autologous HSCT while preserving its safety advantages,” Dr. Pecora noted.



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