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

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.

Autologous and Allogeneic Approaches

“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.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.

The most important of these safety advantages is the absence of risk for graft-versus-host disease (GVHD), which often compromises the benefits of allogeneic HSCT. Immunosuppressive drugs required to control GVHD contribute to an increased risk for infections and possible relapse. The higher risk for relapse after autologous than allogeneic HSCT has been attributed to the harvesting of malignant cells along with stem cells that are then reintroduced at engraftment and the absence of an effective graft versus tumor response that does occur after allogeneic transplant. If checkpoint inhibitors permit T cells to attack residual cancer cells after autologous HSCT, it may permit this approach to achieve the greater antitumor effect of allogeneic HSCT without impairing its safety advantage.

In CPIT001, which is a Phase Ib-IIa study, patients are eligible who have diffuse large B-cell lymphoma, T-cell lymphoma, or multiple myeloma if they have relapsed or have recurrent disease with specific high-risk characteristics and also have a good performance status of 2 or lower on the Eastern Cooperative Oncology Group (ECOG) scale. In this study, which is testing checkpoint inhibitors after autologous HSCT, a combination of 1 mg/kg ipilimumab and 3 mg/kg nivolumab will be administered every three weeks. Patients will receive six doses of ipilimumab and 12 doses of nivolumab. Although primarily a safety study, complete response and PFS will be compared with published standards.

In CPIT002, which is a Phase I study, patients with intermediate- or high-risk AML or myelodysplastic syndrome will be assigned to six doses of 1 mg/kg ipilimumab every three weeks, 12 doses of 3 mg/kg nivolumab every three weeks, or a combination of the two agents after allogeneic HSCT. The safety of the combination relative to single-agent checkpoint inhibition will be monitored carefully. An evaluation of PFS at 12 and 18 months after initiation of therapy is also included among primary end points.

“HSCT is a standard of care for many hematologic malignancies, but I and many others have spent 30 years looking for strategies that will increase the proportion of patients who remain in remission after this procedure. The recent advances in immunotherapy have been enormously exciting throughout the field of hematology and oncology, but there is a particularly strong rationale for predicting major clinical benefits after HSCT,” Dr. Pecora said.

This innovative strategy will now be tested in these initial studies led by the John Theurer Cancer Center investigators.

To learn more about John Theurer Cancer Center or other clinical advancements happening at JTCC, please go to www.jtcancercenter.org.

^aCPIT001 is named “Phase Ib-IIA Study of Combined Check Point Inhibition After Autologous Hematopoietic Stem Cell Transplantation in Patients at High Risk for Post-transplant Recurrence,” and its identifier is NCT02681302.

^bCPIT002 is named “Phase I Study of Single-agent and Combined Checkpoint Inhibition After Allogeneic Hematopoietic Stem Cell Transplantation in Patients at High Risk for Post-transplant Recurrence,” and its identifier is NCT02846376.

ABOUT JOHN THEURER CANCER CENTER AT HACKENSACK UNIVERSITY MEDICAL CENTER

John Theurer Cancer Center at Hackensack University Medical Center is New Jersey’s largest and most comprehensive center dedicated to the diagnosis, treatment, management, research, screenings, and preventive care as well as survivorship of patients with all types of cancers. The 14 specialized divisions covering the complete spectrum of cancer care have developed a close-knit team of medical, research, nursing, and support staff with specialized expertise that translates into more advanced, focused care for all patients. Each year, more people in the New Jersey/New York metropolitan area turn to John Theurer Cancer Center for cancer care than to any other facility in New Jersey. Housed within a 775-bed not-for-profit teaching, tertiary care, and research hospital, John Theurer Cancer Center provides state-of-the-art technological advances, compassionate care, research innovations, medical expertise, and a full range of aftercare services that distinguish John Theurer Cancer Center from other facilities. For additional information, please visit www.jtcancercenter.org.

ABOUT HACKENSACK MERIDIAN HEALTH

Hackensack Meridian Health is a leading not-for-profit health care organization that is the most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care. Hackensack Meridian Health comprises 13 hospitals, including two academic medical centers, two children's hospitals and nine community hospitals, physician practices, more than 120 ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, and urgent care and after-hours centers. Hackensack Meridian Health has 28,000 team members, more than 6,000 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.

The Network's notable distinctions include having one of only five major academic medical centers in the nation to receive Healthgrades America's 50 Best Hospitals Award for five or more consecutive years, the number one hospital in New Jersey as ranked by U.S. News and World Report, consistently achieving Magnet® recognition for nursing excellence from the American Nurses Credentialing Center, recipient of the John M. Eisenberg Award for Patient Safety and Quality from The Joint Commission and the National Quality Forum, a six-time recipient of Fortune's "100 Best Companies to Work For," one of the "20 Best Workplaces in Health Care" in the nation, and the number one "Best Place to Work for Women." Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies.

The hospitals of Hackensack Meridian Health include: academic medical centers — Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune; children's hospitals – Joseph M. Sanzari Children's Hospital in Hackensack, K. Hovnanian Children's Hospital in Neptune; community hospitals – Ocean Medical Center in Brick, Riverview Medical Center in Red Bank, Mountainside Medical Center in Montclair, Palisades Medical Center in North Bergen, Raritan Bay Medical Center in Perth Amboy, Southern Ocean Medical Center in Manahawkin, Bayshore Medical Center in Holmdel, Raritan Bay Medical Center in Old Bridge, and Pascack Valley Medical Center in Westwood. For additional information, please visit www.HackensackMeridianHealth.org.

Press contact:

Katherine Emmanouilidis

Hackensack Meridian Health

John Theurer Cancer Center

60 2nd Street

Hackensack, NJ 07601

O: 551-996-3764 C: 201-956-7191

katherine.emmanouilidis@HackensackMeridian.org