Patients with relapsed and refractory leukemia and lymphoma currently have few curative options. Through a combination of leading-edge scientific research, clinical trials and advanced patient care, cancer specialists at the University of Minnesota Health Cancer Care are transforming management strategies for refractory disease.
Jeffrey Miller, MD, hematologist/oncologist, Deputy Director of Masonic Cancer Center and Professor of Medicine, Division of Hematology, Oncology and Transplantation
Translational research underlies the advances taking place at University of Minnesota Health (M Health). Research is underway at Masonic Cancer Center, University of Minnesota, the central hub for the university’s cancer research in a variety of areas, including immunology, screening, prevention, etiology, survivorship and cell signaling.
M Health investigators studying leukemia and lymphoma have found particular promise in the field of immunology. Immunotherapies harness the power of the body’s immune system to target and destroy malignancies. These therapies may involve stimulating the patient’s immune system to attack cancer cells or the administration of synthetic agents, such as laboratory-produced immune-stimulating molecules. Depending on the stage and type of cancer, these therapies may be used as an alternative or complement to chemotherapy and radiation therapy.
In cases of leukemia and lymphoma where first- and second-line therapies have failed or where patients are at a high risk of relapse, M Health physicians may recommend immunotoxins, checkpoint inhibitors, immunologic treatments, such as stem cell transplantation, or the use of biologic agents to stimulate natural killer cells.
The Role of Stem Cell Transplantation
Stem cell transplantation is a potentially curative therapy for cases of high-risk acute leukemia and lymphoma. In the case of leukemia, M Health physicians may recommend allogeneic transplantation, while autologous transplantation is more often indicated for those with lymphoma.
Masonic Cancer Center, University of Minnesota staff collaborate on cases.
Allogeneic donor stem cell transplantation for treatment of leukemia first requires conditioning using high doses of chemotherapy and radiation therapy to deplete the cells in the patient’s bone marrow and suppress the patient’s immune system. The patient then receives an infusion of donor stem cells allowing development of an entirely new blood compartment and immune system.
Autologous stem cell transplant utilizes the patients’ own stem cells, which are harvested from blood following mobilization with growth factors. Following administration of high-dose chemotherapy, the stem cells are reinfused to repopulate the bone marrow. To improve on standard approaches and increase cure rates, University of Minnesota researchers developed an innovative strategy to augment the function of the immune system post-autologous transplant. The approach is based on the discovery that monoclonal antibody rituximab when combined with novel inhibitor of protein ADAM17 can augment killing of lymphoma cells. The clinical trial is underway for patients with aggressive types of non-Hodgkin lymphoma.
While stem cell transplantation has been utilized for more than 50 years, the technique is continually evolving to become safer and more effective, according to Veronika Bachanova, MD, PhD, M Health hematologist and Associate Professor of Medicine, Division of Hematology, Oncology and Transplantation at University of Minnesota.
One potential challenge associated with donor stem cell transplantation is availability of an appropriate donor. As patient populations become more diverse, finding a fully matched donor for every patient is often difficult. Ongoing research at Masonic Cancer Center seeks to overcome this challenge by testing the efficacy of stem cells derived from umbilical cord blood and from haploidentical, partially matched stem cell donors.
To identify appropriate donor matches, physicians perform human leukocyte antigen (HLA) typing. HLA, a protein found on most cells in the body, directs the immune system to distinguish the body’s own cells from infected or damaged cells. During matching, physicians compare numerous HLA markers on donor and patient cells.
To reduce the risk of graft-versus-host disease and improve the likelihood of engraftment, physicians traditionally only considered donors matches if they were fully matched at all HLA markers. As researchers learned more about the immunogenetics, however, University of Minnesota Health transplant physicians learned they could achieve comparable outcomes following transplantation of grafts from partially mismatched donors.
Masonic Cancer Center activated a clinical study using reduced-intensity conditioning with haploidentical stem cells from partially matched related donors, usually children, siblings or parents.
“We are enthusiastic about this trajectory,” Dr. Bachanova says. “With these donor options, patients with hematologic malignancies have nearly 100 percent assurance that we will find a suitable donor.”
Bolstering the Body’s Natural Killers
The immune system contains three major types of lymphocytes: natural killer cells, T-cells and B-cells. Natural killer cells comprise 10 to 15 percent of the body’s lymphocytes, and their role is to identify and destroy damaged, infected or malignant cells. For more than two decades, investigators at Masonic Cancer Center have sought an improved understanding of natural killer cell biology and how these cells target tumors, with the hope of finding ways to exploit the cells’ abilities to destroy malignancies.
In the mid-1990s, Jeffrey Miller, MD, hematologist/oncologist, Deputy Director of the Masonic Cancer Center and Professor of Medicine, Division of Hematology, Oncology and Transplantation at the University of Minnesota, and a team of researchers administered interleukin-2 to lymphoma patients recovering from autologous bone marrow transplant with the goal of expanding the number of natural killer cells in the body.
“The concept was to see if we could boost immunity to prevent relapse, which is still a major problem after an autologous transplant,” Dr. Miller says. “By the year 2000, we realized that natural killer cells have inhibitory receptors that influence their activity, and we think this is the particular limitation with autologous natural killer cells, so we started using healthy related donor natural killer cells.”
Investigations using related donor natural killer cells yielded promising results. For example, clinical research published in Blood in 2014 found that the use of related-donor natural killer cells in patients with refractory acute myeloid leukemia led to remission rates of 30 to 40 percent, compared with remission rates of less than 10 percent following salvage chemotherapy.
“This is what really put us on the map,” Dr. Miller says. “Since that time, we’ve been trying to understand how to make this therapy better and expand its applications beyond the treatment of acute myeloid leukemia. An even bigger goal is to understand how to make natural killer cells more specific by combining them with novel molecules that we have developed here to help them recognize specific tumor antigens on solid tumors in addition to hematologic malignancies.”
“When patients have failed first- and second-line therapies, they’re unlikely to be cured if they have advanced cancer. That’s one reason physicians are so excited about immune-based therapies. There is such potential in clinical trials to offer these patients hope.”
— Jeffrey Miller, MD, hematologist/oncologist, Deputy Director of Masonic Cancer Center and Professor of Medicine, Division of Hematology, Oncology and Transplantation
One way in which the team is trying to enhance the function of natural killer cells is by using growth factors, such as interleukin-15. Clinical trials are currently in progress to test the effectiveness of interleukin-15 and a specially generated tri-specific killer engager (referred to as a TriKE).
“This combines all of our basic knowledge of how to stimulate natural killer cells and how to make them antigen specific,” Dr. Miller says. “This TriKE binds with a molecule on the natural killer cell and another target on the tumor and contains an interleukin-15 component between those two immune-engaging components to bring the natural killer cell right next to the tumor in hopes of getting better, more specific killing than we’re getting with the natural killer cells alone.”
By the end of 2017, Dr. Miller and his team hope to have clinical trials up and running that will test the use of antigen-targeted natural killer cells in patients with breast, head and neck, and possibly colorectal cancers, as an expansion of their work on hematologic malignancies. A clinical trial in which physicians infuse natural killer cells directly into the abdominal cavities of women with ovarian cancer is also underway.
Advances in Immunotherapy Drugs
New immunotherapies are emerging rapidly for patients with hematologic malignancies and solid tumors. In the realm of lymphoma management, two innovative therapies are available at M Health. The first therapy, a form of adoptive cell transfer, involves genetically engineering patients’ T-cells to express chimeric antigen receptors (CARs), enabling these cells to recognize tumor-specific antigens.
“Our team at M Health is unique because we’re not just testing new drugs — we’re actually developing them. We have been at the forefront of immunotherapy discoveries for many years, and we are excited that the results of our efforts are reflected in the portfolio of clinical trials available for patients with hematologic malignancies.”
— Veronika Bachanova, MD, PhD, hematologist and Associate Professor of Medicine, Division of Hematology, Oncology and Transplantation
“So far, we have had the most success administering CAR-19 targeting CD19 antigen on lymphoid cells, which we expect to receive FDA approval for soon as a treatment for refractory B-cell lymphoma,” Dr. Bachanova says. “This technique is also being utilized with remarkable success in the management of pediatric acute lymphoblastic leukemia.”
The second therapy involves the development and administration of immunotoxins. At Masonic Cancer Center, researchers have developed a bispecific immunotoxin known as DT2219, as a treatment for B-cell lymphoma that targets CD19 and CD22 proteins on the surface of malignant B cells. Following the recent completion of a successful phase I study, Masonic Cancer Center is currently enrolling patients with acute lymphoblastic leukemia and B-cell lymphoma in a phase II clinical trial.
“We were extremely pleased to observe complete remissions in some patients with chemotherapy refractory disease,” Dr. Bachanova says. “We have observed benefit in patients with both B-cell lymphoma and B-cell lymphoblastic leukemia and found that this therapy is well tolerated. Adverse events are minimal and different from chemotherapy. Rather, DT2219 seems to be a good choice even for those who are elderly or do not wish to pursue aggressive chemotherapy.”
Teaming Up to Improve Outcomes
M Health is able to offer these clinical trials in large part because of collaboration and shared infrastructure. University of Minnesota, for example, hosts the cell production laboratory where Masonic Cancer Center scientists create and engineer cells, proteins and other molecules necessary to their work, while M Health offers the clinical infrastructure necessary to deliver care in a hospital setting. Beyond shared infrastructure, however, the M Health and Masonic Cancer Center clinicians, scientists and investigators share a central mission and focus of bettering the lives of cancer patients.
“Together, M Health and Masonic Cancer Center share an overarching goal of improving clinical outcomes and the health of people with cancer, especially those with advanced disease who no longer have available standard-of-care treatments,” Dr. Miller says. “The only way to make advances in cancer care is to identify and educate patients about all of their options and engage them in clinical trials. Our investigators partner with the M Health physicians and nurses delivering these trials to ensure we bring state-of-the-art therapies with potential benefits to patients responsibly, enabling us to maximize safety.”
To refer a patient to University of Minnesota Health Cancer Care, call 855-486-7226. For more information about Masonic Cancer Center and the ongoing advances in cancer research underway at the University of Minnesota, visit cancer.umn.edu.