On February 21, 2019 City of Hope reported that it has received its third lymphoma Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI), one of four current NCI-supported lymphoma SPOREs (Press release, City of Hope, FEB 21, 2019, View Source [SID1234533556]). The grant covers a five-year period and totals $12.5 million.
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SPOREs – a cornerstone of the NCI’s efforts to promote collaborative, interdisciplinary translational cancer research – involve both basic and clinical/applied scientists working together to support projects that will result in new and diverse approaches to the prevention, early detection, diagnosis and treatment of human cancers. This interdisciplinary research is currently advanced in the Toni Stephenson Lymphoma Center, which is the foundation of City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute.
"For many years now, City of Hope has led the way in pioneering bone marrow transplantation, immunotherapy and other innovative treatment options for lymphoma patients, both those who are being diagnosed with the disease for the first time and those who have experienced a relapse," said Stephen J. Forman, M.D., City of Hope Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation and leader of the Hematologic Malignancies and Stem Cell Transplantation Institute. "This renewal of lymphoma SPORE will make it possible for us to continue developing leading-edge therapies in our laboratories that will ultimately reach a patient’s bedside."
"City of Hope will do this by developing novel therapeutics and prognostics representing the forefront of knowledge gained from observations in molecular biology and cellular immunology at City of Hope," said Larry W. Kwak, M.D., Ph.D., vice president/deputy director of City of Hope’s comprehensive cancer center, director of the Toni Stephenson Lymphoma Center and the Dr. Michael Friedman Professor in Translational Medicine. "Six clinical trials are proposed in this grant, five of which utilize agents (cellular products, small molecules, radiolabeled antibodies) that will be produced at City of Hope in its Good Manufacturing Practice Manufacturing Core and have been developed from the institution’s preclinical laboratory studies."
The grant is led by Forman and Kwak as multi-principal investigators. This is the 11th year City of Hope has received funding from the NCI for a lymphoma SPORE grant.
The Toni Stephenson Lymphoma Center has helped to create the collaborative, fast-paced culture in which the projects in the new SPORE will be advanced. It is home to many of the accomplished faculty and leading experts who are conducting clinical trials that have come about with SPORE funding, and has a track record of developing new therapies for many types of lymphoma.
Established by Emmet and Toni Stephenson, and their daughter Tessa Stephenson Brand, the Toni Stephenson Lymphoma Center brings together physicians and scientists in a highly-interdisciplinary infrastructure to accelerate City of Hope’s research on the biological mechanisms of lymphoma, identify new molecular targets and produce immunotherapies to treat the disease. In addition, the Stephenson Pilot Grant program funds new ideas for lymphoma or treatment platforms that can be innovatively applied across disease sites, including lymphoma. The cores in the SPORE award are also supported in part by Stephenson funds.
Over the next five years, City of Hope doctors and researchers, as well as scientists from other institutions, will focus on the following projects for the SPORE grant:
CAR T therapy and vaccine combination for non-Hodgkin’s lymphoma
After patients with non-Hodgkin’s lymphoma (NHL) have received a blood stem cell transplant with their own stem cells or that of a donor, there could still be enough cancerous cells not killed by the procedure for the disease to relapse. City of Hope is on a quest to improve current treatment for these patients, as well as those with NHL who are unable to receive a transplant. A treatment option for these patients is combining a transplant with chimeric antigen receptor (CAR) T cell therapy; during the last round of lymphoma SPORE funding, City of Hope started a clinical trial for NHL patients that used a treatment combining a transplant with CD19 CAR T cells. (Researchers published the positive treatment results in the journal Blood and also presented on the research at the American Society of Hematology (ASH) (Free ASH Whitepaper) conference.) The therapy works by taking a person’s immune cells – T cells – and adding a CAR that helps target and wipe out cancerous cells. The institution is now looking for new ways to improve the treatment.
One option that will be tested is adding CD19-specific CAR, which targets the CD19 protein in cancerous B cells, to a virus-specific T cell that can be stimulated to multiply using a vaccine. One such example is the well-studied cytomegalovirus (CMV) – it has the greatest number of T cells in the human body targeting the virus. City of Hope researchers plan to add the Triplex vaccine – developed at City of Hope – to the CAR T cells. Triplex already has been shown to be safe in a City of Hope phase 2 trial in transplant patients. Because Triplex can stimulate T cells to multiply, researchers hope that the vaccine will boost the number and longevity of CMV-CD 19 CAR T cells in these trials in patients’ bodies so they may better fight against their disease.
NHL patients will be able to enroll in three trial designs. In the first trial, patients will receive chemotherapy followed by the Triplex vaccine. For a second trial, patients will receive a hematopoietic stem cell transplant (HSCT) with their own stem cells and the vaccine. In the third trial, patients will undergo HSCT with stem cells from a donor followed by the Triplex vaccine.
The team leading these City of Hope clinical trials includes Forman, who is also scientific director of City of Hope’s T Cell Immunotherapy Laboratory; City of Hope doctors Tanya Siddiqi, M.D., assistant clinical professor of hematology and hematopoietic cell transplantation, and Leslie Popplewell, M.D., associate clinical professor of hematology and hematopoietic cell transplantation, who will lead the autologous transplant trial, and Ryotaro Nakamura, M.D., associate professor of hematology and hematopoietic cell transplantation, who will lead the allogeneic trial. Don J. Diamond, Ph.D., a City of Hope professor in the Department of Hematology & Hematopoietic Cell Transplantation, developed Triplex, and Xiuli Wang, Ph.D., a City of Hope research professor in the same department, developed the CAR T cells for this project.
Two trials for relapsed/treatment-resistant Hodgkin’s lymphoma
Patients with high-risk Hodgkin’s lymphoma who have relapsed or resisted treatment currently only have a 20 to 50 percent chance of achieving a cure. City of Hope is leading two compatible clinical trials for these patients; the therapies are expected to treat the disease that would then enable them to receive a bone marrow transplant. Led by Alex Herrera, M.D., City of Hope assistant professor in hematology and hematopoietic cell transplantation, the first is a phase 2 trial of response-adapted sequential therapy using a combination therapy – nivolumab, an immunotherapy drug known as a PD-1 inhibitor, and ICE (ifosfamide, carboplatin, etoposide phosphate) chemotherapy. Nivolumab works by preventing the PD-1 protein from doing its job, which is to suppress the immune system from fighting cancerous cells. By putting PD-1 in check, a person’s immune system can better fight Hodgkin’s lymphoma. This approach, which utilizes an innovative PET response-adapted treatment sequence, is designed to increase the proportion of patients who have achieved a complete response before they receive a transplant. The trial also gauges the impact of PD-1 inhibitors on a Hodgkin’s lymphoma tumor microenvironment, the area surrounding tumor cells, by using new methods to better evaluate what’s occurring in that area.
A second aim of the project, led by Eileen Smith, City of Hope associate director of the Clinical Research Program, Department of Hematology & Hematopoietic Cell Transplantation, is to start a phase 2 trial that uses an anti-CD25 antibody immunoconjugate, a targeted therapy that uses a CD25 antigen to kill tumorous cells. The antibody will augment high-dose chemotherapy, an autologous stem cell transplant and radiation targeting a tumor’s microenvironment; preliminary data from a similar phase 1 trial showed that the regimen is feasible, remarkably well tolerated and has promising efficacy.
David M. Colcher, Ph.D., City of Hope professor in molecular imaging and therapy, is also a scientific principal investigator.
Fighting STAT3 in non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma (NHL) is the sixth most common cancer in the United States, with more than 70,000 estimated new cases each year. Growing evidence links B cell NHLs to persistent activation of STAT3, a gene that drives tumor cell growth and anti-tumor immune suppression. But there is currently no drug approved by the U.S. Food and Drug Administration that stops the activation of STAT3. Hua Yu, Ph.D., City of Hope’s Billy and Audrey L. Wilder Professor in Tumor Immunotherapy and co-leader, of the Cancer Immunotherapeutics Program, and Marcin Kortylewski, Ph.D., associate professor, Department of Immuno-Oncology, and team have already demonstrated that an immunotherapy developed at City of Hope (CpG-STAT3siRNA) turns off STAT3, and stimulates the immune system to attack tumors, in addition to killing B cell lymphoma tumor cells and making radiation therapy more effective in animal models.
The new lymphoma SPORE grant – as well as funding from The Marcus Foundation – makes it possible for City of Hope to start a phase 1 trial for that drug in patients. The trial will test its safety in patients, and whether the therapy can be injected within tumors; patients will also receive low-dose radiation therapy to augment the new drug.
A more effective, second generation therapy will also be tested in animal models – the goal is to also develop that drug for a clinical trial. That drug is also expected to have a two-pronged effect – attack lymphoma cells and spur the immune system to fight cancer, a crucial step because cancerous cells stop the immune system from killing them.
"B cell lymphomas can be very difficult to treat, which is why City of Hope continues to develop and produce innovative targeted therapies for lymphoma that can also restore the immune system to fight cancer," Yu said. "Our new therapies would be the first drugs to both kill tumor cells and activate the immune system."
In addition, STAT3 is common in other cancers – Yu hopes that the new therapy will be effective, so it can also be used against leukemia, pancreatic and other cancers.
Elizabeth Budde, M.D., Ph.D., an assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, is the project’s clinical principal investigator.
Understanding a serious complication for Hodgkin’s lymphoma patients receiving an autologous stem cell transplant
Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) patients who receive stem cell transplantation can develop a deadly complication that may arise after the procedure. Between 6 to 8 percent of HL/NHL transplant patients can develop therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML), which is more common in older adults and is the leading cause of nonrelapse mortality in this group. It is generally believed that blood stem cells exposed to high doses of chemotherapy and other cytotoxic therapies suffer genetic damage that leads to t-MDS/AML but some patients could also have a genetic predisposition to the disease.
Researchers at University of Alabama at Birmingham, City of Hope, University of Minnesota, University of Nebraska, St. Jude Children’s Research Hospital and Dana Farber Cancer Institute are developing a prediction model that includes clinical and genetic details to determine the probability of a patient’s risk of developing t-MDS/AML. The research will help identify which patients are at risk for developing t-MDS/AML and what a medical team can do to personalize treatment and help prevent a patient from developing the disease.
Smita Bhatia, M.D., M.P.H., and Ravi Bhatia, M.D., both at University of Alabama at Birmingham, and Stephen J. Forman, M.D., of City of Hope are leading the research. Mukta Arora, M.D., M.S. (at University of Minnesota), Julie Vose, M.D. (at University of Nebraska), Ben Ebert, M.D., Ph.D. (at Dana Farber Cancer Institute), and Yutaka Yasui, Ph.D. (at St. Jude Children’s Research Hospital) are also working on the project.