Lymphoma Program Earns Third SPORE Grant

February 26, 2019 | by Letisia Marquez

Larry Kwak Larry W. Kwak, M.D., Ph.D.
An international leader in finding innovative treatments for lymphoma patients, City of Hope has earned its third Lymphoma Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI), one of just four current NCI-supported lymphoma SPOREs in the nation. The grant covers a five-year period and totals $12.5 million.
 
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. City of Hope’s interdisciplinary lymphoma research is currently advanced in the Toni Stephenson Lymphoma Center, which is part of City of Hope's Hematologic Malignancies and Stem Cell Transplantation Institute.
 
“City of Hope is developing novel therapeutics and prognostics representing the forefront of knowledge gained from observations in molecular biology and cellular immunology here,” said Larry W. Kwak, M.D., Ph.D., vice president and 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 GMP Manufacturing Core and have been developed from the institution’s preclinical laboratory studies.”
 
The support of donors Emmet and Toni Stephenson and their daughter Tessa Stephenson Brand through the Toni Stephenson Lymphoma Center has helped to create the collaborative, fast-paced culture in which the projects in the new SPORE grant will be advanced. Attracting blood cancer experts to City of Hope such as Kwak, the Toni Stephenson Lymphoma Center is home to the best and brightest lymphoma researchers. They are driving life-giving discoveries and unique combinations of therapies, with a special focus on rare and aggressive forms of the disease, including T cell lymphoma.
 
Now in remission, Toni Stephenson herself was a patient in a clinical trial supported by SPORE funding.
 
As part of the Toni Stephenson Lymphoma Center, the Stephenson Pilot Grant program funds new ideas for lymphoma and 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.
 
The SPORE grant is led by Stephen J. Forman, M.D., the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Kwak as multiprincipal investigators. This is the 11th year City of Hope has received funding from the NCI for a lymphoma SPORE grant. 
 
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
  • Two trials for relapsed/treatment-resistant Hodgkin's lymphoma
  • Fighting STAT3 (a gene that drives tumor cell growth) in non-Hodgkin's lymphoma
  • Dealing with a serious complication for Hodgkin's lymphoma patients receiving an autologous stem cell transplant (therapy-related myelodysplasia/acute myeloid leukemia)
CAR T therapy and vaccine combination for non-Hodgkin's lymphoma
After patients with non-Hodgkin's lymphoma 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 recur. A treatment option for these patients is combining a transplant with chimeric antigen receptor (CAR) T cell therapy. 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. City of Hope researchers plan to add the Triplex vaccine — developed here — 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.
 
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, which would then enable them to receive a bone marrow transplant. Led by Alex Herrera, M.D., City of Hope assistant professor in the Department of Hematology & 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.
 
A second aim of the project, led by Eileen Smith, M.D., 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.
 
Fighting STAT3 in non-Hodgkin's lymphoma
Non-Hodgkin's lymphoma is the sixth most common cancer in the United States, with more than 74,000 estimated new cases each year. Growing evidence links B cell non-Hodgkin's lymphoma 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.
 
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.
 
Understanding a serious complication for Hodgkin's lymphoma patients receiving an autologous stem-cell transplant
Hodgkin's lymphoma and non-Hodgkin's lymphoma) patients who receive stem cell transplantation can develop a deadly complication that may arise after the procedure. Between 6 to 8 percent of these 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 the University of Alabama at Birmingham, City of Hope, the 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 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.
 
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