Toni Stephenson Lymphoma Center Research Highlights
Modifying CAR T Cells to Increase Transplant Effectiveness: Hematologist Leslie Popplewell, M.D., is building on the success of her two recent phase 1 clinical trials where she found that infusing transplant patients with modified T cells that target lymphoma was safe and did not interfere with transplanted bone marrow cells. Based on the promising results from her trials, Popplewell has illustrated that the design of chimeric antigen receptors (CAR) in T cells may determine the potency of the body’s immune response against cancer cells. Currently, she is awaiting an amendment which will allow her to further modify the CAR T cell to improve longevity thus halting disease progression and increasing the effectiveness of bone marrow transplants.
Novel nucleotide-based approaches for the treatment of lymphoma: Elizabeth Budde, M.D., Ph.D., working together with Marcin Kortylewski, Ph.D., and Hua Yu, Ph.D., from Beckman Research Institute of City of Hope, is developing first-in-human immune-based therapies targeting both lymphoma cells and the suppressive tumor immune microenvironment. This project uses two alternative oligonucleotide-based approaches, CpG-STAT3 siRNA and CpG-STAT3 decoy oligonucleotide, to simultaneously target the cell surface TLR9 receptor and the critical transcription factor STAT3, in both lymphoma cells and in immunosuppressive myeloid cells. This project is funded by the Lymphoma SPORE.
Using Technology to Improve Peripheral T Cell Lymphoma Outcomes: John Chan, M.D., co-leader of the Hematology Malignancies Program, and recently appointed Dr. Norman & Melinda Payson Professor in Hematologic Cancer, successfully identified gene expression signatures that can classify subtypes of peripheral T cell lymphoma (PTCL). This discovery prompted funding from the National Cancer Institute which allowed him to begin translating his findings to a platform suitable for widespread clinical applications. This project will benefit physicians by providing them with a tool to make a more accurate diagnosis of PTCL for clinical trials and treatment. Using a powerful DNA-sequencing technology, Chan has begun categorizing mutations in PTCL and identifying mutations that drive disease development and progression. By analyzing these mutations, he hopes to identify specific genes in tumors that are potentially targetable for treatment. In addition, Chan recently partnered with Dr. Muhammed Murtaza from the Translational Genomics Research Institute (TGen) to develop a liquid biopsy assay on plasma from patients in order to have a sensitive non-invasive assay for diagnosis and follow-up management. Funded by the TSLC, this research has the potential to improve patients’ quality of life and represents one of our first examples of applying the promise of precision medicine to lymphoma patients.
Developing a novel antibody therapy against drug-resistant B cell lymphomas: Larry Kwak, M.D., Ph.D., and Hong Qin, M.D., Ph.D., have developed monoclonal antibodies against the B cell activating factor receptor (BAFF-R). These antibodies, generated using a natively folded BAFF-R protein, showed a remarkable anti-tumor activity against established tumors in vivo and primary patient samples. Drs. Kwak and Qin are now performing IND-enabling studies in order to bring this discovery to a first-in-human clinical trial. Despite the development of new drugs, patients who develop resistance to first-line therapeutic agents often die of their disease. Because they show great efficacy against drug-resistant tumors at the preclinical stage, these BAFF-R antibodies could provide an alternative therapy for patients who progress or relapse after initial treatment. This project was selected by the Strategic Portfolio Optimization Committee (SPOC) for manufacturing and regulatory support through the Hope Portfolio Fund, which accelerates development of breakthrough new drugs to first-in-human clinical trials.
Additionally, team of TSLC investigators, led by Kwak, recently received one of only two prestigious awards from the Leukemia & Lymphoma Society (LLS) resulting in a $2.5 million grant with an additional $2.5 million committed by City of Hope. The Toni Stephenson Lymphoma Center’s support enabled his preliminary studies involving the development of new antibody-based therapeutics to control mantle cell lymphoma (MCL) which made his receipt of this award possible. Kwak plans to build upon his prior work by exploring the use of combining CAR T cell immunotherapy, which is already approved for another type of non-Hodgkin lymphoma, with targeted agents such as ibrutinib.
Restoring the Immune System to Conquer Cutaneous Lymphoma: As director of the Cutaneous Lymphoma Program, Christiane Querfeld, M.D., Ph.D., seeks better treatment options for cutaneous T cell lymphoma (CTCL), a rare form of lymphoma that appears on the skin, but can also spread to the lymph nodes and internal organs. Through her investigations, Querfeld has demonstrated that CTCL growth is fostered by the surrounding nonmalignant cells. These observations have led to the initiation of several targeted and immunologic therapies to restore the immune system thereby killing the cancerous cells.
Identifying biomarkers for response to treatment to brentuximab vedotin: Joo Song, M.D., Robert Chen, M.D. and Alex Herrera, M.D., are mapping the biomarkers affected by brentuximab vedotin — a drug used to treat relapsed Hodgkin lymphoma — and other cancer inhibitors. Identifying which biomarkers are associated with response or resistance to brentuximab vedotin will enable physicians to prescribe this therapy to patients most likely to benefit from this treatment.
Targeting B Cell Lymphoma: Wendong Huang, Ph.D., professor in the departments of Diabetes Complications & Metabolism and Molecular & Cellular Biology, seeks to understand the molecular changes that lead to either T cell or B cell lymphomas in order to create better, more effective treatments. uilding on his previous research into the effectiveness of targeting CAMKII — a key player in the development of lymphomas — to prevent and treat T cell lymphoma, Huang’s group is now expanding their findings to B cell lymphoma. Their results indicate that a similar but distinct pathway is required for the development of B cell lymphoma. In addition, his group is actively designing treatments that utilize different natural products to target this pathway to efficiently destabilize c-Myc protein, thereby bringing lymphoma under control. These discoveries were published in the July 2017 issue of the prestigious medical journal, Cancer Cell. In order to further this novel research that moves City of Hope one step closer to developing more effective treatments for both T cell and B cell lymphoma, Huang was awarded one of five 2018 TSLC Pilot Grants.
In addition to Dr. Huang’s work on B cell lymphoma, Markus Müschen, M.D., Ph.D., and Gang Xiao, Ph.D., discovered a new therapeutic target for B cell malignancies called PP2A. They found that deleting the PP2A gene in B cell lymphoma and leukemia cells eliminated those cells while sparing normal cells. There is currently a clinical trial at City of Hope that uses a drug, LB-100, to target this pathway. Müschen’s team published their research, which also shows promise for patients battling certain autoimmune diseases where B cells are involved, in the prestigious scientific journal Cell. In a landmark advance for City of Hope and the entire cancer research and treatment community, in 2017, the Food and Drug Administration approved its first gene therapies – CAR T cell therapies Yescarta (for B cell lymphoma) and Kymriah (for refractory B cell acute lymphoblastic leukemia). City of Hope is one of the first authorized centers to provide Yescarta and Kymriah. CAR T cell therapy is one of the most promising areas of cancer research and treatment, and this approval is an important milestone, particularly for non-Hodgkin lymphoma patients.
Resources: To provide additional support to the research infrastructure, the Toni Stephenson Lymphoma Center recently launched a dedicated lymphoma tissue bank, and recruited a dedicated biostatistician and a dedicated project development scientist.