- Using immunotherapy to boost transplants: Leslie Popplewell, M.D., works to devise next-generation improvements on transplant technology. Dr. Popplewell recently conducted three related phase 1 clinical trials that combined immunotherapy with bone marrow transplants by infusing transplant patients with modified T cells trained to recognize lymphoma cells. In three successive trials, a patient’s T cells were transduced with chimeric antigen receptors (CARs), designed to target T cells to directly kill tumor cells with CD19 on their surface. The T cells were then transferred into patients three days after their bone marrow transplant. This trial series progressively optimizes the CAR lentiviral construct, the T cell population that is isolated and transduced with CARs, and the manufacturing procedures and duration. In all three trials, T cells bearing a CD19-targeting CAR have proven safe and, importantly, do not interfere with the engraftment of transplanted bone marrow cells. The second-generation CAR T cells exhibited improved expansion after infusion into the patients. The third trial testing alterations in the manufacturing method and CAR vector is still underway, as is two-year follow-up of the effects of CAR T cell therapy on transplant outcomes.
- 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.
- Improving diagnosis through a digital information platform: John Chan, M.D., co-leader of the Hematology Malignancies Program, has made substantial progress toward our understanding of lymphomas. In his first study, Dr. Chan showed that he could accurately distinguish between two types of DLBCL — diffuse large B cell lymphoma — by looking at their genetic signature patterns, or GEPs, and matching them with the known GEP signature of a particular cancer type. Since each kind of cancer responds best to treatments specifically designed to fight it, identifying a patient’s exact subtype optimizes treatment. Recently, Dr. Chan successfully identified GEP signatures that can pinpoint other cancer types, including those of peripheral T cell lymphoma (PTCL). He has submitted a grant application to the National Cancer Institute for a digital platform to house the genetic signatures, called Nanostring. The system is currently being tested by a number of collaborating institutions, and would allow physicians to routinely test for, diagnose and track particular cancer types in patients by using GEPs.
- 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.
- Searching for effective treatments for cutaneous lymphoma: Christiane Querfeld, M.D., Ph.D., director of the Cutaneous Lymphoma Program, seeks better treatment options for cutaneous T cell lymphoma (CTCL), a rare form of lymphoma that first appears on the skin but can also spread to lymph nodes and internal organs. City of Hope is one of the few institutions in the country that offers clinical trials to treat cutaneous lymphomas. Dr. Querfeld’s laboratory investigations are focused on the microenvironment associated with CTCL. She has demonstrated that cancer growth is fostered by the surrounding nonmalignant cells. These observations have led to the initiation of several studies incorporating immunotherapies, microRNA inhibitors and antibody therapies to restore the immune system.
- 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.
- 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.