JCO Supports Lymphoma Research with Presentation of 2008 Young Investigator Award
The Journal of Clinical Oncology (JCO) presented its 2008 Young Investigator Award (YIA) to Brian Till, MD, a senior medical oncology fellow at the Fred Hutchinson Cancer Research Center and University of Washington. Dr. Till will conduct his award-winning research, "A phase I study to evaluate the safety and feasibility of cellular immunotherapy using genetically modified autologous CD20-specific T cells for patients with relapsed or refractory mantle cell and indolent B cell lymphomas," during the coming year.
YIAs, awarded by The ASCO Cancer Foundation Grants Program, provide funding to promising clinical researchers during the transition from a fellowship program to a faculty appointment. A complete list of award terms and eligibility requirements is available online at www.ascocancerfoundation.org/yia.
Dr. Till, who received his medical degree from the University of Chicago Pritzker School of Medicine, discussed the JCO-sponsored YIA and the research it supports in an interview with ASCO Daily News.
Q: What was your reaction when you learned that you had received the JCO-sponsored YIA? A: I was surprised and happy. These awards are very competitive, so I was honored to be chosen at all. To learn that it was a special award sponsored by JCO was an even greater honor.
Q: How did you become interested in your specialty? A: Some of my early research projects were oriented toward cancer; I found it exciting to be working in an area that affects so many people so profoundly. When I began my clinical experience, I felt a connection to the patients I met during my oncology rotations. I found that those relationships were the most meaningful to me, and the possibility of helping people with such serious illnesses was very rewarding.
Q: How did you decide on the topic of adoptive immunotherapy with genetically modified T cells for lymphoma for your research proposal? A: Although chemotherapy can help many patients live longer, improve their quality of life, and, in some cases, actually cure them, there are still numerous side effects associated with most types of chemotherapy. Overall, it seems like a primitive approach to treating cancer, as it essentially uses poison to treat people. I was drawn toward a more specific type of treatment with fewer side effects that could still be as effective, or potentially more effective, than chemotherapy. I have always been fascinated by the complexity of the human immune system and impressed by the results of some immune-based therapies, particularly allogeneic stem cell transplantation, in which alloreactive donor T cells are able to eradicate diseases that are incurable with chemotherapy. The problem, however, with allogeneic stem cell transplantation is the high rate of treatment-related mortality and morbidity, primarily due to graft-versus-host disease (GVHD). It would be nice to harness the same power of that cellular therapy without the risk of GVHD.
One strategy is to modify autologous T cells to recognize tumors by causing them to express a chimeric T cell receptor that recognizes an antigen expressed on the tumors. We chose CD20 as a target antigen because of the success of rituximab in treating lymphoma, which is an anti-CD20 antibody, and also the near-universal expression of CD20 on B cell non-Hodgkin lymphomas.
Q: Can you describe the methods by which your study will be conducted? A: Our team, in collaboration with researchers at the City of Hope Cancer Center, developed a plasmid that encodes a chimeric T cell receptor specific for CD20. This is very similar to a chimeric T cell receptor that we're using in a current phase I clinical trial, but we modified it to express intracellular costimulatory domains of CD28 and CD137, which are costimulatory molecules that are involved with normal T cell activation.
First, we perform an apheresis procedure on patients with lymphoma, specifically, relapsed or refractory indolent lymphoma or mantle cell lymphoma, to collect a fraction of their white blood cells (called peripheral blood mononuclear cells). We then transfect those cells by giving them an electric shock, called electroporation, and introduce the DNA plasmid that encodes the receptor into the cells. This plasmid contains a neomycin-resistance gene that allows us to select for the successfully transfected cells by treating all the cells with the antibiotic G418. Only the cells that have been transfected can resist the antibiotic and survive. We then expand the surviving G418-selected cells in bulk culture until a therapeutic number has been reached, and test the cells to make sure they express the receptor and can kill CD20-positive cells.
In this new trial, we are going to treat patients with 5 days of fludarabine chemotherapy in an effort to deplete their lymphocytes, which we believe will help the infused T cells to grow better. We infuse three different rounds of modified T cells at increasing doses over a period of approximately a week, and then give 14 days of low-dose interleukin-2 injections to help the T cells grow and persist.
Most of the research takes place at the General Clinical Research Center at the University of Washington, where we have a Gene and Cell Therapy Lab to perform the T cell generation and expansion and a clinical setting to infuse patients with the T cells. The fludarabine will be given at the Seattle Cancer Care Alliance, the clinical portion of the Fred Hutchinson Cancer Research Center, and the clinical follow-up will take place there as well.
Q: What are the implications of your study for future research? A: There are many investigators working on similar projects, not necessarily in lymphoma, using adoptive T cell therapy, and impressive progress is being made. I believe we are at the very beginning of this treatment approach, and it will take many years of incremental improvements before it will become a standard, reliable therapy for cancer. I hope that our study will advance upon the previous T cell study that we're currently completing. We would love to have a great breakthrough where the procedure works perfectly, but it's much more likely that we'll learn a little bit each time - working out the unforeseen problems or unanticipated shortcomings of the treatment.
Q: What are the implications of your study for the clinical care of patients? A: These diseases that we're studying, advanced indolent lymphoma and mantle cell lymphoma, are essentially incurable with standard chemotherapy and radiotherapy. Although cellular therapy in the form of allogeneic stem cell transplantation or donor lymphocyte infusion can be curative, there are many risks associated with those procedures. Although the primary endpoints of this study are to assess the safety and feasibility of treating patients with these modified autologous CD20-specific T cells, we're obviously interested in seeing whether the treatment affects the patients' disease course as well. Our hope is that we may see long-term remissions from this clinical trial.
Q: How does receiving this award affect your work as an oncologist? A: Academic medicine is a competitive field in which people who are interested in research typically have to provide their own funding. Grants are competitive, and someone fresh out of an oncology fellowship, like myself, can't compete with established investigators who have many publications and funding sources. Shorter-term career development awards and young investigator awards are crucial for people like me to obtain the support we need to build our way up to the larger grants that will eventually secure our places in academic medicine.
Q: What has been your most rewarding accomplishment so far? A: As I approach the end of my oncology fellowship, I've had the good fortune to be awarded a few grants targeted at young investigators such as the JCO-sponsored ASCO YIA, and I am also starting to see papers I've written get accepted by journals. Seeing these things come to fruition gives me hope that I might be able to continue along this path for the long term.
Q: What are your future career goals and scientific interests? A: I would really like to be a research oncologist at a major academic clinical center like the Fred Hutchinson Cancer Center, where I'm completing my fellowship. I like the type of translational research that I'm doing now, although I would also be interested in phase II clinical trials using immunology-based therapies for lymphoma. At the same time, I want to continue treating patients with lymphoma in a clinical setting.
