Posted by 
Fred Hutchinson Cancer Research Center’s latest findings on cancer immunotherapies, CRISPR for blood disorders, stem cell transplantation and insights on the immune system and cancer will be featured at the 60th annual meeting of the American Society of Hematology, which will be held Dec. 1-4 in San Diego. See highlights below.
ASH PRESS BRIEFING
This year’s ASH press program will include a press briefing, “CAR T-Cell Therapies: New Research and Updates from Pivotal Trials,” featuring Fred Hutch research on a combination therapy for chronic lymphocytic leukemia (more details below). The briefing will take place at 11:30 a.m. PST, Saturday, Dec 1, in Room 23 of the San Diego Convention Center. It is open to all media registered to attend the meeting. More details will be available in an ASH press release to be distributed at the briefing.
- CAR T-cell combination therapy for chronic lymphocytic leukemia. Dr. Jordan Gauthier will describe how patients with relapsed, refractory chronic lymphocytic leukemia (CLL) treated with the drug ibrutinib before, during and after CAR T-cell therapy may experience fewer side effects and may be more likely to see their cancer go into remission compared with patients who received CAR T alone. Gauthier calls the results promising, though he cautions that at this point the study is small (fewer than 20 patients in each group). Ibrutinib is a small-molecule drug that keeps CLL cells from growing, and the CAR T-cell therapy targeted the CD19 protein on leukemia cells. Gauthier is a Fred Hutch senior research fellow and clinician working in the lab of Dr. Cameron Turtle. The study to be presented at ASH is an extension of the team’s 2017 study published in the Journal of Clinical Oncology that showed how the CD19 CAR T-cell therapy led to durable molecular remissions in CLL patients who had failed other treatments.
CAR T-CELL THERAPY
With the success of CAR T-cell therapies for some blood cancers, Fred Hutch physician-scientists are taking a closer look at characteristics and outcomes of patients who have received the therapy with the aim of making the therapy work better for more people. Other CAR T-cell therapy work featured at this year’s meeting includes taking a deep dive into how the cells behave and early findings on a new CAR T for multiple myeloma.
- Factors impacting survival in adults treated with CD19 CAR T-cell therapy for acute lymphoblastic leukemia. Dr. Kevin Hay, a Fred Hutch research fellow and clinician working in the Turtle lab, will present data on characteristics of patients who have a lasting remission following CD19 CAR T-cell therapy for acute lymphoblastic leukemia. He found that disease-related factors, pre-CAR T-cell conditioning and hematopoietic cell transplantation performed after CAR T-cell therapy impacted survival. The findings from about 50 patients contribute to emerging evidence that CAR T-cell therapy can be used to get patients with difficult-to-treat disease into remission and that subsequent stem cell transplantation may enable them to survive longer without their disease returning.
- When CAR T-cell therapy fails: Treatment strategies in lymphoma. CD19 CAR T-cell therapy has shown promise for patients with relapsed or refractory B-cell non-Hodgkin lymphomas, a population with historically poor outcomes and few treatment options. But up to 60 percent of patients do not achieve long-term remission after the therapy and there is no clear standard of what treatments to pursue when CAR T-cell therapy does not work. Dr. Victor Chow, a senior Hematology-Oncology fellow working with Dr. Ryan Lynch, an assistant professor and clinician at Hutch’s clinical care partner, Seattle Cancer Care Alliance, and University of Washington, examined patient outcomes for a group of about 60 patients treated in the past five years whose disease progressed after CD19 CAR T-cell therapy. Chow will report on how the disease progressed following the failed therapy. While most of the patients who went on to receive additional treatment lived longer, their outcomes were still poor. The physicians hope these data will generate new ideas and inform future clinical trial strategies for this population without clear treatment options.
- Profiling the anti-cancer behavior of CD19 CAR T cells. Little is known about the gene signatures of the engineered CAR T cells after they’ve been infused into patients. Dr. Alyssa Sheih, a postdoctoral researcher working in the Turtle lab, will speak about how she used TCR sequencing to track how the cells changed in patients who received the 1:1 ratio of millions of CD4 and CD8 CAR T cells. She compared the gene signatures of CAR T cells from the infused product and from blood samples from patients at different time points after receiving the therapy. Sheih discovered patterns of gene expression that corresponded with cells that expanded more than others after infusion. The researchers are using the proof-of-principle study to gain insight into strategies to improve CAR T-cell immunotherapy.
- Early results from a new CAR T-cell therapy for multiple myeloma. CAR T cells targeted to a protein called BCMA on multiple myeloma cells is an emerging treatment strategy for this typically incurable blood cancer. Dr. Damian Green, a physician-scientist at Fred Hutch and Seattle Cancer Care Alliance will present early findings from a phase 1 first-in-human clinical trial which showed that all patients who had not responded to frontline therapies responded to the lowest dose of the experimental BCMA CAR T-cell therapy administered in a 1:1 ratio of engineered CD4 and CD8 cells. Green describes the findings as showing early promise; the therapy could be safe and effective and may represent a treatment option that improves the long-term prospects for patients with multiple myeloma.
GENE THERAPY
- CRISPR-edited cells persist, effectively boost fetal hemoglobin in genetic blood disorders. Dr. Stefan Radtke, of Fred Hutch’s Stem Cell and Gene Therapy Program led by Dr. Hans-Peter Kiem, will discuss CRISPR editing in a specialized subset of blood stem cells identified in 2017 by the Fred Hutch team as capable of repopulating the entire blood and immune system. The approach reduces by 90 percent the amount of reagents needed to carry out the gene modification (currently a bottleneck in the field) and has the potential to make gene therapy faster and safer. The ASH presentation, of work led by Dr. Olivier Humbert, a staff scientist in the Kiem Lab, is a first proof-of-principle that the edited cell subset persisted for at least a year in a large animal model and was able to increase fetal hemoglobin to counteract the defective hemoglobin produced in the genetic blood disorders sickle cell and beta thalassemia. Humbert and colleagues presented preliminary findings earlier this year.
STEM CELL TRANSPLANTATION
- Bone marrow transplantation in older, frail adults with acute myeloid leukemia. Survival rates continue to improve for patients treated for AML, but treatment options for older and more frail patients have been limited, and these patients are often left out of clinical trials due to comorbidities. Dr. Mohamed Sorror, a Fred Hutch blood cancer physician and outcomes research scientist, is an expert in identifying patients in this demographic who would fare well – or not – in hematopoietic cell transplantation, which is considered the standard curative treatment for the disease. He will present on survival differences among some 700 patients enrolled on a multicenter trial.
ON THE HORIZON
Other notable experts and newsy topics being presented at ASH:
- Regenerating immune function in the thymus. The thymus is a gland in the chest that acts like a boot camp for T cells, training them to identify and kill foreign invaders. The gland wears out with stress, infection and age, and finding ways to boost its productivity could help sustain human health. Dr. Jarrod Dudakov, a Fred Hutch immunologist, studies the signaling pathways of the thymus, and he and members of his lab will present the latest chapter in his quest to find master regulators that could be targets for helping the thymus to repair itself. In this video, Dudakov talks about how the thymus degenerates and the cells and molecules involved in repairing it, a mechanism he described earlier this year in Science Immunology.
- The role of the microbiome in recovering from stem cell transplantation. The population of gut microbes changes when patients go through blood stem cell transplants as a result of antibiotics and other agents they receive as part of the life-saving treatment. Fred Hutch researchers are investigating how the microbiome interacts with immune cells in hopes of better understanding and treating graft vs. host disease, a common side effect of transplantation that occurs when the newly transplanted immune system attacks healthy tissue. Dr. Alyssa Sheih, postdoctoral fellow working in the Turtle Lab, will present a poster on how a common type of T cell called MAIT cells is linked to the populations of different microbes in stool samples of patients before, during and after stem cell transplantation. She says that the regrowth of MAIT cells — which can comprise up to 10 percent of T cells — accompanies the presence of gut bacteria species that are linked to not developing GVHD. The project is part of the Fred Hutch Microbiome Research Initiative, which is led by infectious disease expert Dr. David Fredricks.
- Cord blood transplantation for cancer and other blood disorders. Transplantation of blood stem cells from umbilical cord blood can treat blood disorders in patients who have not been able to find a suitable match among other donor sources, which is particularly difficult for patients of mixed ethnicity. Dr. Filippo Milano is associate director of Fred Hutch’s Cord Blood Program, and he cares for patients at Seattle Cancer Care Alliance. He will be available at the ASH meeting to discuss cord blood transplantation for cancer and other blood disorders. He was lead author of a 2016 New England Journal of Medicine study which found that high-risk leukemia patients who received cord blood transplants had a lower risk of relapse. He will lead a newly funded clinical trial for HIV-positive patients with leukemia, which has the potential to treat both cancer and HIV by using donor cells that are resistant to the virus.
- Long-term outcomes for patients receiving stem cell transplantation. Dr. Stephanie Lee, vice president of ASH, is a physician-scientist at Fred Hutch who cares for stem cell transplant patients at Seattle Cancer Care Alliance. She will become president of ASH in 2020. Lee is an expert in chronic graft vs. host disease and long-term survivorship following transplantation.