City of Hope investigators present breakthrough research at 60th American Society of Hematology meeting

December 5, 2018 | by Letisia Marquez

The American Society of Hematology (ASH) annual meeting hosted more than 25,000 hematology professionals — including many from City of Hope — who focus on research and treatment for blood cancers and other diseases.
“City of Hope clinical and laboratory investigators enjoyed sharing our leading-edge research findings and demonstrating our continued commitment to advancing the most promising cures against cancers, including finding new targets in CAR T cell therapy,” said Stephen J. Forman, M.D., leader of City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute and the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation.
City of Hope physician-scientists presented clinical trials that provide the foundation for new treatments for patients with T cell lymphoma, non-Hodgkin's lymphoma and acute lymphoblastic leukemia. They also discussed mouse studies that experimented with a different and possibly more effective way of delivering chimeric antigen receptor (CAR) T cells for leukemia and lymphoma in the central nervous system. The research is discussed in more detail below.

Delivering CD19-CAR T cells directly into cerebrospinal fluid to treat lymphoma

This mouse study, by Xiuli Wang, Ph.D., research professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, is touted as the first to demonstrate that local brain delivery of CAR T cells is capable of treating systemic lymphoma.
The experiment also demonstrated that delivering CAR T locally into the cerebro-spinal fluid appears to be more efficacious than intravenous delivery. When researchers imaged the mice, they found that CAR T cells migrated to tumor sites outside of the brain. In addition, the CAR T cells persisted in the mice with the experimental treatment much longer than when they are delivered intravenously – helping to maintain an anti-tumor environment to ward off relapse.
Wang hypothesizes that intracerebroventricular infusion of CAR T therapy may be safer and more effective than intravenous infusion. Her team will test this hypothesis in a phase 1 clinical trial next year.

A chemotherapy-free immunotherapy that uses a special two-armed antibody

In a multisite, international phase 1/1b clinical trial, Lihua Elizabeth Budde, M.D., Ph.D., assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, et al. are testing a promising two-armed antibody that could strong-arm relapsed/refractory B cell non-Hodgkin’s lymphoma into remission. If proven effective, the treatment heralds a new age where chemotherapy and its painful side effects will be obsolete in the treatment of this disease.
The ongoing first-in-human study testing for safety has recruited more than 98 patients to receive varying doses of mosunetuzumab, an experimental antibody.
The trial’s response rate is around 70 percent, which is promising because the maximum tolerated dose has not yet been reached. Most of the patients are in complete remission and have stayed in remission – the longest patient has been cancer-free for more than two years – without needing any other treatment, Budde said.

Novel regimen for patients with certain lymphomas undergoing a stem cell transplant

In a phase 1 clinical trial designed to test the safety and tolerability of a novel conditioning regimen for patients with peripheral T cell lymphomas undergoing autologous stem cell transplants (which use the patient’s own stem cells), Jasmine Zain, M.D., director of City of Hope’s T cell Lymphoma Program, and her colleagues found that City of Hope-manufactured 90Yttrium-radiolabeled ( 90Y) basiliximab appears to be safe when used in combination with BEAM. There was no increased toxicity compared to using BEAM chemotherapy alone, and side effects were minimal, the study found.

Memory-enriched CAR T cells: High response rates and low toxicity

CAR T cell therapy reportedly achieves complete remission in patients with acute lymphoblastic leukemia about 80 percent of the time; however, a large proportion of these patients have side effects such as cytokine release syndrome and neurotoxicity. Samer Khaled, M.D., associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, said he may have found a CAR T product that is more potent and less toxic – a potential game-changer if the early results of his ongoing phase 1 clinical trial holds through future testing.
So far, the clinical trial has enrolled 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia, a disease that has poor survival rates. The physician-scientists treated 13 eligible patients with T cells engineered to express CD19:28z-CAR. Investigators used a unique manufacturing platform developed at City of Hope that generates therapeutic cells from enriched memory and “naïve T cells” – immune soldiers known for their capacity for long-term persistence.
Eleven out of 11 patients evaluable for response received the treatment and are in complete remission, showing a 100 percent response rate with no significant increase in toxicity.

City of Hope research on a new CAR T therapy, BAFF-R

Hong Qin, Ph.D., associate research professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, and Larry Kwak, M.D., Ph.D., Dr. Michael Friedman Professor in Translational Medicine and director of the Toni Stephenson Lymphoma Center, have conducted new research demonstrating that a CAR T cell therapy targeting the B cell activating factor receptor (BAFF-R), a protein that is primarily expressed on B cells and various subtypes of B cell non-Hodgkin's lymphoma and acute lymphoblastic leukemia, can be used to help patients who are experiencing relapse after receiving other CAR T therapies.
“City of Hope is planning a clinical trial in the coming year that will be the first BAFF-R CAR T trial for patients, providing new hope for patients who have no other therapeutic options,” Qin said.
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