New research presented at 60th annual ASH meeting

December 19, 2018 | by City of Hope

The 60th American Society of Hematology meeting recently took place in San Diego and was host to more than 25,000 hematology professionals who focus on research and treatment for blood cancers and other diseases. Novel research from several City of Hope investigators was presented during this meeting.
 
 
This study is touted as the first to demonstrate that local brain delivery of chimeric antigen receptor (CAR) T cells are capable of treating both systemic lymphoma and lymphoma in the CNS. Notably, CNS lymphoma, a disease limited to the brain, cannot be treated through surgery because the tumors are widespread, and chemo drugs cannot pass through the protective blood-brain barrier. CAR T cell therapies are usually delivered intravenously and have not been used in treatment for CNS lymphoma due to concerns of effectiveness and potential side effects such as cytokine release syndrome.
 
Xiuli Wang, Ph.D., research professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, and her team used a mouse model to test the intracerebroventricular delivery of T cells modified to express a CD19-CAR. They found that a single local infusion was enough to completely eradicate CNS lymphoma and systemic lymphoma throughout the mouse body after 14 days. The mice remained tumor-free for 300 days, the length of the experiment. The control mice received intravenous CAR T cell therapy and had delayed anti-tumor activity that led to temporary remission and death before day 180.
 
Imaging results of mice who received intracerebroventricular therapy delivery showed that the CAR T cells were able to migrate to tumor sites outside the brain. Moreover, 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 I clinical trial in 2019.
 
 
In a multisite, international phase I/Ib clinical trial, Lihua Elizabeth Budde, M.D., Ph.D., assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, and her team are testing a promising immunotherapy in relapsed/refractory B cell non-Hodgkin lymphoma. If proven effective, this treatment will herald a new treatment paradigm for this disease.
 
The ongoing first-in-human study testing for safety has recruited more than 98 patients to receive varying doses of the two-armed antibody mosunetuzumab. Delivered intravenously, mosunetuzumab works by binding T cells with one arm and lymphoma cells with the other. Being in such close proximity allows the T cells to better recognize and attack the lymphoma cells.
 
The maximum tolerated dose has not yet been reached but so far, most of the adverse events have been  low-grade and manageable. Eighteen patients (27%) had a complete response and have stayed in remission, with the longest period of remission being over two years.
 
 
A phase I clinical trial is testing the safety and tolerability of a novel conditioning regimen for patients with peripheral T cell lymphomas who are undergoing autologous stem-cell transplants. Peripheral T cell lymphomas have a poor prognosis, and despite autologous stem-cell transplants, patients often relapse within a few years.
 
The current trial, headed by Jasmine Zain, M.D., director of City of Hope’s T Cell Lymphoma Program, is testing a radiolabeled version of basiliximab, an antibody that targets the CD25 protein, which is differentially expressed in T cell lymphomas. By providing targeted radiation to the tumor cells, 90Y basiliximab can specifically inhibit the growth of T cell lymphomas.
 
Three different dose levels of targeted radiation are being explored in combination with BCNU, etoposide, cytarabine and melphalan (BEAM chemotherapy). Results so far show that 90Y basiliximab does not increase toxicity when added to BEAM chemotherapy, and a safe dose level has been established. Eight of the 14 patients who underwent the experimental treatment over a nearly three-year period remain in remission. The study was not designed to assess the efficacy of the regimen, but a dose-expansion phase is in progress to answer that question.
 
 
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 and Hematopoietic Cell Transplantation at City of Hope, may have found a CAR T product that is more potent and less toxic.
 
Investigators have used a unique manufacturing platform developed at City of Hope that generates therapeutic cells from a pool of T cells enriched for memory and naïve T cell populations. These T cells were engineered to express CD19:28z-CAR and then injected into patients with relapsed/refractory acute lymphoblastic leukemia.
So far, 11 out of 11 patients evaluable for response are in complete remission, showing a 100 percent response rate with no significant increase in toxicity.
 
 
Hong Qin, Ph.D., associate research professor in City of Hope’s Department of Hematology and 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 with a CAR T cell therapy that targets the B-cell activating factor receptor (BAFF-R). BAFF-R is primarily expressed on B-cells and various subtypes of B-cell non-Hodgkin’s lymphoma and acute lymphoblastic leukemia, and can be used to help patients who are experiencing relapse after receiving other CAR T therapies.
 
Data suggest that targeting BAFF-R may add to existing alternative strategies to overcome relapse from CD19 antigen loss. According to Qin, a clinical trial at City of Hope is under development for 2019 that will be the first BAFF-R CAR T trial for patients who have no other therapeutic options.
 
Have a patient who may be a candidate for CAR T cell therapy?
 
Call the dedicated CAR T cell therapy referral line 833-310-CART (2278), or visit cityofhope.org/cart
 
For a full listing of clinical trials, visit clinicaltrials.coh.org
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