Mounting Success in Trials of Genetically Engineered T Cells to Treat Leukemias and Lymphomas
Mounting Success in Trials of Genetically Engineered T Cells to Treat Leukemias and Lymphomas
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David L. Porter, MD
Stephan A. Grupp, MD, PhD
Michael Kalos, PhD
James N. Kochenderfer, MD
Reports have been trickling in from centers conducting research on the use of chimeric antigen receptor–modified T cells (CAR-T) in hematologic cancer, and the news is encouraging. When directed against CD19, such personalized therapeutic T cells are known as CTL019, and petite pilot trials of this treatment have shown dramatic improvement in some patients who had been gravely ill.
Investigators from different institutions reported practice to date with CTL019 in patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma at the 55th Annual Meeting of the American Society of Hematology (ASH) in Fresh Orleans. The abstracts summarized here represent studies that are furthest along in the development of CTL019; at least seven other oral presentations at the ASH meeting focused on practice from other institutions.
The promise of the “smart bomb” treatment with this immunologic therapy has attracted industry to playmate with some investigators and their institutions. For example, CAR-T cells developed at the National Cancer Institute have been licensed to Kite Pharmaceuticals, and CAR-T cells developed at the University of Pennsylvania have been licensed to Novartis. In fact, Novartis is building a manufacturing facility to produce these cells near the University of Pennsylvania campus. Most recently, Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and Seattle Children’s Research Institute have joined coerces to launch Juno Therapeutics, a fresh biotechnology company that will develop CAR-T cells.
Experts predict that CTL019 therapies may become commercially available sometime inbetween two thousand sixteen and 2020.
The treatment harnesses the power of the immune system by reprogramming a patient’s own T cells to recognize cancer cells for a precision immunologic attack. The patient’s cells are extracted, engineered ex vivo to include CAR, and programmed to target the CD19 antigen present on most leukemic cells. A viral vector is inserted, and then the cells are reinfused into the patient for a single treatment. The viral vector triggers the T cells to expand and proliferate once they are reinfused. The engineering process takes about ten days.
In several pilot studies, patients have experienced varying degrees of the cytokine release syndrome, which is characterized by high fevers, muscle agony, low blood pressure, and breathing difficulties. The University of Pennsylvania investigators originally demonstrated that the interleukin-6 inhibitor tocilizumab (Actemra) tamps down this response, one which typically is seen when the engineered T cells are expanding in the assets, and several of the groups have reported rapid improvement in the cytokine release syndrome after treating with this drug.
Acute Lymphoblastic Leukemia
Stephan A. Grupp, MD, PhD, Director of Translational Research in the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia and Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, reported on practice with relapsed/refractory ALL in adults and children. Two Twenty-two pediatric patients and five adult patients with relapsed, treatment-resistant ALL have been treated with CTL019 at the University of Pennsylavnia.
Among the children, nineteen achieved a accomplish response, and remission is ongoing in 14, with five patients experiencing relapse. The very first patient treated with the protocol remains in remission twenty months later. All five of the adults achieved accomplish remission, the longest of which has been six months. One patient subsequently underwent bone marrow transplant and remains in remission. One patient relapsed after three months in accomplish remission, and his disease tested negative for the engineered cell target. The overall finish response rate in this group was 89%.
“Our results serve as another significant milestone in demonstrating the potential of this treatment for patients who truly have no other therapeutic options,” Dr. Grupp said.
A separate report from the University of Pennsylvania discussed the quantity, lifespan, and activity of the engineered T cells once they were reinfused into the pediatric and adult patients with ALL (described above) and adults with advanced relapsed/refractory CLL. Three Testing demonstrated that patients with the greatest in vivo expansion of CTL019 cells (to more than 5% of all CD3-positive cells) were the most likely to achieve accomplish remission. Those with less sturdy but still detectable cell expansion were partial responders, while those with no or minimal detectable T-cell expansion were nonresponders. The CTL019 cells that were detected persisted for many months after infusion and continued to function as anticancer T cells.
“These fresh and expanded data provide significant proof that T cells engineered to express cancer-targeting CARs not only work, but work dramatically and in a sustained manner in patients with relapsed/treatment resistant leukemia. [The results] further demonstrate the potential of this treatment to help these patients achieve finish remission,” said explore author Michael Kalos, PhD, Director, Translational and Correlative Studies Laboratory, Stellar-Chance Laboratories, and Adjunct Associate Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania.
“Further, … we can potentially measure and track these engineered cells as a way to monitor treatment, an titillating finding considering that this treatment is often the last hope for these patients,” he added.
Chronic Lymphocytic Leukemia
David L. Porter, MD, Director of Blood and Marrow Transplantation at the University of Pennsylvania’s Abramson Cancer Center, reported on practice in the treatment of thirty two adults with CLL. Fifteen patients (47%) responded to therapy (7 accomplish responses and fifteen partial responses). The accomplish remissions are ongoing, he noted.
The thirty two CLL patients included fourteen who were in the pilot trial and the very first eighteen in a phase II dose-optimization trial. Four,Five
“We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells,” Dr. Porter said. “We’ve now seen remissions lasting for more than three years, and there are clues that the T cells proceed to kill the leukemia cells in the bod for months after treatment. Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow and their lymph knots continued to shrink over time. In some cases, we have seen partial responses convert to finish remissions over several months.”
Very first Report in B-Cell Lymphoma
James N. Kochenderfer, MD, an investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute, Bethesda, Maryland, described successful treatment with anti-CD19 CAR-T cells in a total of fifteen patients with chemorefractory B-cell lymphomas: nine had aggressive large B-cell lymphomas, and six had a multiplicity of indolent B-cell lymphomas. Patient ages ranged from thirty to sixty eight years. 6
“Our data provide the very first true peek of the potential of this treatment in patients with aggressive lymphomas that—until this point—were virtually untreatable and have a very poor prognosis. The novel finding is that anti-CD19 CAR-T cells can eradicate a solid tumor mass,” Dr. Kochenderfer said.
Patients underwent a conditioning regimen with cyclophosphamide and fludarabine prior to receiving a single infusion of their own genetically modified T cells. This conditioning regimen was used because prior chemotherapy has been shown to enhance the activity of anti-CD19 CAR-T cells in patients.
Seven patients achieved a finish response, five achieved a partial response, and one patient had stable disease. One patient died of cardiac arrhythmias, and a 2nd patient was lost to follow-up. Acute toxicities included fever, low blood pressure, focal neurologic deficits, and delirium. These toxicities resolved in less than three weeks.
“We are particularly encouraged by the partial and finish responses that we observed in a number of patients with diffuse large B-cell lymphomas who had weary all other treatment options,” Dr. Kochenderfer said. “This treatment offers an option for patients with chemotherapy-refractory large B-cell lymphomas who are generally not thought to be good candidates for hematopoietic stem cell transplantation.”
In the protocol used by Dr. Kochenderfer and co-investigators, the CAR is encoded by a gamma retrovirus and incorporates regions of an anti-CD19 antibody, part of CD28, and part of CD3-zeta. The anti-CD19 CAR-T cell protocols are evolving and still in early stages, he noted.
“We will proceed our research to further improve the protocol and evaluate its value in extra patients with treatment-resistant disease,” he said. ■
Disclosure: The NCI trial was supported in part by Kite Pharma. Dr. Kochenderfer has no private financial ties and has received no payments from Kite Pharma. Dr. Porter reported research funding and intellectual property/royalties in association with Novartis, as well as spouse employment with Genentech. Dr. Kalos reported patents and royalties in association with Novartis and is a member of the scientific advisory board for Adaptive Biotechnologies. Dr. Grupp receives research funding from Novartis.
1. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013.
Trio. Kalos M, Nazimuddin F, Finklestein JM, et al: Long-term functional persistence, B cell aplasia, and anti-leukemia efficacy in refractory B cell malignancies following T cell immunotherapy using CAR-redirected T cells targeting CD19. ASH Annual Meeting. Abstract 163. Introduced December 8, 2013.
Four. Porter D: Randomized phase II dose optimization explore of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. ASH Annual Meeting. Abstract 873. Introduced December Ten, 2013.
Five. Porter D, Kalos M, Frey N, et al: Chimeric antigen receptor modified T cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL. ASH Annual Meeting. Abstract 4162. Introduced December 9, 2013.
6. Kochenderfer J, Dudley ME, Kassim SH, et al: Effective treatment of chemotherapy-refractory diffuse large B-cell lymphoma with autologous T cells genetically-engineered to express an anti-CD19 chimeric antigen receptor. ASH Annual Meeting. Abstract 168. Introduced December 8, 2013.
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Accomplished Point of View: Prashant Kapoor, MD
At the latest American Society of Hematology Annual Meeting, Prashant Kapoor, MD, Assistant Professor of Hematology at Mayo Clinic, Rochester, Minnesota, agreed that CTL019 is a promising, arousing, and novel treatment to treating patients with advanced B-cell hematologic malignancies.
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