Building on research momentum and attention in the field of hematology over the past several years, chimeric antigen receptor T-cell therapy took center stage at the annual American Society of Hematology Annual Meeting and Exposition in Orlando, Fla.
Promising results presented on the use of CAR T cells in the treatment of patients with hematologic malignancies — from lymphoma and leukemia to myeloma — left experts excited about the potential for not only improved survival outcomes, but possible cure.
Relapsed or refractory non-Hodgkin's lymphoma
Diffuse large B-cell lymphoma, chronic lymphocytic leukemia
Joshua Brody, MD, director of the Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai Hospital, New York, called the new data a significant development and offered insight on the implications.
“With these CAR T-cell therapies, we saw people getting remissions, including complete remissions, and some of those complete remissions lasting for a long time,” he told Healio.com
Brody highlighted an investigation by Stephen Schuster, MD, and colleagues at the University of Pennsylvania, Philadelphia, looking at the safety and efficacy of anti-C19 CAR T-cell therapy in patients with diffuse large B-cell lymphoma.
“It’s possible that those patients are cured,” he said, noting that several years of continued follow-up is necessary for certainty.
Steven I. Park, MD, associate professor of medicine in the division of hematology/oncology, University of North Carolina School of Medicine, and director of the UNC Lineberger Lymphoma Oncology Program, agreed the results were “exciting.”
Park pointed to the overall response rate of 68%, highlighting all patients with follicular lymphoma were responders, as well as the PFS rate of 62% at 1 year.
“Toxicity was felt to be manageable,” he said, noting 16 patients developed cytokine release syndrome. “The follow-up period is relatively short, but it is certainly a very promising treatment for lymphoma.”
With lymphoma currently the fifth most common cancer in the United States, affecting approximately 80,000 people each year, and DLBCL the most common subtype, Brody said the findings were among the most compelling in the subspecialty.
“These patients do not have other great therapies that can offer long remissions — and certainly not ones that can give them cures.”
An investigation by Cameron J. Turtle, MBBS, PhD, and colleagues at Fred Hutchinson Cancer Research Center, Seattle, studying the use of anti-C19 CAR T-cell therapy to treat patients with chronic lymphocytic leukemia also demonstrated positive results.
“In this study, the treatment appeared more effective when fludarabine was added to the cyclophosphamide-based therapy for lymphocyte depletion,” said Park, highlighting the complete response rate of 42%. “Again, a very promising number.”
Steven I. Park
Brody said although it has been a standard part of CAR T-cell trials to give patients some type of chemotherapy before administering the genetically-engineered immune cells in order to remove the competitor cells and “make space,” these findings offer clear direction.
“The researchers tried gentler and more aggressive chemotherapies,” Brody said. “It turns out the more aggressive type, not very surprisingly, allows the CAR T cells to live longer in the person, to amplify more and to fight cancer better. That’s good to know.”
Despite knowing the best treatment strategy, Brody said it is not all good news. With more chemotherapy comes additional side effects — the primary one being cytokine release syndrome.
“That’s a big obstacle that we still have to face,” he said. “People basically get low blood pressure, fast heart rate and have to go into the intensive care unit; they can get very sick from it.”
Managing toxicity with CAR T-cell therapy
Current approaches, looking ahead
Brody touched on two “fixes” — the anti-interleukin-6 receptor antibody tocilizumab (Actemra, Genentech), which seems to improve the cytokine release syndrome by half, and a new generation of CAR T-cell therapies featuring a molecular safety switch that can be activated with a pill. He underscored discussing these is somewhat premature.
Catriona Jamieson, MD, PhD, associate professor of medicine, division of hematology-oncology, co-leader of the hematologic malignancies program, and director of stem cell research at UC San Diego Moores Cancer Center, highlighted novel research into modifying CAR T-cell technology by Reona Sakemura, MD, and colleagues from Nagoya, Japan.
“The investigators were trying to make a CD19 chimeric antigen receptor system that could be turned on with tetracycline,” she said. “You give the person tetracycline to activate the CAR T cell, and then without tetracycline it would turn off.”
Jamieson noted the researchers did encounter “leakiness” issues, with some activity observed even in the absence of tetracycline, but said the strategy would indeed be interesting if it were possible.
“It was very innovative,” she said. “If you have problems with cytokine release syndrome, and you just can’t turn it down with anti-IL-1 blockade or anti-IL-6 blockade, maybe this would be a way of turning that off before it becomes lethal.”
Although the challenges in precision medicine are often around gauging whether enough therapy was given, Jamieson noted the issue in implementing CAR T-cell therapy is that sometimes “it can just be too much … and you have to curtail the activity.”
Research motion, new potential
Although the field has yet to see evidence for the use of CAR T-cell therapy in other common cancers, research to move the approach from lymphoma and leukemia into malignancies of the breast and lung as well as multiple myeloma is underway.
Mark Levis, MD, PhD, professor of pharmacology and molecular sciences, Johns Hopkins University School of Medicine, Baltimore, said he was “quite excited” by first-in-human findings from a clinical trial of T cells expressing an anti-B-cell maturation antigen CAR in advanced MM.
“Sure enough, it looked like the therapy worked just as well as it did for the [acute lymphoblastic leukemia],” he said. “They got some dramatic responses in a very tough-to-treat disease.”
Levis said figuring out how to make CAR T cells work in MM could radically change the field, with an impact potentially as significant, if not more so, than in ALL, for which it was originally developed.
“There are a lot more patients with myeloma, and I’ll bet that that cancer will respond more effectively,” he said. “This will lead to a pronounced prolongation of survival for a much larger fraction.” - by Allegra Tiver
Schuster SJ, et al. Abstract 183. Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas.
Turtle CJ, et al. Abstract 184. Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and Persistence of CAR-T Cells and Clinical Outcomes.
Sakemura R, et al. Abstract 4424. A Novel Strategy of Switching on/Off CD19CAR Expression Under Tetracycline-Based System.
Abbas S, et al. LBA-1. Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor.
Brody and Levis report no relevant financial disclosures. Jamieson reports that her lab receives unrestricted research funding from CTI Biopharma and Johnson & Johnson. Park reports receiving research funding from Seattle Genetics and Teva.