Immunotherapy with CD19+ chimeric antigen receptor (CAR) T cells made up of a defined 1:1 ratio of CD8+ and CD4+ resulted in a durable complete response (CR) in a high proportion of adult patients with refractory or resistant acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL). The results from this phase I/II trial were presented by Cameron John Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center at the Clinical Science Symposium, “The View Beyond Single-Agent Checkpoint Blockade,” held Saturday, June 4 (Abstract 102).
Dr. Cameron John Turtle
CAR T cells combine an antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein. Using gene transfer technology, the CAR molecule is stably expressed on a T cell that confers novel antigen specificity to that cell.
In this study, 90 patients with CD19+ B-cell malignancies including ALL (36 patients), NHL (41 patients), and CLL (13 patients) underwent leukapheresis to produce autologous CAR T cells. After lymphodepletion, patients were infused with one of three CAR T cell dose levels from 2 x 105, 2 x 106, and 2 x 107 cells/kg.
The best responses were achieved in the subset of patients with ALL. Thirty-two of 34 patients with ALL (94%) who completed a response assessment had a bone marrow CR. In vivo CAR T cell expansion and persistence and disease-free survival were superior in the two-thirds of the ALL group who received cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion compared with one-third who received cyclophosphamide without fludarabine. At 18 months, a disease-free survival rate of approximately 60% was seen in Cy/Flu ALL group compared with less than 10% of the cyclophosphamide-only arm (p = 0.0005). Overall survival was not yet significant.
In this investigation, in vivo CAR T cell expansion and toxicity correlated with bone marrow blast count and the infused CAR T cell dose. “As such, patients with higher levels of blasts in the bone marrow should receive lower CAR T doses, and those with lower initial levels should receive higher doses,” said Dr. Turtle.
In NHL, the study identified the maximum tolerated dose to be the dose level two (2 x 106 cells/kg). An objective response rate (ORR) of 80% was achieved among those patients receiving 2 x 105 cells/kg CAR T infusion with Cy/Flu lymphodepletion (16 of 20 patients). Of these, half achieved a CR (10 of 20). With this preferred regimen, the median PFS survival or OS for those NHL patients who achieved a CR had not yet been reached.
The ORR among patients with CLL who underwent Cy/Flu lymphodepletion and CAR T cell immunotherapy was 91% (10 of 11); 45% (5 of 11) achieved a CR. The median PFS and OS survival among these patients was not reached.
In this study, the number of patients with high-grade cytokine release syndrome was 26% for risk-adapted ALL, 10% for NHL with preferred level dosing, and 23% for CLL. Neurotoxicities (Common Terminology Criteria for Adverse Events grade 3 or greater) were 26%, 10%, and 23% in ALL, NHL, and CLL, respectively.
“CAR T cells can recognize the tumor antigen they did not previously recognize, hopefully leaving behind a dead tumor cell,” said David L. Porter, MD, of the Abramson Cancer Center of the University of Pennsylvania, who commented on the study results. “Ultimately, this type of targeted cellular immunity is going to be able to overcome many of the limitations of conventional forms of chemotherapy and other types of immunotherapy.”
Explaining that CAR T cells are “living drugs that can grow in the body,” this type of cell expansion amplifies any antitumor response. Similarly, CAR T cells have the ability to persist for long periods of time, persisting beyond 5 years, providing ongoing antitumor activity.
Dr. Porter also pointed out several unknowns about CAR T cells, such as the ideal CAR construct and cell dose, composition, target, and source. Similarly, the limits of autologous CAR T-cell therapy may point the way to donor CAR T cells or use in combination therapy with other immune inhibitors such as checkpoint inhibitors.