Checkpoint inhibitors are not the only means of modulating the immune system to treat advanced forms of cancer. One such alternative, chimeric antigen receptor (CAR)-T cells, is already showing great clinical promise in patients with hematologic malignancies.
“I think adoptive cell therapy will make it into the mainstream,” said Jeffrey Weber, MD, PhD, Senior Member and Director of the Comprehensive Melanoma Research Center, at Moffitt Cancer, Tampa, FL. “There are about 30 ongoing CD19 immunologic malignancy CAR-T cell trials. One or more of those re-agents will get approved, I’m sure, in the next year or so.”
CAR-T cells are engineered receptors used to graft the specificity of a monoclonal antibody onto a T-cell. In a technique called adoptive cell transfer, T-cells are removed from a patient and modified so that they express receptors specific to the particular form of cancer. These T-cells are then reinfused into the patient with the potential benefit of recognizing and killing cancer cells.
Although still a relatively new technique, research is moving fast. Data from 3 separate clinical trials presented at ASCO 2015 highlight the progress being made.
A phase 2 clinical trial of CTL019 (a second-generation anti-CD19 CAR) in 22 patients with relapsed or refractory CD19+ non-Hodgkin lymphoma (NHL) showed a 50% response rate among patients with diffuse large B-cell lymphoma and a median progression-free survival (PFS) of 3 months; in patients with follicular lymphoma, 100% of evaluable patients responded, and the median PFS was not reached. Data on patients with mantle-cell lymphoma were immature. The toxicity level was acceptable.
A phase 1 clinical trial of 19-28z CAR-T cells (after high-dose therapy and autologous stem-cell transplantation) in 11 patients with relapsed or refractory aggressive B-cell NHL showed that 4 of 10 evaluable patients remained alive and progression-free from 13 to 21 months posttransplant. Overall, 7 of the 11 patients experienced cytokine-release syndrome, but this was effectively treated.
A phase 1 study of CTL019 in patients with advanced multiple myeloma showed evidence of clinical benefit in 3 of 4 patients with >100 days of follow-up (NCT02135406).
Safety and Efficacy Issues
According to Madhav Dhodapkar, MD, Professor of Medicine and Immunobiology at Yale University, however, if CAR-T cells are to progress beyond limited centers, the safety and efficacy of these agents must improve.
“The trials show promising clinical activity, but we need to better understand the biology of cytokine-release syndrome and neurotoxicity,” he said, “and we must have better predictors and biomarkers.”
Another limitation cited by Dr Dhodapkar is the duration and persistence of CAR-T cells.
“We don’t really know yet how efficiently these CAR-T cells infiltrate lymph nodes,” he said. “We need to understand how to improve survival, effector function, persistence within the tissues themselves, and homing of CARs.”
In addition to overcoming immune suppression, Dr Dhodapkar stressed the importance of integrating CAR-T cells with other therapies, including combination therapies, such as checkpoint blockade.
David E. Avigan, MD, Associate Professor of Medicine, Harvard Medical School, also discussed the need to modulate this therapy, voicing concern about toxicities and emphasizing the need to eliminate the “off target” effects of CAR-T cells.
“We need to understand better how we might select T-cell populations to improve persistence…and ultimately to integrate these types of therapies with some of the other strategies, such as checkpoint blockade and vaccines, to think about a broader targeting pattern,” Dr Avigan said.
Coming to Fruition
Despite these obstacles, Dr Weber is confident that CAR-T cells will ultimately thrive, even predicting that this technology would soon find success outside of hematologic malignancies.
“CAR-T cells will be expanded to show benefit in solid tumors,” Dr Weber said, predicting that phase 3 trials will likely be positive. “There will be all kinds of clever, innovative strategies to limit the side effects, but maintain the benefit. You’re going to see a lot of adoptive cell therapy in the next 5 years…the best is yet to come.”
Stephen J. Schuster, MD, Director, Lymphoma Translational Research, Abramson Cancer Center of the University of Pennsylvania, shared a similar enthusiasm for this rapidly evolving field.
“We have been able to see the persistence of CAR-T cells in our patients beyond 3 years,” Dr Schuster said. “Furthermore, we have found that CAR-T cells are not only persistent…, they are still functional.”
He added, “and the patients with very durable responses have an ongoing immune surveillance by the CAR-T cells against the tumor. I really like what I am seeing in the patients I am treating.”
For patients with chronic lymphocytic leukemia, acute lymphocytic leukemia, or NHL, Dr Schuster envisions a future in which CAR-T cells could even replace stem-cell transplants.
“For those three diseases, I will go out on a limb and say that this kind of smart autologous immunocellular therapy may someday be the ‘transplants’ of the future,” Dr Schuster predicted.