Chicago, IL—Chimeric antigen receptor (CAR) T-cell therapy is changing cancer care. In 2010, there were just 3 CAR T-cell clinical trials. As of May 2017, 183 clinical trials are underway, and for the first time, there are more clinical trials in China than in the United States, according to Carl H. June, MD, Director, Translational Research Program, University of Pennsylvania, Philadelphia, at the 2017 ASCO annual meeting. Dr June discussed how this rapidly evolving technology is taking immuno-oncology to the “next level” of precision medicine.
“Engineered T-cells can be resistant to immunosuppressive and toxic effects of tumor microenvironments and can proliferate on demand so that they can be self-replicating in a so-called living drug. CAR T directed against CD19 and BCMA [B-cell maturation antigen] molecules has potent activity in leukemia and myeloma, with the progeny of as few as 1 anti-CD19 CAR T-cell able to eliminate leukemia,” said Dr June.
Having started with advanced refractory chronic lymphocytic leukemia (CLL), researchers at the University of Pennsylvania have now treated nearly every form of B-cell malignancy with the same technology—anti-CD19 CAR T-cell therapy that involves a 10-day manufacturing process, with the cells frozen at the end and shipped to the patient for infusion.
At last year’s annual meeting, David L. Porter, MD, Director, Blood and Marrow Transplantation, Hospital of the University of Pennsylvania, Philadelphia, reported the results of a multicenter clinical trial involving patients with relapsed or refractory CLL that showed several complete responses with anti-CD19 CAR T-cell therapy.
“The most remarkable aspect about CLL is that there have been no relapses. Patients go into remission, and it’s very durable. Our first patients are out now 6 years,” said Dr June.
Targeted plus CAR T-Cell Therapy
At the recent ASCO annual meeting, anti-CD19 CAR T-cells combined with ibrutinib (Imbruvica) were shown to induce a high rate of complete remission in patients with CLL that was refractory to up to 12 lines of treatment. The treatment was well-tolerated, and 9 of 10 patients who received anti-CD19 CAR T-cell therapy plus ibrutinib reached ≥1 months of follow-up. Overall, 89% of patients had minimal residual disease–negative complete remission. Next-generation sequencing showed that the leukemic clone had been eradicated at 3 months in 4 of 7 patients.
“We’ve seen that by combining targeted therapy with CAR T-cells, it becomes an outpatient trial. No patients required admission to the hospital for cytokine release syndrome. However, this is recent data, so durability remains to be established,” said Dr June.
Although the safety of CAR T-cell therapy remains a concern, recent clinical trials have demonstrated improved treatment of CAR T-cell therapy–related adverse events, especially cytokine release syndrome, which is managed with tocilizumab (Actemra), cetuximab (Erbitux), or corticosteroids.
Results from the ELIANA clinical trial, which were presented in December 2016, showed that it is possible to globalize a CAR T-cell clinical trial, while yielding deep and durable remissions and limiting severe adverse events. There were no cases of cerebral edema–related deaths or cytokine release syndrome in the ELIANA study, noted Dr June.
Combination therapies with checkpoint inhibitors are also being explored for potential synergy. Based on research by Darcy and colleagues, Dr June and colleagues at the University of Pennsylvania are investigating the use of PD-1 antagonists to prolong T-cell function in PD-1–positive cancer cells. Pembrolizumab (Keytruda) is being combined with CD19-targeted CAR T-cells in a clinical trial of adults with diffuse large B-cell lymphoma and in a clinical trial for pediatric acute lymphocytic leukemia.
In addition to CD19, CAR T-cell therapy targets include BCMA, which is a very promising target for multiple myeloma, because the majority of multiple myelomas express this protein. In the first cohort tested at the University of Pennsylvania, where no lymphodepletion regimen was given, investigators observed a 44% response rate with CAR T-cell therapy directed against BCMA, and the first patient is now more than 1 year out. Recent data have also shown that, with a highly proliferative cell, only 1 CAR T-cell may be needed to treat a patient with CLL, although researchers are still learning from a single, exceptional responder.
As CAR T-cell therapy continues its global expansion, the challenge is to forge a new therapeutic pillar of healthcare to accompany pharmaceuticals, biopharmaceuticals, and medical devices. One approach will be to use off-the-shelf cells from unrelated donors, cord blood, or induced pluripotent stem cells.
“This has already been done with infants. I think in the future, we’ll see both patient-specific, autologous-engineered cells, as well as off-the-shelf cells. This will be a huge area of growth,” concluded Dr June.