Last year results from two early clinical trials indicated that immunotherapy using chimeric antigen receptor (CAR) T-cell therapy may be effective in patients with multiple myeloma.1,2
Given as a single treatment, CAR T-cell therapy uses a patient’s own immune system to fight their disease. Blood is collected from the patient and T-cells are separated and engineered to express and target specific CARs.
“We have been able to extend the lives of patients with myeloma with many different novel therapies, but myeloma has long been considered an incurable disease,” said Michael Milone, MD, PhD, Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania in Philadelphia. “We want to cure patients and give them long-term disease control, and we feel that CAR has the potential to do that.”
CAR T-cell therapy has already had some initial success with the approval of tisagenlecleucel (Kymriah) for the treatment of children and young adults with advanced leukemia and adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, and axicabtagene ciloleucel (Yescarta) for patients with large B-cell lymphoma whose cancer had progress after at least two prior therapies.3
Finding a Target
In leukemia and lymphoma, the approved CAR T-cell therapies target the human CD19 antigen, a known biomarker for normal and neoplastic B cell development. In myeloma, the CARs are targeting a protein on myeloma cells called B-cell maturation antigen (BCMA).
When looking for a target for CAR T-cell therapy there are several important features, according to Damian Green, MD, associate professor at the University of Washington School of Medicine and associate member at Fred Hutchinson Cancer Research Center in Seattle.
First, the selected target must be present on the tumor cells. BCMA is detectable in most, but not all, patients with myeloma, Dr Green said. Second, ideally the selected targeted would be restricted to just the tumor cells, with no or limited expression on other normal tissues. Finally, it is important that the target is not only expressed on the tumor cells, but expressed at relatively high levels.
Once a target is established, the next step is to develop a CAR T-cell therapy that will effectively expand in the patient and persistently fight the cancer.
“We need high peak levels of expansion so that when we put cells in, they expand to a level where we are confident that they will go after and take out myeloma wherever it may be hiding,” Dr Green said. “Persistence is also important so that the cells stick around in the patient to not just have an immediate effect, but a long-term benefit with ongoing ‘surveillance’ against the tumor cell.”
At the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, initial results from a Chinese trial testing anti-BCMA CAR T-cell therapy were presented.2 The trial included patients with relapsed or refractory disease treated with LCAR-B38M CAR T-cell therapy, of whom 33 of 35 went into complete remission within 2 months of infusion. Of 19 patients who had been followed for 4 months or longer, 14 had stringent complete response, with no evidence of disease.
In December, updated results of another CAR therapy targeting BCMA were presented at the 2017 American Society of Hematology Annual Meeting.1 This study looked at bb2121 (Celgene) in patients with relapsed or refractory myeloma. Among 21 patients, a one-time infusion of bb2121 resulted in an 86% overall response rate. In 18 patients who received a high dose of infused CAR T cells, the response rate increased to 94%, with 10 patients achieving complete response.
Dr Green is also involved in a clinical trial at Seattle Cancer Care Alliance, where they are currently treating their fifth patient with BCMA-targeting CAR T-cells.
“Preliminarily, it looks to be working extremely well,” he said. “We continue to increase the dose to find the right one to ensure high peak levels and ongoing surveillance, but our experience so far has been responses that are quite dramatic in patients that have received lots of prior therapies.”
CAR T-cell therapy targeting myeloma is also being explored in clinical trials at Memorial Sloan Kettering Cancer Center, the University of Pennsylvania, and other institutions, each with a slightly different CAR construct.