CAR-T viewed as ‘pinnacle’ of immunotherapy for advanced ALL
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Chimeric antigen receptor T-cell therapies are the apex of a practice-changing shift in the treatment of acute lymphoblastic leukemia, according to a presenter at NCCN 2020 Virtual Congress: Hematologic Malignancies.
Despite conferring unprecedented response rates among patients with relapsed or refractory disease, proliferation of CAR T-cell therapies remains a challenge, according to Patrick A. Brown, MD, associate professor of oncology and pediatrics and director of the pediatric leukemia program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine.
“CAR T cells are the pinnacle of the technological advances of immunotherapy in that they combine three different modalities into one therapy,” Brown said during his presentation.
First, he said, CAR-T is a cellular therapy that uses the patient’s own cells. Second, it is a gene therapy that requires genomic manipulation of the patient’s T cells to create a chimeric antigen T-cell receptor.
Finally, he added, “it’s an immunotherapy that harnesses the power of the patient’s own immune system to treat their disease.”
Immunotherapy ABCs
Brown outlined what he called the “ABCs” of immunotherapy for ALL — antibody-drug conjugates, bispecific T-cell engagers and CAR T-cell therapies.
All three immunotherapies have led to “a paradigm shift in response rates in the relapsed or refractory setting,” Brown said, with CAR T cells having the highest response rates when accounting for both initial complete response rates and minimal residual disease-negativity.
CAR T-cell therapy — specifically the autologous anti-CD19 agent tisagenlecleucel (Kymriah, Novartis) — is the only immunotherapy that appears to have a “prolonged, durable survival advantage without subsequent therapy,” Brown said.
Currently available therapies have induced durable responses in approximately 40% to 50% of patients, he said.
“So, CAR T cells can represent definitive therapy in a subset of patients with ALL,” Brown said. Conversely, the bispecific T-cell engager blinatumomab (Blincyto, Amgen) typically is used as bridging therapy before patients undergo hematopoietic stem cell transplantation.
Studies of patients with ALL showed minimal residual disease-negative rates of 81% with tisagenlecleucel, 63% with the antibody-drug conjugate inotuzumab ozogamicin (Besponsa, Pfizer) and 33% with blinatumomab.
Nevertheless, half of patients who have an initial response to CAR T-cell therapy will experience disease progression. Although research is ongoing to improve CAR constructs with the aim of increasing response durability, Brown said one of the challenges facing CAR T-cell therapy is determining which patients will achieve durable responses without additional treatment.
“There are some emerging biomarkers that may help us with this, but as of now it is very difficult to predict,” Brown said.
‘A very complicated process’
CAR T-cell therapies are groundbreaking, but they require an entire health care ecosystem to deliver, Brown said.
“It is a very complicated process,” he said.
Execution involves dozens of personnel from multiple centers — as well as the product’s manufacturer. These factors make for a high price tag that limits access to the treatment.
The timeline, from the initial consultation to the first post-treatment scans, can be 2 to 3 months. The process begins with collection of the patient’s cells via leukapheresis, followed by cryopreservation of those cells. Then, the cells are sent for manufacturing, which takes 2 to 4 weeks. Once the cells are manufactured, the patient will undergo up to 3 days of lymphodepleting chemotherapy, followed by infusion of the CAR T cells. Patients are closely monitored as inpatients for the next 7 to 14 days, with a first tumor assessment approximately 30 days after infusion.
Brown said the number of centers that can provide CAR T cells is approaching 100 in the U.S., compared with 20 or 30 initially.
“Access continues to expand but [remains] an issue due to the resources needed to administer these therapies,” Brown said.
References:
- Kantarjian HM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1609783.
- Kantarjian HM, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1509277.
- Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
- Topp MS, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(14)71170-2.
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Brown PA. Emerging therapeutic options in acute lymphoblastic leukemia. Presented at: National Comprehensive Cancer Network 2020 Virtual Congress: Hematologic Malignancies; Oct. 8-10, 2020.
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