Third-generation engineered chimeric antigen receptor (CAR) T-cell (CAR-T) therapies are in clinical testing and show early promise against advanced B-cell malignancies, researchers recently reported in the journal Clinical Cancer Research.1,2 More work is needed to identify and validate response-predictive biomarkers. But after more than 25 years of research and development, CAR-T therapies are entering clinical use, according to Michel Sadelain, MD, PhD, a pioneer in the field, and director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
CARs are engineered receptors that repurpose immune T cells, composed of antigen-recognition, T-cell activation, and costimulation domains. There are more than 240 CAR-T cell clinical trials registered at ClinicalTrials.gov, and more than 20 CAR targets have either been or are currently being tested in clinical trials, most involving second-generation CARs with CD28 or 4-1BB costimulatory receptor domains for improved specificity.1,2
Authors of the phase 1/2a clinical studied the safety of third-generation CD19-targeting CAR-T cells with both CD28 and 4-1BB costimulatory domains. They administered the therapy to 15 patients with B-cell lymphoma or leukemia, following chemotherapy and, in 11 of the patients, following low-dose pre-CAR–infusion cyclophosphamide and fludarabine conditioning therapy.1
Four of the 15 patients were hospitalized for cytokine release syndrome and/or neurotoxicity.1
“During the first few weeks, most patients had mild symptoms of cytokine release, such as elevated C-reactive protein (CRP) and/or IL6, chills, fever, fatigue, and flu-like symptoms,” the team reported.1
Six patients — 4 of 11 with lymphoma and 2 of 4 with acute lymphoblastic leukemia (ALL) — had initial complete responses (CRs); 3 of the 4 lymphoma patients were in remission 3 months after infusion, the authors reported.1
The report follows 2017 FDA approvals for earlier-generation CD19-targeting CAR therapies as treatments for pediatric ALL (tisagenlecleucel) and adult refractory or relapsed large B-cell lymphoma (axicabtagene ciloleucel).2
“We started engineering T cells over 25 years ago, identified CD19 as a promising CAR target 15 years ago, initiated the first trials at Memorial Sloan Kettering 10 years ago,” said CAR pioneer Dr Sadelain.
The FDA approvals and continuing advances with next-generation CAR-based therapies are “gratifying,” Dr Sadelain acknowledged — a sentiment reinforced after being told for 2 decades, “over and over again,” that CAR therapy would not work.
“CD19 CAR therapy has paved the way for a new field of medicine based on the genetic instruction of T-cell responses. We can anticipate considerable evolution of this concept in the next decades.”