CAR T-Cell Therapy: FDA Approves ‘Living Drugs’ for Cancer Treatment in Children and Adults
WHAT IS IT?
‘CAR’ (chimeric antigen receptor) refers to the synthetic receptors that are genetically engineered and integrated into the T-cell surface
CAR T-cell therapy is a type of adoptive cell transfer (ACT) where a patient’s cells are removed, genetically engineered to attack her cancer cells and then returned back to the patient
HOW ARE CAR T-CELLS MADE AND USED TO ATTACK CANCER CELLS?
The genetically engineered CAR is not an antibody found in nature but rather is a synthetic construct that is made up of various fragments and domains
T-cells from a patient with cancer are engineered to produce these CAR T-cells, outfitted with synthetic antibodies specific to the target cancer cell antigen, which are then infused back into the patient
Scientists choose domains that will maximize recognition of the target antigen on the tumor cell
Domains within the cell are also important and designed to affect cell function
Continuing research has led to improvements in
Expansion (ability of CAR T-cells to multiply after infusion into the patient)
Persistence (survival after infusion into the patient)
Production time (from weeks to days)
FDA APPROVAL 2017:
FDA (August 2017) approved the first CAR T-cell therapy, tisagenlecleucel, for children with acute lymphoblastic leukemia (ALL) who have relapsed at least twice or who have not responded to standard therapy
The synthetic antibodies target the CD19 antigen found only on B-cells
The CAR T-cells undergo expansion in the laboratory, are infused back into the patient following lymphodepletion and then will undergo expansion again
Many of the children in the tisagenlecleucel trials have had complete long lasting remissions
Previously, no known treatment available
The FDA granted tisagenlecleucel Priority Review and Breakthrough Therapy designations
FDA (October 2017) approved the first drug for adults, axicabtagene ciloleucel, for the treatment of an aggressive type of non-Hodgkin lymphoma
This CAR T-cell therapy targets CD19 cells and is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
Individuals with DLBCL will go into remission after treatment but approximately a third either don’t respond or relapse and on average will survive only 6 months
In a drug trial that included 101 patients, 36% went in to remission and in 82%, the tumor shrank by ≥ 50%
Known risks were seen in the trial, including brain toxicity
Examples of ACT: TCR T-cells and CAR T-cells (tap to enlarge)
Credit: National Cancer Institute
Other examples of ACT beyond CAR T
Tumor-Infiltrating Lymphocytes (TILs): Immune cells that can penetrate tissues around the tumor based on cancer mutation recognition
Currently being studied in colorectal and liver cancer
T-cell Receptors (TCRs): As opposed to CAR T approach, TCRs use naturally receptors that recognize antigens within tumor cells
Currently being studied in melanoma and sarcoma
CAR T-cell therapy side effects include
Cytokine-release syndrome (CRS) that results from rapid and massive release of cytokines into the bloodstream resulting in fevers and hypotension
Indicates T-cells are working
CRS manageable with supportive therapies
B-cell aplasia, where B-cells, including normal cells, are killed off by the CAR T-cell therapy
Treatment includes immunoglobin therapy to fight dangerous infection
Cerebral edema noted in some trials but not others
Neurotoxicity (confusion or seizure-like activity) which is short lived and reversible
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