The History Behind the Development of CAR-T Cell Therapy

Targeting therapy against cancer cells to avoid damage to healthy cells began in 1977 with tamoxifen. The tamoxifen blocked estrogen receptors on breast cancer cells resulting in cell death. Antibodies are made by our immune system to remove infections or malignant cells from our body. In 1997, a human antibody, Rituxan (rituximab), was approved to attach to lymphoma cells. This resulted in cells from the patient’s own immune system attacking the lymphoma. These treatments were effective only as long as the drug or antibody was in the patient's bloodstream.

In the 1980’s the use of allogeneic stem cell transplant therapy became widespread. This procedure used chemotherapy with or without radiation to destroy malignant cells and replace their immune system with a healthy immune system from a donor. It became clear that as much as the huge doses of chemotherapy used, it was the new immune system that helped keep the patient in remission. In patients who relapsed, an infusion of mature immune cells from the donor could result in achieving complete remission and even cure. Unfortunately, these living immune cells can attack normal cells in the patient (graft versus host disease, also known as GVHD) as well as fight the malignant cells.

Using this knowledge led to the development of CAR therapy. This therapy uses immune cells from the patient and genetically modifies them in the lab to specifically attack the malignant cells. As these cells are obtained from the patient, there is no risk of GVHD. These living cells are then infused in the patient. The patient needs close monitoring initially as a potentially fatal immune response can develop as the new immune cells attack the malignant cells. After this initial phase (typically one month), the cells continue to divide and attack the malignant cells. This results in some patients requiring several months to achieve a complete remission, and those that are in remission at 6 months, tend to stay in remission. Two CAR treatments have been approved for treating patients.

CAR

Disease

Complete Response Rate

Duration of Response

Axicabtagene ciloleucel

Relapsed Large B cell NHL

54 percent

41 percent at 15 months

Tisagenlecleucel

Relapsed B-ALL

83 percent

Not reached

Success with CAR therapy has also been seen with chronic lymphocytic leukemia (CLL). Studies are ongoing to test CAR therapy for glioblastoma, myeloma, renal cell carcinoma and many other cancers. In addition, new CARs are being developed to link the cell therapy to more than one site on the malignant cell to avoid resistance.

James H. Essell, M.D., is an oncologist and hematologist with Oncology Hematology Care, a practice in The US Oncology Network