Adoptive Cell Transfer Therapy for Cancer

This is an exciting new technology that may be classified as immunotherapy.  It involves removal of white blood cells called T-cells from the tumor. The logic is that these particular T-cells have identified the tumor as something they want to fight which is why they have located in the tumor.  Outside the body doctors do genetic modification of the cells, and then the cells are cultured (multiplied in laboratory glassware). The cells are then reinserted to the patient with the hope that they will fight the cancer.  These are “living drugs”. They aren’t made from scratch in a chemical lab, or taken from nature, or even produced by fermentation or the technology used to produce monoclonal antibodies.  Strictly speaking they are not drugs in the usual sense.

Adoptive cell therapies are based on ex-vivo manipulation of immune cells to enhance their anti-tumor activity. The cells are isolated from either the peripheral blood or the tumor, undergo expansion or other manipulation and are reinfused into the patient.

Three kinds of adoptive cell therapies are being developed.

Autologous tumor-infiltrating lymphocytes (TIL) are white blood cells that have made their way to a tumor.  This part of the immune system is working as lymphocytes (B-cells and T-cells) are attacking and have “infiltrated” the foreign body (tumor).  In this treatment, the tumor is surgically removed from the patient and lymphocytes are then removed from the tumor and grown (induced to multiply) in solution containing interleukin-2 in lab glassware.  This takes several weeks, but it results in a big supply of lymphocytes (descended from the patient’s own cells) that can be reinjected to the body to fight cancer. It is essentially an amplification of the immune system.

In a 2013 paper, researchers called adoptive transfer TIL “very bright” and predicted it would reach the clinic in a few years, but as of this writing none have been approved by regulators.

Gene therapy with T-cells transduced with high-affinity T-cell receptors (TCR) is another ACT scientists are working on.  In this process T cells from the patient are modified to include genes that encode for antigen-specific receptors. This essentially redirects the immune system against the cancer cells.  One advantage of this technology is that the therapeutic T cells can persist in the immune system after the initial treatment, which does not happen with monoclonal antibody treatment.

The area of ACT that has progressed the farthest is Chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell Therapy

CARs are engineered antigen receptor proteins consisting of an antigen binding region and T-cell receptor signaling domains. T cells are grafted with DNA that encodes the chimeric antigen receptor. When injected into a patient they both recognize the cancer cells and attack it.  Early work in this field has focused on blood cancers and lymphoma.

CD 19 is an antigen present on blood cancer cells. Clinical studies with CAR T-cell therapy targeting the B cell protein CD19 T-cell antigen have been successful in the treatment of B-cell acute lymphoblastic leukemia.

In August 2017 the FDA approved Tisagenlecleucel, the first ever chimeric antigen receptor T cell (CAR-T) therapy to be approved.  To carry out this leukemia treatment, doctors must remove blood from a patient, separate out T-cells, and modify their DNA before inserting them back into the patient.  This was approved only for B-cell precursor acute lymphoblastic leukemia, but there is big potential. It is estimated than 4 percent of advanced cancers have the genetic signature that this medicine treats.

In October 2017 the FDA approved axicabtagene ciloleucel, sold under the name Yescarta for treatment of lymphoma.

CAR-T has been less effective against solid tumors, where the low oxygen environment is hostile to immune cells.  Solid tumors are also more heterogeneous than leukemias and lymphomas and the high specificity of this therapy means only some of the cells are affected.  Others have mutated and are not affected by the same T-cells.  Liquid tumors tend to be more homogeneous.  Following on success against the CD 19 antigen, scientists are developing other CAR-T therapies for other receptors that may expand the use of this technology in hematology.

Like other forms of immunotherapy, CAR-T is risky and can produce side effects that can be dangerous and even fatal.  Cytokine release syndrome (CRS) or the “cytokine storm” has happened in trials on humans as scientists try to work out the correct dose.