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.  Treatment involves on injection of modified T cells into the patient’s bloodstream.  If it works, the patient now has an improved immune system that can attack the malignant cells.  The new genes help the immune system produce CAR and other proteins.

Before the enhanced cells are inserted, the patient typically gets a strong dose of chemotherapy.

Tisagenlecleucel was approved only for a certain type of 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.  Science magazine named CAR-T therapy the “breakthrough of the year”.  

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.

The oncology world (and biotech company investors) are excited about  CAR-T.  The consulting firm McKinsey wrote in 2019 that CAR-T could be a “disruptive technology” in cancer care, and they predicted that by 2024 over 20 CAR-T products would be FDA approved and would be generating over $10 billion per year in worldwide revenue.

Safety Concerns and Feedback Loops

In systems theory (a branch of engineering) there is a concept of feedback loops, in which the results or output of a system influence the level, type, and/or nature of input.  Many systems employ “negative feedback loops” to keep the results more or less constant. The thermostat system in a building operates on a negative feedback loop. In the winter when the temperature inside drops before a preset level, the heat comes on.  When the temperature climbs past another present level, the heat is shut off.

The homeostatic mechanisms in biological systems often function along the lines of negative feedback loops.  A human body is the same temperature to within a few degree all the time. The lymph and blood have levels of salinity and pH that don’t change much, because the body actively takes measures to keep those levels in a certain range.

A positive feedback loop is one where the result of the system changes the inputs to make the result of the system go in the same direction.  So a positive feedback look on a home heating system would continue to produce hot air even after the temperature rises. A cooling system would continue to ratchet the temperature down when it is in a positive feedback loop.  Industrial processes can become dangerous when a positive feedback loop occurs – think of a runaway chemical reaction.

preparation of Adoptive Cell TransferThe immune system is complex, but it also uses some feedback loop mechanisms.  The system sends out cytokines into the blood and the level more or less depends on the infection load in the body.  However, a positive feedback loop sometimes forms. The 1918 Spanish flu is an example. Decades after it happened scientists figured out that it was more fatal than most flu epidemics because that particular virus induced a positive feedback loop and turned the human immune system into a weapon against the body’s own tissues.  This explained why young healthy people with strong immune systems died in rates greater than expected while old frail people did okay.

Immunotherapy has been plagued by positive feedback loops in the forms of cytokine storms that patients experience when artificial immunostimulants are injected into their bloodstreams.  Patients who were in trials for some of these experimental therapies got very sick and often had to be sent to intensive care. The risk of cytokine storm positive feedback loops hangs over immunotherapy.  CAR T-cell therapy often results in cytokine release syndrome a week after treatment is given.

Several CAR T-cell treatments have been approved by the FDA for cancer.  To gain approval, the developer must show the drug is safe or at least that the benefits outweigh safety risk.  Three drugs – Axicabtagene ciloleucel, Brexucabtagene autoleucel, and Tisagenlecleucel  – were approved by the FDA but only with the stipulation they be administered under a REMS protocol.  This is to ensure safety measures are employed and to reduce the chances of a cytokine storm.

More reading:

The Lancet: CAR T-cell therapy for indolent lymphoma: a new treatment paradigm?

Off-the-shelf, gene-edited CAR-T cells forge ahead, despite safety scare

Lancet: CAR T-cell therapy for multiple myeloma: state of the art and prospects