Chimeric antigen receptor (CAR) T-cell therapy is a new, immune system-based cancer treatment that has garnered recent media attention. In a clinical trial, CAR T-cell treatment left no signs of tumors in 70% to 90% of children and adults with the aggressive blood cancer acute lymphocytic leukemia (ALL). ALL is almost always fatal, and the results observed with CAR T-cell treatment are nothing short of spectacular.
This is how CAR T-cell therapy works: immune cells (T-cells) are harvested from a patient’s blood. They are genetically modified in the lab to be equipped with a protein called CAR. The modified cells are then injected back into the patient’s bloodstream. Part of the CAR protein (an antibody-like domain) protrudes outside of each T-cell and directly binds to its target protein on a cancer cell. Upon binding, the inside part of CAR instantly activates the T-cell to attack the cancer cell. This approach bypasses the multilayered activation process that is required by unmodified T-cells to attack their targets. A good description of the approach and some of its history can be found here.
In a couple of the hugely successful small trials in ALL patients, the target protein for CAR in modified T-cells was CD19. CD19 is expressed on the surface of normal blood cells known as B cells, as well as on ALL cells that are cancerous B cells. Dozens of new CAR T-cell therapy trials are now testing CAR proteins that target other proteins expressed on the surface of blood cancer cells. These proteins are not found on other tissues or organs in the body.
The big question in the future development of CAR T-cell therapy is whether it can be adopted to treat solid tumors. There are several reasons why the CAR T-cell approach faces more obstacles in solid cancers versus blood cancers. Foremost is that there are not many proteins on the surface of cancer cells that are not also found on normal cells. If a target protein is also expressed on normal cells, unleashing CAR T-cells recognizing this target could be homicidal.
Still, several proteins that are selectively expressed on some solid tumors have been identified. One of them is mesothelin, found in mesothelioma (predictably), as well as in brain, ovarian, breast, and pancreatic cancers. Ongoing trials are testing mesothelin-directed CAR T-cell therapy in these cancers: (NCT01583686, NCT02159716, NCT02465983), as well as in cancers of the breast and lung, in patients who have developed malignant pleural effusion (NCT02414269).
A protein called EGFRvIII, found frequently on brain cancer glioblastoma cells, is being targeted in two trials: (NCT01454596 and NCT02209376); and the protein HER2, also found on glioblastoma, is being targeted in trial NCT02442297.
CAR T-cells that seek out the protein CEA, which is expressed on colon cancer cells, are being tested in patients with liver metastases (NCT02416466). The modified T-cells are infused into each patient’s hepatic artery to ensure delivery to the liver. The safety stage of this trial has already been completed satisfactorily, with some indications of efficacy. Another target being explored is GD2, a protein highly expressed in melanoma, neuroblastoma, and some sarcoma cancers (NCT02107963).
The second problem with CAR T-cell therapy for solid tumors is that, when injected into the blood stream, the modified T-cells may have difficulty reaching the tumor site. An experimental approach tested in mice was to inject the T-cells close to the tumor. In this case, CAR T-cells targeting mesothelin were introduced into the pleural cavity (space around the lungs) of mice with mesothelioma tumors. Surprisingly, these CAR T-cells not only destroyed the lung tumors, but were able to travel to distant metastases to destroy them as well.
In another study, CAR-engineered immune cells of a different ilk than T-cells were effective in mice with glioblastoma when injected directly into the brain.
And yet another study has found that T-cells engineered to express CAR may be more effective in getting to the tumor if they are also equipped with an enzyme that degrades stroma (the hard coating that surrounds some tumors).
A recent industry report counted more than 35 companies engaged in developing CAR T-cell technologies for cancer treatment. Some good is bound to come out of this effort.