An Update on Efforts to Use Chimeric Antigen Receptor T-Cells as a Treatment for Cancer
Engineering a patient's own T-cells to express chimeric antigen receptors (CARs) has shown considerable promise as a cancer treatment. This alteration steers the immune cells to attack tumor cells, and has for example been used to drive leukemia into remission in trials. Here researchers are preparing a trial to test the use of CARs in targeting the brain cancer glioblastoma:
Immune cells engineered to seek out and attack a type of deadly brain cancer were found to be both safe and effective at controlling tumor growth in mice that were treated with these modified cells. The results paved the way for a newly opened clinical trial for glioblastoma patients. The new preclinical study details the design and use of T cells engineered to express a chimeric antigen receptor (CAR) that targets a mutation in the epidermal growth factor receptor protein called EGFRvIII, which is found on about 30 percent of glioblastoma patients' tumor cells.First, the team developed and tested multiple antibodies, or what immunologists call single-chain variable fragments (scFv), which bind to cells expressing EGFRvIII on their surface. The scFvs recognizing the mutated EGFRvIII protein must be rigorously tested to confirm that they do not also bind to normal, non-mutated EGFR proteins, which are widely expressed on cells in the human body. Out of the panel of humanized scFvs that were tested, the researchers selected one scFv to explore further based on its binding selectivity for EGFRvIII over normal non-mutated EGFR.
The lead scFv was then tested for its anti-cancer efficacy. Using human tumor cells, the scientific team determined that the EGFRvIII CAR T cells could multiply and secrete cytokines in response to tumor cells bearing the EGFRvIII protein. Importantly, the researchers found that the EGFRvIII CAR T cells controlled tumor growth in several mouse models of glioblastoma. On the basis of these preclinical results, the investigators designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII for both newly diagnosed and recurrent glioblastoma patients carrying the EGFRvIII mutation.
The investigational approach begins when some of each patient's T cells are removed via an apheresis process similar to dialysis, the cells are engineered using a viral vector that programs them to find cancer cells that express EGFRvIII. Then, the patient's own engineered cells are infused back into their body, where a signaling domain built into the CAR promotes proliferation of these "hunter" T-cells. In contrast to certain T cell therapies that also target some healthy cells, EGFRvIII is believed to be found only on tumor tissue, which the study's leaders hope will minimize side effects.
Link: http://www.uphs.upenn.edu/news/News_Releases/2015/02/maus/
Perhaps even more exciting is the ongoing development of TCR (T cell receptor) like CAR T cells. Rather than targeting cell membrane proteins on the surface of the cell these chimeric antigen receptors bind to internal peptites presented on the MHC molecules of the cell. This will perhaps allow targeting of previously undruggable proteins involved in cancer.