The amount of drugs and treatments for cancer, like radiation, is extraordinary. This approach has been very successful in certain settings, where the radiation will “poison” the cancer cells and cause mass destruction of the tumors. Unfortunately, cancers often return because the drugs cause debilitating target toxicities and even new malignancies. However, recently we have seen signs of a decisive victory over certain cancers, which is personalized cancer immunotherapy. “The past decade has witnessed a revolution in our understanding of the immune system and our ability to develop safer and more effective immunotherapies.” “The induction and maintenance of immune tolerance has been the holy grail of immunotherapy because it would translate a short course of immunotherapy into long-term benefit while maintaining immune competency,” something radiation cannot do notes scientists at Harvard University.
Below is a picture that explains how this therapy works.
The tumor cells are recognized by cytotoxic T cells. Normally, the cytotoxic T cells would kill the tumor cell, but the tumor cell also gives negative inhibitory signals to the cytotoxic T cells. On the left panel, if the tumor cell (green cell) uses B7 to bind to CTLA4, the cytotoxic T (blue) cell doesn't kill the cell.
On the right panel, if the tumor cell uses PD-L1 to bind to PD-1 on the cytotoxic T cell, then the T cell doesn't kill the tumor cell. Immune blockade therapy uses antibodies to bind to CTLA4, or PD-1 or PD-L1 so that tumor cells can't tell cytotoxic T cells to stop killing them so they can do their initial job of killing the tumor.
Once scientist understood the molecular basis of immune activation, which revealed myriad T-cell receptors (TCR) subunits and TCR costimulatory and coinhibitory molecules, they put together that the “intricate system of checks and balances is hijacked by cancer cells to evade immune rejection and, in reverse, is defective in auto inflammatory diseases that lead to the disruption of normal tissue functions.”
The next step, after understanding how immunotherapy works, is to create the drugs that cure the cancer. The understanding of the human immune system “system drove the discovery of a plethora of new drugs (several of which are U.S. Food and Drug Administration–approved) that target immune regulatory pathways. For example, the monoclonal antibody (mAb) ipilimumab (anti–CTLA-4 mAb) is an immune checkpoint–blockade therapy for the treatment of several different cancer types. Pembrolizumab and nivolumab, two mAbs that target the programmed cell death–1 receptor (PD-1) on activated T cells, remove the brakes imposed by coinhibitory molecules so that cancers can be recognized and destroyed by the immune system.” Scientists “evolved a number of immune “checkpoints” that work as braking mechanisms to counterbalance immune activation. Studies in animals have shown that inhibition of these checkpoints—such as with an antibody against cytoxic T-lymphocyte associated antigen 4 (CTLA-4) molecule, an inhibitory membrane protein that is expressed after T-cell activation—enhances activation againt cancer cells, resulting in significant antitumor effects.”
Jeffery Bluestone from the Hormone Research Institute conveys that these drugs are unlike traditional drugs in that “a precise understanding of the target antigens on tumors and self tissues” give improved “understanding of TCR signal transduction pathways, and tools to genetically modify cells” that “have enabled the generation of therapeutic T cells with improved target precision.”
In an issue of the Journal, Hodi et al. reports the results of the first randomized clinical trial to show an overall survival benefit with this approach among cancer patients. Patients with metastatic melanoma were randomly assigned to receive either an anti– CTLA-4 agent (ipilimumab), a vaccine based on a melanoma antigen, or a combination of the anti– CTLA-4 agent and the vaccine. An improvement in overall survival, as well as an improvement in progression-free survival and best overall response rate, was seen in the patients who received anti– CTLA-4 therapy, as compared with the patients who received the vaccine only. These results are especially important, since metastatic melanoma has historically been resistant to treatment. These findings with a cure to a common and highly dangerous cancer prove the worth of Immune therapy and give the much needed attention it deserves for future uses to fight cancer.
Hwu, P. MD. Treating Cancer by Targeting the Immune System The New England Journal of Medicine . August 19 2010. Downloaded from nejm.org at Harvard Library on March 25, 2015
Image: nejme1205943.PDF Tumor Immunotherapy Directed at PD-1. June 28 2012. The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on March 25, 2015
J. A. Bluestone, Q. Tang, Immunotherapy: Making the case for precision medicine. Sci.Transl. Med. 7, 280ed3 (2015).
Lesokhin, A, MD. On being less tolerant: Enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Memorial Sloan Kettering Cancer Center. New York City. March 2015.
Ribas, A. M.D. Ph.D. Tumor Immunotherapy Directed at PD-1. June 28 2012. The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on March 25, 2015