Immunotherapy

1. About Immunotherapy & Cell Therapy For the last few decades scientist have been researching the involvement of the immune system in cancer development to discover potential cure. Immune cells has been known to play an important role in regulating tumor progression, thus stimulating immune reactions towards tumors can be an attractive therapeutic targeting cancer. More and more clinical data has been shown positive signs of immunotherapy and cell therapy as potential cure for cancer. PD-1/PDL-1 Inhibitors Recent studies have illustrate how cancer cells circumvents the immune system through overexpression of PD-L1, which binds to and activates the PD-1 protein on the T cell leading to immune tolerance. Thus PD-1/PD-L1 inhibitors pharmacologically preventing the PD- 1/PD-L1 interaction may provide a potential way to facilitate immune response to kill the tumor. There are quite PD-1 inhibitors in clinical trials as well as available in the market approved by FDA.

2. CAR T Cells Therapy After the success of PD-1/PDL-1 inhibitors on the market, many researchers are turning their attention to CAR-T therapy, which treated leukemia and lymphoma successfully. In a CAR-T therapy, T cells from a patient was extracted and then genetically modified to express a Chimeric Antigen Receptor (CAR) on their cell membrane and expanded in vitro. This receptor consists of an external target- binding domain designed to recognize a specific tumor antigen and an internal activation domain responsible for activating the T cell when the CAR-T binds its target. Finally, these T cells are reinfused into the patient to kill the cancer cells. Immunotherapies using checkpoint inhibitors such as of PD-1/PDL-1 inhibitors have already been proven successful in clinical trials. They block a mechanism that tumor cells use to hide from immune system. CAR-T cells therapy goes one step further by engineering the T cells themselves to enhance the response from the immune system against tumor cells. Currently two CAR-T therapies have recently been approved — the first from Novartis and the second from Gilead and Kite Pharma. A lot of CAR-T therapies are running actively in clinical trials.

3. Neoantigen Vaccine Neoantigens is a class of HLA-bound peptides that arise from tumor- specific mutations. They are highly immunogenic because they are not present in normal tissues, thus can be used as biomarkers differentiating cancer cells from normal cells. It has been shown that recognition of these individual-specific neoantigens opens a new door for cancer immunotherapy. Several clinical studies indicated that vaccination with neoantigens could both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients. Since these neoantigen peptides are patient specific, developing personalized vaccine would target cancer cells of an individual specifically and effectively. It is worth mentioning that produce vaccines that contains multiple individual- specific neoantigens minimize the chance of tumor escape by loss of antigen. References: [1] Hashem O. Alsaab, Samaresh Sau, Rami Alzhrani, Katyayani Tatiparti et al, PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol., 23 August 2017. [2] Carl H. June, Roddy S. O’Connor, Omkar U. Kawalekar et al, CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).

4. [3] Patrick A. Ott, Zhuting Hu, Derin B. Keskin et al, An immunogenic personal neoantigen vaccine for patients with melanoma, Nature. 2017 Jul 13;547(7662):217-221. [4] Ton N. Schumacher, Robert D. Schreiber, Neoantigens in cancer immunotherapy, Science. April 3 2015 • vol 348 issue 6230.