Research Projects

Breast cancer (BC) is the most prevalent malignancy among women around the world. BC has increased significantly in India with a mortality rate of 12.7 and an age adjusted rate of 25.8 per 100,000 women, respectively. The traditional BC treatments of surgery, chemotherapy, and radiotherapy have limitations in terms of loco-regional failure rates, invasive growth or metastatic spread, and normal tissue complications. Chimeric antigen receptor (CAR)-based cell therapy is a new weapon in the battle against cancer, known for its superior specificity and ability to serve as a "living drug". Natural Killer (NK) cells are innate component of mammalian defence against virus and cancer. NK cells can recognize altered self-cells by array of germline encoded surface receptors and rapidly kill those cells by release cytotoxic granules containing perforin and granzymes. For decades, scientists have investigated NK cell-based immunotherapies against cancer due to their rapid killing power without any prior sensitization. Initial data from the on-going clinical trials have demonstrated outstanding safety of NK cell infusion, even in the allogeneic setting. However, several challenges using NK cells must be overcome, such as limited persistence in vivo, limited infiltration into solid tumors, and exhaustion in BC tumor microenvironment (TME). BC TME known to harbour immunosuppressive cells like myeloid derived suppressive cells (MDSC), Treg that adversely affect NK cell function. The cytokines are also crucial to the activation and maintenance of the NK culture. IL-15 was shown to be a key player in enhancing interferon gamma (IFN-γ) production, cytotoxic functions, and survival in NK cells. However, at higher doses for long periods of time, it can induce NK cell exhalation and proliferative arrest. Moreover, proinflammatoroty (IL21) or antiinflammatory (TGF-β) cytokine can synergize or antagonize IL-15 signaling by an unknown molecular mechanism(s). Modelling of dose response and combinatory effect of IL21 or TGF-β in IL15 signalling would be of great importance in predicting the phenotypic and functional property of NK cells both in vitro and in vivo. In this proposal we develop a platform to generate effective and persistent NK cells for the treatment of breast cancer and potentially against other solid cancers. This study will further develop a novel inducible dual CAR-NK (idCAR-NK) cells that can overcome the TGF-β induced immune exhaustion of NK in the BC TME. Moreover, the bioengineering of NK cells will be guided by a novel mathematical modelling approach to achieve cytokine induced programmable phenotype. Most of the ongoing NK-based clinical trials focus on haematological malignancies and its effectiveness against solid tumours like BC are still in developmental phase and require further studies.