Research Projects

Triple Negative Breast Cancer (TNBC) accounts for 15-20% of breast cancers and lacks Estrogen, Progesterone, and HER-2 expressions, thus making it difficult to develop targeted therapies. It is the most aggressive breast cancer with high recurrence rates, metastasis, and poor survival. The existing chemotherapy regimens have been linked to resistance in early-stage cancer and poor prognosis in patients with recurrence and metastasis. Although the recently approved T-cell immune checkpoint inhibitor, pembrolizumab (a PD-L1 inhibitor monoclonal antibody) combined with chemotherapy has unveiled the clinical potential of Immunotherapy. However, the upregulation of other immune checkpoints, including the TIM family (TIM-1/3) members, poses resistance to anti-PD-L1 therapy. Therefore, the development of effective therapeutic strategies is needed to mitigate the TNBC and especially the metastatic tumours. T and natural killer cells have been the primary target for tumour immunotherapy, neglecting the role of B cells. The intratumoral B cells can directly present antigens to T cells, reduce T-regulatory phenotype, and inhibit tumour growth. Recently, TIM-1 deletion/blocking on B cells has been shown to activate B cells, enhance antigen presentation, promote effector T cells, and enhance anti-tumour responses. Since interactions of B and T cells are crucial to fine-tune the tumour microenvironment (TME), we hypothesize that targeting TIM-1 and PD-1 checkpoint molecules associated with B and T cells by hydrogel-mediated local release of antibodies can overcome PD-L1 resistance and instigate the B cells to activate T cells in inhibiting tumour growth and recurrence. Further, local delivery combined with existing chemotherapies can expose antigens for B and T cells through Immunogenic cell death (ICD) and aid in inhibiting the tumour growth and metastasis via activating the systemic T cell immunity. As systemic release of Immunotherapeutics has been associated with off-target cytotoxicity, we propose to engineer a novel glyoxal-hydrazone crosslinked N-(2-hydroxypropyl)methacrylamide-N-(3-aminopropyl)methacrylamide) (HPMA-APMA)-Gelatin hydrogel to covalently load the antibodies and drug molecules through free glyoxal and hydrazide groups and provide pH-sensitive, sustained, long-term co-release at tumour site to minimize systemic toxicity and generate systemic immunity. Apart from treatment challenges, mastectomy causes severe psychological issues in patients and impacts the outcomes. As leakage, contamination, and lump formation limit the application of silicone/saline-based implants, we also propose extracellular matrix (ECM)-mimicking components in the hydrogel implants for promoting breast reconstruction. Therefore, we propose engineering of an all-in-one breast implant for tuning the TME for effective eradication of tumour, minimize therapeutic toxicity, clearing the metastatic tumours and providing ECM support for breast reconstruction.