Research Projects

Rationale of the Research- Oral cancer poses a major health burden in India, with high mortality and poor outcomes for advanced cases. Current treatments are often inadequate. While CAR-T cells and bispecific antibodies have transformed blood cancer therapy, their application to solid tumors like oral cancer faces challenges: high cost, immunogenicity, complex production, limited tumor penetration, and an immunosuppressive microenvironment. Aptamers—short, structured nucleic acids selected via SELEX—offer a promising alternative. They are low-cost, synthetically produced, and can be easily modified for stability and specificity. Unlike CAR-T therapy requiring patient-specific customization, aptamer-based therapies can be developed as universal, off-the-shelf agents. Despite these advantages, bispecific aptamers have not been explored as T-cell engagers for solid tumors such as oral cancer. Scientific Objectives- We aim to develop a bispecific aptamer that engages T-cells to selectively kill oral cancer cells. The construct will consist of two aptamer domains: one targeting a tumor-specific marker (e.g., EpCAM or EGFR), and the other binding CD3 on T-cells. This aptamer will bridge T-cells and cancer cells to induce targeted immune activation and cytotoxicity. Hypothesis/Model to be Tested- We hypothesize that a chemically synthesized bispecific aptamer can engage T-cells and direct them toward oral cancer cells, mimicking the action of bispecific antibodies or CAR-T cells. The model proposes that such a molecule will trigger immunological synapse formation, T-cell activation, and selective tumor cell killing—while being cost-effective and broadly accessible. Main Experiments to be Carried Out- Aptamers targeting oral cancer markers will be selected via SELEX and validated using SPR, flow cytometry, and microscopy. A CD3-binding aptamer will be incorporated through an optimized linker. The bispecific construct will be tested in co-cultures of T-cells and oral cancer cells to assess activation markers, cytokine release, and cytotoxicity. Lead candidates will be evaluated in preclinical mouse models of oral cancer. Estimate of the Significance- This project seeks to establish a novel class of synthetic bispecific T-cell engagers specifically for oral cancer—a critical unmet need in India. In contrast to CAR-T therapy, which requires ex vivo engineering, complex logistics, and high cost, aptamers can be mass-produced and used off-the-shelf. Compared to bispecific antibodies, they offer reduced immunogenicity, lower production costs, and easier chemical tuning. If successful, this work will provide a new precision immunotherapy for oral cancer and validate a modular platform adaptable to other solid tumors. This approach could transform cancer treatment by enabling customizable, safer, and affordable immunotherapies that do not rely on protein biologics. At the fundamental level, this study will enhance understanding of how synthetic nucleic acids can be engineered to engage immune cells and mediate tumor-specific killing, opening new directions in cancer immunotherapy and synthetic biology. This platform has the potential to position India at the forefront of next-generation immunotherapy innovation.