Research Projects

Triple Negative Breast Cancer (TNBC) is characterized by the absence of three receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 1, 2. The prevalence of TNBC in India is reported at 31%, as per data from 17 studies involving 7,237 breast cancer patients, emphasizing the need for immediate attention3. Due to the absence of hormone receptors or lack of HER-2 amplification, TNBC does not respond to hormonal therapies like tamoxifen, aromatase inhibitors, or to HER2-targeted therapies like trastuzumab4, 5. Therefore, new therapeutic approaches for this poor prognosis breast cancer subtype are profoundly needed. Given that a few targeted therapies directed towards Folate receptor alpha (FRA) are in late-stage clinical development (implying efficacy and safety profile)6, 7, developing novel biologics targeting this receptor for patients with TNBC in India holds prospect. FRA is expressed in 86% of high grade TNBC patients 7. This protein plays a crucial role in the cellular uptake of folate, a vitamin essential for cellular processes, such as DNA synthesis, repair, and methylation8, 9. Significant overexpression of FRA in TNBC, with low coordinate expression in normal tissues, makes FRA an attractive target10. So here I propose to first engineer and evaluate a novel bispecific T cell engager (TCE) targeting FRA through engagement of adaptive immunity against TNBC with the long-term goal of managing patients with recalcitrant TNBC in India, for whom the existing treatment modalities are highly limited. Bispecific TCEs represent an important recent tool in the field of antibody technology for cancer therapy with five FDA approvals so far11. Since, most TNBCs are extremely aggressive and highly heterogenous in nature, engaging additional immune effector components may further help. NK cells are implicated in cancer immunosurveillance, however, strategic approaches for maximizing NK reactivity to target TNBC are in their infancy 12. We reasoned that focusing on Siglec-7, an important NK target to engage specific tumors more directly through a bispecific strategy could further improve antitumor immunity in TNBC. We propose to engineer a unique NK cell engager (NKCE) to simultaneously bind Siglec-7 and FRA, to draw the NK cells into direct contact with FRA on TNBC cells. There are only a handful of NKCE studies focusing on the NK receptors, CD16 and NKp46 13, but no studies till now report NKCE targeting Siglec-7 for TNBC or other breast cancers. We expect our studies to demonstrate the utility of targeting Siglec-7 against a major subset of TNBCs representing a potentially important tool for targeted destruction of TNBC cells. My hypothesis is that the FRA targeted bispecific T and NK cell engager will be able to function effectively against TNBC and synergize with checkpoint inhibitors, so that this therapy (alone/combination) can be translated to TNBC patients.