Vineet K Gupta, PhD

Overview

Aim: Treatment/Therapy

Pancreatic cancer remains one of the most difficult malignancies to treat, with standard and emerging immunotherapies showing limited success due to the profound immunosuppressive tumor microenvironment. Unlike other cancers where immune checkpoint inhibitors (ICIs) have achieved significant breakthroughs, pancreatic tumors are defined by a low mutational burden, dense desmoplastic stroma, and poor infiltration of effector T cells. These features enable immune evasion and promote resistance to immunotherapy. Recent studies have identified tissue-resident memory T cells (Trms) as critical mediators of anti-tumor immunity, capable of providing durable immune surveillance and sustaining localized effector responses within the tumor. Enhancing Trm recruitment and persistence in tumors offers a promising strategy to overcome immune resistance, improve tumor regression, and reduce recurrence, an approach that could transform therapeutic outcomes for pancreatic cancer patients.

In this proposal, we employ a novel Antibody-siRNA Conjugate (ARC) platform to selectively induce Trm differentiation within the pancreatic tumor microenvironment, addressing key barriers that limit current immunotherapies. This technology uses T cell-specific antibodies to deliver siRNA targeting pathways that regulate retention, differentiation, and effector function of Trm cells. By downregulating negative regulators and enhancing pro-survival and activation signals, this approach is designed to suppress immunosuppressive mechanisms while promoting robust Trm accumulation. The resulting Trm-enriched tumors are expected to maintain heightened immune surveillance, sustain cytotoxic activity, and mount rapid responses upon antigen re-exposure, creating a more immunologically active and responsive tumor microenvironment. We will assess the therapeutic efficacy of this Trm-enhancing strategy in combination with immune checkpoint blockade across multiple preclinical pancreatic cancer models, assessing tumor regression, survival benefit, and long-term control in multiple preclinical pancreatic cancer models. Additionally, we will evaluate whether Trm enrichment reduces post-surgical recurrence, a major clinical hurdle in pancreatic cancer care. By directly targeting the immunological barriers that limit the effectiveness of current therapies, this strategy offers a promising path to significantly improve outcomes for pancreatic cancer patients across the United States, where the disease remains a major contributor to cancer-related mortality.