Tumor Immunology and Immunotherapy

Through the expression of numerous activating receptors that recognize tumor antigens and stress ligands, natural killer (NK) cells exhibit potent cytolytic activity against cancer cells. Additionally, they express cytolytic granules and secrete cytokines and chemokines that recruit and activate other immune cells within the tumor microenvironment (TME), enabling NK cells to transform the immune suppressive “cold” tumors into immune-responsive “hot” tumors. Similarly, plasmacytoid dendritic cells (pDCs) play a key role in anti-tumor immunity as potent producers of type I interferons (IFN⍺, IFNβ), which are essential for antigen presentation, CD8+ T cell priming, and activation of immune cells, including NK-, B-, and T-cells. These mechanisms not only remodel the tumor-immune microenvironment but also potently enhance memory immune responses to cancer-derived antigens. Despite these capabilities, the TME often suppresses NK cells and pDCs anti-tumor activities through inhibitory signals and immunosuppressive mechanisms, necessitating the development of innovative therapeutic strategies to restore their antitumor activities. This project focuses on engineering tri-specific antibodies that co-activate NK cells and plasmacytoid dendritic cells (pDCs). These novel immune cell engagers are engineered to achieve dual functions: enhancing NK cell cytotoxicity against tumor cells while boosting pDC-driven type I interferon (IFN) production. Together, these mechanisms establish a synergistic innate immune assault on tumors and indirectly potentiate T- and B cell-mediated adaptive immune responses. In addition, we are investigating therapeutic synergies through rational combination strategies integrating tri-specific antibodies with immune checkpoint inhibitors, CAR-based cellular therapies, and small molecule epigenetic modulators. This program has the potential to generate a new therapeutic class of innate immune engagers that surpass current antibody-based approaches.

Andrea Amalfitano, Sergey Seregin, Monther Alalwan.