Moghe, Manish

Lung cancer is among the most common and lethal cancers and warrants novel therapeutic approaches to improving patient outcomes. Although immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits, most patients remain unresponsive to currently approved ICIs or develop resistance after initial response. Many ongoing clinical studies are investigating combination therapies to address the limited efficacy of ICIs. Here, we have assessed whether p53 gene therapy via a tumor-targeting nanomedicine (termed SGT-53) can augment anti-programmed cell death-1 (PD-1) immunotherapy to expand its use in non-responding patients. Using syngeneic mouse models of lung cancers that are resistant to anti-PD-1, we demonstrate that restoration of normal p53 function potentiates anti-PD-1 to inhibit tumor growth and prolong survival of tumor-bearing animals. Our data indicate that SGT-53 can restore effective immune responses against lung cancer cells by reducing immuno-suppressive cells (M2 macrophages and regulatory T cells) and by downregulating immunosuppressive molecules (e.g., galectin-1, a negative regulator of T cell activation and survival) while increasing activity of cytotoxic T cells. These results suggest that combining SGT-53 with anti-PD-1 immunotherapy could increase the fraction of lung cancer patients that responds to anti-PD-1 therapy and support evaluation of this combination particularly in patients with ICI-resistant lung cancers.

Because lung cancer remains the most common and lethal of cancers, novel therapeutic approaches are urgently needed. RB94 is a truncated form of retinoblastoma tumor suppressor protein with elevated anti-tumor efficacy. Our investigational nanomedicine (termed scL-RB94) is a tumor-targeted liposomal formulation of a plasmid containing the gene encoding RB94. In this research, we studied anti-tumor and immune modulation activities of scL-RB94 nanocomplex in preclinical models of human non-small cell lung cancer (NSCLC). Systemic treatment with scL-RB94 of mice bearing human NSCLC tumors significantly inhibited tumor growth by lowering proliferation and increasing apoptosis of tumor cells in vivo. scL-RB94 treatment also boosted anti-tumor immune responses by upregulating immune recognition molecules and recruiting innate immune cells such as natural killer (NK) cells. Antibody-mediated depletion of NK cells blunted the anti-tumor activity of scL-RB94, suggesting that NK cells were crucial for the observed anti-tumor activity in these xenograft models. Treatment with scL-RB94 also altered the polarization of tumor-associated macrophages by reducing immune-suppressive M2 macrophages to lower immune suppression in the tumor microenvironment. Collectively, our data suggest that the efficacy of scL-RB94 against NSCLC is due to an induction of tumor cell death as well as enhancement of innate anti-tumor immunity.