Lipid Nanoparticle-IFN-I

Development of Lipid nanoparticle-IFNa2-encoding DNA (IFNA2-LNP01) immunotherapy for tumor metastases

Lung metastases occurs in approximately 30% of cancer patients with a metastatic disease and is the 2nd most common metastases in human cancer patients. ChemMedImmune Inc. is developing IFNA2-LNP01, a cationic lipid nanoparticle-encapsulated IFNα2-encoding mini-plasmid DNA for treatment of patients with lung metastases. IFNA2-LNP01 will be administered in the clinically neoadjuvant setting, where it “forces” tumor cells to express type I interferon (IFN-I, IFNα2) to activate the IFN-I signaling pathway in lung metastases microenvironment to increase the expression of T cell chemokines CXCL9 and CXCL10, resulting in enhanced T cell recruitment to the tumor site to suppress lung metastases or at least reduce the lung metastases size prior to lung metastasectomy. Two key differentiating features of IFNA2-LNP01 immunotherapy are local IFNα2 production by tumor cells and administration in the neoadjuvant setting, which are necessary to reduce toxicity and to give patients the best chance to fight their metastatic tumor ahead of other lines of therapies (e.g., chemotherapy) that can negatively affect T cells.

IFNA2-LNP01 is designed based on recently published data. Our published data determined that loss of IFN-I expression is a major mechanism underlying immune evasion of lung metastases. We determined, in mouse tumor models of triple negative breast cancer (TNBC), colon cancer, and melanoma, that tumor cell PD-L1 engages myeloid cell PD-1 to activate SHP2 to antagonize IFN-I expression to repress T cell chemokines CXCL9, resulting in impaired cytotoxic T lymphocyte (CTL) recruitment to lung metastases. Our data therefore suggests that IFN-I therapy is an effective approach to enhance CTL tumor infiltration to suppress lung metastases.

IFNα2 protein is an FDA-approved agent for human cancer. However, high doses and administration frequencies are required due to its short half-life, which is associated with severe adverse effects. The 2nd generation IFNa2 is a polymer polyethylene glycol (PEG)-conjugated IFNa2 (Pegasys and PegIntron) which has a longer half-life with increased efficacy. However, this 2nd generation IFNα2 protein have minimal decrease in adverse effects, which limits the clinical use.

      IFNA2-LNP is the 3rd generation IFNα2 agent that “forces” tumor cells to produce human IFNα2 locally in the lung metastases microenvironment to increase CTL recruitment to suppress lung metastases. Because IFNα2 protein is produced locally in the tumor microenvironment, we expect low systemic toxicity of IFNA2-LNP01 therapy.

IFNA2-LNP01 mechanism of action: Tumor cell PD-L1 engages myeloid cell PD-1 to activate SHP2 to suppress the IFN-I/STAT1/CXCL9 pathway to impair CTL recruitment in lung metastases. Loss of IFN-I expression is therefore a key determinant of tumor lung metastases immune escape (Klement et al., Cancer Cell 2023, 47:620-636)(right panel). IFNA2-LNP01 immunotherapy (right panel) transfects tumor cells to force tumor cells to express IFNα2 to re-activate the STAT1/CXCL9 pathway to enhance CTL recruitment to lung metastases to suppress tumor in the lung niche. a2=IFNα2.   

Supporting publications:

  1. John D Klement, Priscilla S Redd, Chunwan Lu, Alyssa D Merting, Dakota B Poschel, Dafeng Yang, Natasha M Savage, Gang Zhou, David H Munn, Padraic G Fallon, Kebin Liu. 2023. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell. 41:620-636.e9.
  2. Zeinab Y. Al Subeh, Dakota B. Poschel, Priscilla S. Redd, John D. Klement, Alyssa D. Merting, Dafeng Yang, Megh Mehta, Huidong Shi, Yolonda L. Colson, Nicholas H. Oberlies, Cedric J. Pearce, Aaron H. Colby, Mark W. Grinstaff, and Kebin Liu. 2022. Lipid nanoparticle delivery of Fas plasmid restores Fas expression to suppress melanoma growth in vivo. ACS Nano. 16:12695-12710.
  3. Chunwan Lu, John D. Klement, Wei Xiao, Mohammed Ibrahim, Priscilla S. Redd, Asha Nayak-Kapoor, Gang Zhou, and Kebin Liu. 2019. Type I IFNs activates STAT3 to regulate effector expression of cytotoxic T lymphocyte effectors to suppress tumor development. J Immunother Cancer. 7:157.