Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 9; pp. 1 - 12
• Main Authors: Zhang, Ying, Xie, Xuemei, Yeganeh, Pourya Naderi, Lee, Dian-Jang, Valle-Garcia, David, Meza-Sosa, Karla F., Junqueira, Caroline, Su, Jiayu, Luo, Hongbo R., Hide, Winston, Lieberman, Judy
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.03.2021
• Series: Inaugural Article
• Subjects: Animals; Antigen Presentation - drug effects; Antineoplastic Agents, Immunological - chemistry; Antineoplastic Agents, Immunological - pharmacology; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - immunology; Aptamers, Nucleotide - pharmacology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biological Sciences; CD47 Antigen - antagonists & inhibitors; CD47 Antigen - genetics; CD47 Antigen - immunology; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - immunology; Epithelial Cell Adhesion Molecule - genetics; Epithelial Cell Adhesion Molecule - immunology; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates - chemistry; Immunoconjugates - immunology; Immunoconjugates - pharmacology; Immunotherapy - methods; INAUGURAL ARTICLE; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - therapy; Mice; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - immunology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Phagocytosis - drug effects; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - immunology; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - immunology; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - immunology; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy; Tumor Burden - drug effects; checkpoint blockade; EpCAM aptamer; CD47; gene knockdown; immunotherapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2022830118

New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM⁺ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2⁺ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti–PD-1 checkpoint inhibition.