PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-12, Vol.114 (52), p.13655-13660
• Main Authors: Langut, Yael, Talhami, Alaa, Mamidi, Samarasimhareddy, Shir, Alexei, Zigler, Maya, Joubran, Salim, Sagalov, Anna, Flashner-Abramson, Efrat, Edinger, Nufar, Klein, Shoshana, Levitzki, Alexander
• Format: Article
• Language: English
• Subjects: Acids; Adoptive Transfer; Animals; Anticancer properties; Antigens; Antigens, Surface - genetics; Antigens, Surface - metabolism; Antitumor activity; Apoptosis; Biological Sciences; Bystander Effect; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Cells; Diabetes mellitus; Disease Models, Animal; Disease resistance; Gene Expression; Glutamate Carboxypeptidase II - antagonists & inhibitors; Glutamate Carboxypeptidase II - genetics; Glutamate Carboxypeptidase II - metabolism; Humans; Immune response; Immune system; Immunity; Immunotherapy; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Male; Medical treatment; Metastases; Mice; Peripheral blood mononuclear cells; Pheochromocytoma cells; Poly I-C - chemistry; Poly I-C - pharmacology; Polyethylene glycol; Polyethyleneimine; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Protein Binding; Recruitment; Statistical analysis; Toxicity; Tumor Burden - drug effects; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1714587115

There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine–polyethyleneglycol (PEI–PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.