Intratumoral Administration of a Novel Cytotoxic Formulation with Strong Tissue Dispersive Properties Regresses Tumor Growth and Elicits Systemic Adaptive Immunity in In Vivo Models

• Published in: International journal of molecular sciences 2020-06, Vol.21 (12), p.4493
• Main Authors: Bender, Lewis H, Abbate, Franco, Walters, Ian B
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Animals; Antigen (tumor-associated); Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Biocompatibility; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cancer; Cancer therapies; Caprylates - chemistry; Cell death; Cell Proliferation; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Cytotoxic agents; Cytotoxicity; Dispersion; Dosage; Drug Compounding; Drug dosages; Drug therapy; Female; Humans; Immune checkpoint; Immune system; Immunosuppressive agents; Lipids; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Payloads; PD-1 protein; Solid tumors; Survival; Tumor Cells, Cultured; Tumor-infiltrating lymphocytes; Tumors; Vinblastine; Vinblastine - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21124493

The recent development of immune-based therapies has improved the outcome for cancer patients; however, adjuvant therapies remain an important line of treatment for several cancer types. To maximize efficacy, checkpoint inhibitors are often combined with cytotoxic agents. While this approach often leads to increased tumor regression, higher off target toxicity often results in certain patients. This report describes a novel formulation comprising a unique amphiphilic molecule, 8-((2-hydroxybenzoyl)amino)octanoate (SHAO), that non-covalently interacts with payloads to increase drug dispersion and diffusion when dosed intratumorally (IT) into solid tumors. SHAO is co-formulated with cisplatin and vinblastine (referred to as INT230-6). IT dosing of the novel formulation achieved greater tumor growth inhibition and improved survival in in vivo tumor models compared to the same drugs without enhancer given intravenously or IT. INT230-6 treatment increased immune infiltrating cells in injected tumors with 10% to 20% of the animals having complete responses and developing systemic immunity to the cancer. INT230-6 was also shown to be synergistic with programmed cell death protein 1 (PD-1) antibodies at improving survival and increasing complete responses. INT230-6 induced significant tumor necrosis potentially releasing antigens to induce the systemic immune-based anti-cancer attack. This research demonstrates a novel, local treatment approach for cancer that minimizes systemic toxicity while stimulating adaptive immunity.