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

Abstract

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.

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

“…While intra-tumoral treatment delivery decreases off-target toxicities, it fails to account for metastatic disease and has not led to significant survival benefit compared to systemic administration [65]. Clinical use of intra-tumoral drugs is also impractical for some tumor subtypes such as ovarian and pancreatic cancers, which are inaccessible through transdermal injection.…”

In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice

“…The maximum level of cytotoxicity was found in tumors of 6b -HD- and gefitinib-treated nude mice. Previously reported studies have represented that increase in the interstitial space leads to a high extent of penetration of paclitaxel and doxorubicin, which results in apoptosis in head and neck cancers and prostate cancer, respectively [ 26 , 27 ].…”

Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer

“…As noted above, crenolanib inhibits not only PDGFRs but also FLT3 and reduces cell proliferation [23][24][25][26][27]. To minimize its systemic effects on both types of receptors and its inhibitory effect on cell proliferation, we injected 0.1 mL of 10 µM crenolanib directly into tumors five times every 12 h. Intratumoral injection has been used to deliver agents into tumors to kill cancer cells or to activate immune cells [28]. As shown in Figure 4A, there was no significant difference in tumor weight (left panel), We also injected 200 µg Trapidil twice per day for one week and collected sera and tumors.…”