ASCO 2019

CytImmune is excited to announce that our collaborative work with the US National Cancer Institute has resulted in an ASCO abstract.

ASCO Submission Category
Developmental Therapeutics and Tumor Biology (Nonimmuno), New Targets and New Technologies

Authors and Institutions
Naris Nilubol, Surgical Oncology Program, National Cancer Institute, NIH, Bethesda, MD 208921
David Oarr and Lawrence Tamarkin,  CytImmune, Rockville, MD 208502

Sponsor
Brigitte C. Widemann, Pediatric Oncology Branch, NCI, Bethesda, MD 20892

Title
Preclinical studies evaluate pivotal TNFα nanomedicine clinical trial design.

Body
Background: The clinically-tested CYT-6091 nanomedicine is comprised of TNF alpha (TNF) bound to 27 nm pegylated gold nanoparticles. Preclinical research has shown that CYT-6091 disrupts solid tumor blood vessels, reduces interstitial fluid pressure and increases accumulation of follow-on chemotherapy in the tumor microenvironment. While systemic toxicity has limited treatment of cancer patients with TNF, isolated limb perfusion of patients with in-transit melanoma using 1-4 mg of TNF followed by chemotherapy has demonstrated up to 90% complete response rates with one treatment. In a single-agent, phase I clinical study in advanced-stage cancer patients, we found that multiple CYT-6091 treatments can systemically and safely deliver up to 1.2 mg of TNF per dose.

Methods:
Our current research was conducted to validate administering CYT-6091 prior to standard-of-care chemotherapy in a phase II clinical trial. As part of the NCI’s Experimental Therapeutics (NExT) evaluation, CYT-6091 was studied in combination with paclitaxel (PTX) in C57BL/6 murine xenografts, using three cancer cell lines: MC-38 colon carcinoma (cancer cells sensitive to TNF, but insensitive to PTX), B16/F10 melanoma (cancer cells insensitive to TNF, but sensitive to PTX), Lewis lung carcinoma (cancer cells insensitive to both TNF and PTX), where sensitivity was based on inhibiting cancer cell growth at the studied dosing amounts and frequency. CYT-6091 was administered 3-hours before PTX, and three PTX doses were administered in each model.

Results:
In every model, CYT-6091 + any dose of PTX was more effective in reducing or controlling tumor growth than the highest dose of PTX alone (p<0.01). We also found that CYT-6091 alone demonstrated significant anti-cancer activity (p<0.01), suggesting that additional studies may be warranted to determine optimal frequency and dose of CYT-6091 as a single agent.

Conclusions:
These preclinical studies demonstrate for the first time that CYT-6091 + PTX was superior to PTX (p<0.01) or CYT-6091 alone (P<0.05) in TNF insensitive cell lines, which represent the majority of cancers. Findings support systemically administering CYT-6091 plus standard-of-care chemotherapy in a pivotal clinical trial.

Related Articles and Background (Not included with Submission):
Nilubol N, Yuan Z, Paciotti GF, et al. Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors. J Natl Cancer Inst. 2018;110(9):1019-1029.

Koonce NA, Quick CM, Hardee ME, et al. Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models. Int J Radiat Oncol Biol Phys. 2015;93(3):588-96.

Remco van Horssen, Timo L. M. Ten Hagen, Alexander M. M. Eggermont TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006 Apr; 11(4): 397–408. doi: 10.1634/theoncologist.11-4-397

Libutti SK, Paciotti GF, Byrnes AA, et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res. 2010;16(24):6139-49

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