NanoStilbene Enhances Anticancer Immunity in Cancer Patients through
Modulation of Inflammatory Mediators
Pterostilbene is a methyl ether of resveratrol, known to possess anti-inflammatory and anticancer activity in various model systems. It is known that in advanced cancer, excess inflammatory signaling may be associated with a reduction in CD3 zeta chain signaling and inhibited function of natural killer (NK) cells. Given the importance of NK cells in activity of various Immunotherapeutics, we sought to determine whether administration of a nanoparticle formulation of pterostilbene may reverse cancer associated suppression of NK activity. An initial study in heathy volunteers was performed to elucidate the amount of NanoStilbene needed to be administered to achieve sufficient plasma concentration for induction of anti-inflammatory activity. Subsequent to this, the selected NanoStilbene dose was administered to twelve patients with advanced solid cancers for 3 weeks. Daily treatment with NanoStilbene caused reduction in serum levels of inflammatory markers TNF-alpha, IL-6, and CRP. Assessment of peripheral blood mononuclear cell ability to generate IFN-gamma subsequent to stimulation with anti-CD3 and anti-CD28 was increased. Additionally, NK cytotoxicity was augmented. These results suggest that NanoStilbene may be a useful adjuvant to immunotherapy of cancer rescuing T cell and NK cell activities. Augmentation of NK cell function may stimulate efficacy of approved therapies that depend on an active NK compartment such as Herceptin, Rituximab, and Cetuximab.
All twelve patients signed informed consent and were told of the investigational nature of the clinical trial. To be eligible patients must have at least 6 months life expectancy, ECOG over 2, metastatic advanced solid tumor, be ambulatory, and not suffer organ failure.
Reduction of Inflammatory Markers by NanoStilbene
CRP, TNF-alpha, and IL-6 have been reported by numerous groups to possess immune suppressive properties. Based on the characteristic profiles of cytokine production, levels of inflammatory cytokines were assessed by ELISA, as seen in Figure 1. This dramatic reduction suggests clinically relevant levels of downregulation of inflammatory cytokines as a result of NanoStilbene administration. In comparison to other anti-inflammatory approaches such as N-acetylcystein administration did not accomplish a similar reduction.
Stimulation of Interferon Gamma Production
Caspace-3 mediated cleavage of the T cell receptor zeta chain has been previously associated with cancer initiated immune suppression. Specifically, Whiteide et al showed hydrogen peroxide produced by granulocytes from cancer patients acts as a potent immune suppressant for T cell activity. Th1 immune responses are conventionally stimulated by interferon gamma, and suppression of interferon gamma is a hallmark of cancer immune evasion. Given that this cancer immune evasion is typically associated with inflammatory mediators such as TNF-alpha, we assessed the impact of NanoStilbene administration on CD3 and CD28 stimulated production of interferon gamma. As seen in Figure 2, augmentation of interferon gamma production was observed following administration of NanoStilbene.
Augmentation of Natural Killer Cell Activity
Activity of NK cells is one of the most sensitive indicators of anticancer immunity, given the ability of the NK cell to kill cells lacking HKA antigens such as neoplastically transformed cells. Previous studies have shown efficacy of antibody as well as chemotherapy induced cancer cell death is dependent on NK activity. Unfortunately, cancer patients have suppressed NK activity, usually as a result of oxidative stress, therefore, it was postulated that NanoStilbene may reverse cancer associated NK depression. As observed below in Figure 3, increased NK activity was seen.
*The data provided here is partial and does not contain all materials submitted for publication and is preliminary until peer review is complete. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.