Compositions and methods useful to enhancing, improving, or eliciting anti-tumor immune responses.

ProJuvenol® Patent No.: 9,682,047

On June 20th, 2017, Therapeutic Solutions International, Inc. was granted U.S. Patent No.: 9,682,047 for ProJuvenol® titled “Augmentation of Oncology Immunotherapies by Pterostilbene Containing Compositions”.

Patent Abstract:
Compositions and methods useful to enhancing, improving, or eliciting anti-tumor immune responses are disclosed. A pterostilbene containing composition is administered to a cancer patient at a sufficient concentration and frequency to induce de-repression of tumor targeting immune responses. The composition enhances antibody dependent cellular tox­icity (ADCC) and augments efficacy of antigen specific immunotherapeutics such as trastuzumab and other mono­clonal antibody therapies useful for treating cancer.

FIELD OF THE DISCLOSURE
The disclosure relates generally to compositions and methods for treating cancer and improving responses to cancer drug therapies using a nutraceutical formulation containing pterostilbene.

BACKGROUND
Cancer is second only to cardiovascular disease as a cause of death in the United States. According to the American Cancer Society, there will be an estimated 1,658,210 new cancer cases diagnosed and 595,690 cancer deaths in the US in 2016. (The Agency for Healthcare research and Quality (AHRQ) estimates that the direct medical costs (total of all health care costs) for cancer in the US in 2011 were $88.7 billion.

Modalities useful in the treatment of cancer include chemotherapy, radiation therapy, surgery, immunotherapy, and other gene-, protein- or cell-based treatments. Conventional cancer therapies have many drawbacks including toxicity and significant side effects often limit the ability of patients to continue treatment, including immunosuppression, and damage to vital organs. Cancer cells eventually develop multi-drug resistance after being exposed to one or more anticancer agents. Most chemotherapeutic drugs act as anti-proliferative agents, targeting different stages of the cell cycle, thereby interfering with the function of healthy tissues and organs. Given the differing sensitivity of tumor cells to treatment, the ability of tumors to mutate and adapt to therapies, as well as the plethora of mechanisms that the tumor uses simultaneously in order to subvert host defenses, it is commonplace for multi-drug regimens to be used in cancer treatment. In turn, drug interactions and side effects that patients must contend with can increase exponentially.

Innumerable researchers and companies have searched for improvements in the treatments for the wide array of cancers. Companies are advancing bioactive agents including chemical entities, e.g., small molecules, and biologics, e.g., antibodies, with the desire of providing more beneficial therapies for cancer. Some bioactive agents have worked and provided beneficial therapeutic effects in some individuals or cancer types and others have failed or had minimal therapeutic effects or side effects that precluded completion of treatment due to organ toxicity, acute events such as thrombosis, and/or patient intolerance.

Analysis of the immunologic features of the tumor microenvironment is enabling rapid development of multiple new therapeutic strategies against various types of cancer as well as the identification of potential biomarkers for clinical benefit. Some cancers display hundreds or even thousands of mutations in coding exons, representing a large repertoire of antigens to serve as potential targets for the immune system. However, despite these abundant antigens, most cancers can evade immune mediated rejection, despite the ability to detect spontaneous anti-tumor immune responses in the majority of cancer patients (Gajewski, T. F., H. Schreiber, and Y. X. Fu, Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol, 2013. 14(10): p. 1014-22), which is incorporated herein by reference in its entirety.

There is an emerging portfolio of inhibitory checkpoints that can influence the physiology of innate immune cells including dendritic cells, macrophages, natural killer (NK) cells, and T cells to harness their effector function in order to over-ride the tumor’s inhibitor signals. A focal point of cancer therapeutics is therefore the discovery of novel therapeutic strategies of fine tuning and augmenting the appropriate anti-tumor responses. Moreover, it is known in the art that a synergistic combination of strategies directed toward overcoming the cancer’s immune inhibitory signals and stimulating the endogenous anti-cancer immune response is believed to offer therapeutic advantages. Finding the right combinations of drugs to effectively treat a particular cancer, as well as limiting toxicity, have remained the two major thrusts in the art of clinical cancer research.

Different polyphenolic compounds of natural origin, such as trans-resveratrol (trans-3,5,4′-trihydroxystilbene, t-RESV), have been studied for their potential antitumor properties (3). Resveratrol (trans- or (E)-3,5,4′-trihydroxystilbene (1)) is a phytoalexin produced in plants and popularized as a beneficial ingredient of red wine. Resveratrol, its cis- or (Z)-isomer (2), and another stilbene derivative, pterostilbene (3), exhibit some anti-cancer activity. Cancer chemopreventive activity of t-RESV was first reported by Pan et al. (4). However, anticancer properties of t-RESV are limited due to the low systemic bioavailability of t-RESV (5). Thus, structural modifications of the t-RESV molecule appeared necessary in order to increase the bioavailability while preserving its biological activity. Resveratrol has also been produced by chemical synthesis and is sold as a nutritional supplement derived primarily from Japanese knotweed.

SUMMARY
The present disclosure is directed to compositions and methods for enhancing, improving, or eliciting anti-tumor immune responses in a subject. A pterostilbene containing composition is administered to a cancer patient at a sufficient concentration and frequency to induce de-repression of tumor targeting immune responses. The composition enhances antibody dependent cellular toxicity (ADCC) and augments efficacy of antigen specific immunotherapeutics such as trastuzumab and other monoclonal antibody therapies useful for treating cancer.

In some embodiments is provided a method of treating cancer in a subject having a tumor. In some embodiments, the method includes administering to the subject a composition having an effective amount of pterostilbene and an anti-cancer antibody.

In some embodiments, the effective amount of pterostilbene increases an immune response in the subject. In some embodiments, the effective amount of pterostilbene does not kill cancer cells. In some embodiments, an effective amount of pterostilbene increases an anti-tumor immune response in a subject. In some embodiments, the effective amount of pterostilbene does not kill tumor cells.

In some embodiments, an effective amount of pterostilbene includes an amount is an amount sufficient to cause an increase in an anti-tumor immune response in a subject. In some embodiments, an effective amount of pterostilbene is a daily dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, or a value within a range defined by any two of the aforementioned values.

In some embodiments, the anti-cancer antibody is selected from the group of rituximab, trastuzumab, nimotuzumab, alemtuzumab, gemtuzumab, ipilimumab, tremelimumab, nivolumab, pembrolizumab, and pidilizumab.

In some embodiments is provided a method of treating cancer in a subject. In some embodiments, the method includes administering a composition having an effective amount of pterostilbene to elicit an immune response in the subject. In some embodiments, eliciting an immune response in a subject includes increasing the ability of immune cells to inhibit cancer cell proliferation.

In some embodiments, eliciting an immune response in the subject is determined by assessing the function of immune cells. In some embodiments, the immune cells are selected from the group of B cells, T cells, innate lymphoid cells, natural killer cells, natural killer T cells, gamma delta T cells, macrophages, monocytes, dendritic cells, neutrophils, and myeloid derived suppressor cells.

In some embodiments, the immune cells include Th1 cells. In some embodiments, the Th1 cells are capable of secreting cytokines selected from the group of interferon gamma, interleukin 2, and TNF-beta. In some embodiments, the Th1 cells express markers that are selected from the group of CD4, CD94, CD119 (IFNγ R1), CD183 (CXCR3), CD186 (CXCR6), CD191 (CCR1), CD195 (CCR5), CD212 (IL-12Rβ1&2), CD254 (RANKL), CD278 (ICOS), IL-18R, MRP1, NOTCH3, and TIM3. Thus, in some embodiments, the method of treating cancer by administering pterostilbene relates to the production and quantification of secreted cytokines.

In some embodiments, the immune cells include Th2 cells. In some embodiments, the Th2 cells are capable of secreting cytokines selected from of the group of IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. In some embodiments, the Th2 cells express markers that are selected from the group of CRTH2, CCR4, and CCR3.

In some embodiments, the composition further includes a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an anti-cancer antibody. In some embodiments, the anti-cancer antibody is selected from the group of rituximab, trastuzumab, nimotuzumab, alemtuzumab, gemtuzumab, ipilimumab, tremelimumab, nivolumab, pembrolizumab, and pidilizumab.

In some embodiments, pterostilbene is administered daily at a concentration of about 0.007 mg to about 1500 mg pterostilbene per kg metabolic weight. In some embodiments, pterostilbene is administered daily at a concentration of 0.007, 0.01, 0.02, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, 150, 200, 500, 1000, or 1500 mg of pterostilbene per kg of metabolic weight, or a value within a range defined by any two of the aforementioned values. In some embodiments, pterostilbene is administered in capsules at a dose of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 400, or 500 mg at least twice daily, or a value within a range defined by any two of the aforementioned values. In some embodiments, pterostilbene is administered in capsules at a dose of 100 mg at least twice daily.

In some embodiments, the composition further includes one or more of superoxide dismutase, curcumin, dimethylaminoethanol (DMAE), alpha lipoic acid, and piperine.

In some embodiments is provided a composition for enhancing, improving, or eliciting anti-tumor immune responses in a cancer patient. In some embodiments, the composition includes pterostilbene. In some embodiments, the composition further includes one or more of superoxide dismutase, curcumin, alpha lipoic acid, piperine, 2-dimethylaminoethanol, and a pharmaceutically acceptable carrier. In some embodiments, pterostilbene is formulated as liposomal pterostilbene.

In some embodiments, the composition is contained in capsules. In some embodiments, the capsules each contain the following amounts, or a value defined within a range of any of the amounts described herein: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400 or 500 mg pterostilbene; 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400 or 500 mg superoxide dismutase; 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 106, 150, 200, 300, 400 or 500 mg curcumin; 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400 or 500 mg alpha lipoic acid, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50 mg piperine; and 10, 20, 30, 40, 50, 60, 62, 70, 80, 90, 100, 150, 200, 300, 400 or 500 mg 2-dimethylaminoethanol. In some embodiments, the capsules each contain about 100 mg pterostilbene, 100 mg superoxide dismutase, 106 mg curcumin, 50 mg alpha lipoic acid, 5 mg piperine, and 62 mg 2-dimethylaminoethanol.

In some embodiments, the composition further includes a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an anti-cancer antibody selected from the group of rituximab, trastuzumab, nimotuzumab, alemtuzumab, gemtuzumab, ipilimumab, tremelimumab, nivolumab, pembrolizumab, and pidilizumab.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the synergistic inhibition of B16 melanoma in mice when treated with the combination of IL-2 and pterostilbene. Mice were treated every second day with: saline (diamonds—⋄); 25 μg/kg pterostilbene (squares—□); 500 IU/mouse IL-2 (triangles—Δ); and a combination of IL-2 and pterostilbene at the indicated concentrations (X).


FIG. 2 illustrates the stimulation of mitogen induced IFN-gamma production by pterostilbene in mice. Mice were treated as described in FIG. 1 (from left to right: saline; 25 μg/kg pterostilbene; 500 IU/mouse IL-2; and a combination of IL-2 and pterostilbene at the indicated concentrations). Mononuclear cells were obtained and plated in 96-well plates and treated with Concanavalin A at 5 μg/mL. IFN-gamma was assessed by ELISA. The y-axis is expressed as ng/mL.

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