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Health Protocols

Cancer Immunotherapy

Integrative Interventions

Vitamin D

This “sunshine vitamin,” long valued for its role in bone health, is now being studied extensively for its ability to improve immune function. The risk of some cancers may be increased in people with low vitamin D levels (Bandera Merchan 2017). Both cancer cells and immune cells have vitamin D receptors (Vuolo 2012; Aranow 2011; Buras 1994).

Vitamin D modulates the activity of numerous immune cells, including monocytes, dendritic cells, and T and B cells, and promotes the ability of the innate immune system to fight off infections (Prietl 2013). There is evidence that vitamin D might enhance vaccine response (Lang 2015), possibly through its potent effect on dendritic cells (Barragan 2015). Vitamin D’s capacity in this regard may also extend to cancer vaccine response.

Dendritic cells process vaccine antigens and present them to other cells of the immune system. In mouse studies, vitamin D at the time of vaccination increases the number of dendritic cells that move into the immune-cell-rich lymph nodes (Enioutina 2008; Enioutina 2009). Other studies have confirmed that vitamin D can increase the amount of antibody produced to a vaccine (Ivanov 2006). Several studies of the effects of vitamin D on response to vaccines in humans are ongoing (Sadarangani 2015).

One study found tumor growth increased levels of a type of immature immune cell, and these immature cells suppressed the function of certain types of T cells. However, vitamin D caused these cells to mature into non-suppressive cell types (Wiers 2000). These suppressive cells are often found in tumors, where they protect the tumor from immune attack and, in some patients, immunotherapy (Camisaschi 2016). In a small clinical trial, patients with head and neck cancer were treated with 800 to 2400 IU of vitamin D daily. The number of suppressive cells was reduced (Lathers 2004). In mice, vitamin D increased T cell activity in tumors and, intriguingly, improved the response to a type of immunotherapy (Wiers 2000).

This evidence that vitamin D may be able to improve dendritic cell response to vaccines and reduce suppressive immune cells that could hamper immunotherapy makes vitamin D a logical candidate for additional large studies of its ability to complement immunotherapy.

Zinc

Zinc is a trace mineral essential for immune system function relevant to cancer (Grattan 2012). Zinc deficiency is associated with reduced innate and adaptive immune responses and systemic inflammation (Cabrera 2015). Many elderly people are mildly deficient in zinc, and this deficiency likely contributes to immune senescence (Cabrera 2015; Haase 2009).

T cells mature in the thymus (Janeway 2001c), a gland situated behind the sternum. As humans age, the ability of the thymus to produce T cells diminishes (Mitchell 2006). People with zinc deficiency have the same thymus problems (Wong 2009; Fraker 2000). In a study in which zinc levels were intentionally reduced in humans, the number of cytotoxic T cells capable of fighting cancer on their own or in response to immunotherapy was also reduced (Beck 1997).

When elderly patients took 30 mg zinc for three months, the number of T cells in their blood increased almost 30 percent (Barnett 2016). This boost in T cells could complement immunotherapy. In mice, supplementation with zinc helped reverse some of the age-related problems with the thymus (Wong 2009).

NK cells are a critical line of defense against cancer cells (Waldhauer 2008), and NK cells are critical to the success of many immunotherapies, especially antibody-dependent cellular cytotoxicity (ADCC) monoclonal antibodies (Souza-Fonseca-Guimaraes 2016; Romee 2015). As we age, our NK cells become less powerful, and zinc deficiency can contribute to this change (Mocchegiani 2013). Studies in elderly people have shown that zinc supplementation can restore healthy levels of zinc in the body and restore NK cell cytotoxicity (Mocchegiani 2003; Mariani 2008). Zinc supplementation may also help the body produce new NK cells. When immature immune cells were grown in a laboratory, supplementation with zinc increased the number that matured into NK cells (Muzzioli 2009).

Enzymatically Modified Rice Bran

In immune senescence, NK cells become less effective at finding and destroying cancer cells. A specific enzymatically modified rice bran preparation called MGN-3 can boost NK cell function (Ghoneum 2004; Perez-Martinez 2015; Park 2017). Enzymatically modified rice bran is made by partially breaking down the fiber arabinoxylan with enzymes from shitake mushrooms to expose the polysaccharides and other cell wall components (Kim, Kim 2007; Choi 2014). In aged mice, MGN-3 injection dramatically increased NK cell activity within two days, and the NK cells could bind more effectively to cancer cells (Ghoneum 2004).

Sixty-eight patients with liver cancer participated in a clinical study that found oral MGN-3 improved the survival rate after two years compared with controls—35% versus less than 7%. Also, the MGN-3 group had a lower rate of disease recurrence—32% versus 47% (Bang 2010). The investigators in that study did not look for any immune-related effects. In a clinical trial with 48 multiple myeloma patients, a three-month regimen of MGN-3 significantly activated NK cells and increased the number of dendritic cells in the blood (Cholujova 2013). In the laboratory, human dendritic cells treated with MGN-3 more effectively activated cytotoxic T cells (Ghoneum 2014).

Pu-erh Tea & Cistanche

Pu-erh tea, made from fermented leaves of Camellia sinensis, has a long history of use in traditional Chinese medicine for anti-aging and preventing infections (Chu 2011). Cistanche (Cistanche tubulosa) is a highly respected tonic herb that grows in dry climates and which has earned the moniker “Ginseng of the desert” (Jiang 2009). Recent laboratory studies show Pu-erh tea and Cistanche can boost the immune system and reverse some aspects of immune senescence. A mouse model of human aging showed that some aspects of immune senescence were reversed when the mice were fed either Pu-erh tea or Cistanche(Zhang 2012; Zhang 2014). Both Pu-erh tea and Cistanche increased the numbers of NK cells and naïve T cells in these mice. One study found that Pu-erh tea reduced markers of inflammation in patients with metabolic syndrome (Chu 2011).

Curcumin

Results from several early clinical studies have shown that curcumin (a constituent of Curcuma longa) can help fight tumors (Kotecha 2016). Research in the lab suggests curcumin might fight tumors partly by modulating the immune system (Bose 2015).

In two studies, curcumin reduced the number of suppressive immune cells in mouse tumors and increased the number cytotoxic T cells that can attack cancer cells (Singh 2013; Luo 2011). Similarly, in a model of esophageal cancer, a form of curcumin activated dendritic cells, increased cytotoxic T cell activity up to about 3-fold, and reduced inflammatory cytokines. The authors of the study speculated that these effects of curcumin could make dendritic cell-based immunotherapy more effective (Milano 2013).

Furthermore, curcumin is being tested in preclinical models as a cancer vaccine adjuvant (Lu 2016; Jiang, Xie 2015). Because of curcumin’s ability to reduce inflammatory cytokines, researchers tested whether it could improve the cancer vaccine-induced response to an aggressive form of breast cancer in mice. Curcumin not only improved the response of the tumor to the vaccine but also reduced the number of metastases (Singh 2013).

Combinations of curcumin and cancer vaccines have also been used to successfully treat melanoma models (Jiang, Xie 2015). Vaccines reduced the tumor size more effectively in the presence of curcumin (Lu 2016). The researchers also found that curcumin increased cytotoxic T-cell response and decreased suppressive immune cells (Lu 2016).

One type of suppressive immune cell is called a myeloid-derived suppressor cell. Myeloid-derived suppressor cells accumulate in tumors and promote tumor growth. In mice, curcumin has been successfully used to block accumulation of these cells (Tu 2012; Liu, You 2016).

Vitamin E

Vitamin E is an antioxidant present in the membranes of most cells, including immune cells (Coquette 1986; Wang 2000; Pae 2012). Vitamin E deficiency causes many problems with the innate and adaptive immune systems (Morel 2011; Pae 2012).

Vitamin E supplementation of healthy elderly people improved T cell-mediated immune responses in several studies and reversed many aspects of immune senescence (De la Fuente 2008; Pae 2012; Wu 2008; Meydani 1997). When healthy elderly people took supplemental vitamin E (200 to 800 mg daily), their T cells were more responsive to antigens, and their B cells produced more antibodies to vaccines (Meydani 1997). A more recent study on elderly men and women taking 200 mg of vitamin E daily confirmed the effect on T cells and also found that NK cells were more active (De la Fuente 2008). A small study on colorectal cancer patients taking 750 mg of vitamin E daily also found increased NK cell activity (Hanson 2007).

Vitamin E exists in eight forms, or isomers, in nature: four tocopherols and four tocotrienols (NASEM 2017). In one study, tocotrienols were used as an adjuvant to a dendritic cell vaccine in mice. Mice treated with the adjuvant had increased cytotoxic T cells and NK cells in their blood (Hafid 2010). The same research group went on to confirm that growth of breast tumors in mice treated with a dendritic cell vaccine along with tocotrienols was dramatically inhibited. Furthermore, metastases were rare in these mice (Abdul Hafid 2013). Early data suggest tocotrienols might also enhance the response of humans to cancer vaccines. Healthy adults supplemented with a tocotrienol-rich fraction of palm oil produced more antibodies to a tetanus vaccine (Mahalingam 2011).

Selenium

Like zinc, selenium is a trace mineral that plays many roles in immune function (Ojeda 2017; Hoffmann 2008). Low selenium levels have been associated with increased risk of cancer (Hughes 2016; Hughes 2015). Also, selenium supplementation decreased the incidence of prostate cancer in patients with low baseline selenium levels (Duffield-Lillico 2003).

Studies in mice suggest selenium supplementation shifts the immune system toward cytotoxic T cells that can fight infection and cancer, and boost vaccine response (Huang 2012). In a small study of healthy adults with low selenium levels, supplementation with selenium (50 or 100 micrograms of sodium selenite daily) improved cellular response to a polio vaccine (Broome 2004). Mouse studies, using other types of vaccines, have confirmed this effect (Mahdavi 2017; Yazdi 2015).

When mice were fed selenium along with fish oil, suppressive immune cells decreased and anti-tumor immunity increased (Wang 2013). Supplementation with selenium (200 micrograms of sodium selenite daily) of a small group of patients with head and neck cancer improved lymphocyte activity, including the activity of cancer-cell-killing cytotoxic T cells (Kiremidjian-Schumacher 2001). T-cell numbers in elderly people increased in response to selenium (400 micrograms daily) in another study. Interestingly, NK cell function also improved in this study (Wood 2000).

Probiotics

Probiotics are microorganisms that improve health when used as a supplement (Lesbros-Pantoflickova 2007). They keep “bad” bacteria in check and help balance the immune system between efficient pathogen destruction and damaging inflammation. Supplemental probiotics are used to treat digestive problems, including chemotherapy-induced diarrhea (Wang, Yao 2016), but there is compelling evidence that probiotics could also influence response to immunotherapy (Tang 2015; Liu, Chen 2016; Shida 2013).

In a small group of people, supplementation with Lactobacillus casei strain Shirota significantly enhanced NK cell activity, particularly for those with low NK activity at the start of the study (Nagao 2000). Additional studies have found that probiotics increase NK cell activity in elderly patients (Makino 2010) and in patients undergoing surgery for cancer (Sugawara 2006).

The adaptive immune system is also affected by probiotics. In mice, Saccharomyces boulardii significantly increased antibodies produced to a vaccine (Silveira 2017). In a recent study of people over 85 years old, a heat-killed L. paracasei MCC1849 supplement increased the antibody response to a flu vaccine (Maruyama 2016). Healthy people aged 50 to 70 were treated with L. gasseri TMC0356 in another study. The number of cytotoxic T cells, the ones that can destroy cancer cells, were significantly increased in these people (Miyazawa 2015).

Two papers published together in the journal Science in 2015 presented data that the type of bacteria present in the gut can significantly influence the response to immune checkpoint inhibitors in mouse models (Sivan 2015; Vetizou 2015). Treatment of the mice with bifidobacteria alone shrank the tumors, and when treated with the bacteria along with a checkpoint inhibitor, the tumors were almost entirely destroyed (Sivan 2015). Additional research is required to determine whether supplementation with probiotics can increase response to checkpoint inhibitors and other immunotherapies in humans.

Beta Glucans

Beta glucans are naturally occurring chains of carbohydrate molecules (polysaccharides) from the cell walls of yeast, mushrooms, bacteria, seaweed, and other organisms (Akramiene 2007; Chan 2009; Bobadilla 2013). They modulate both innate and adaptive immune systems in animal studies (Ding 2015). Beta glucans increase T-cell proliferation and NK cell activity (Jin 2016).

In small studies of patients with advanced lung cancer and colorectal cancer, treatment with Reishi mushroom, Ganoderma lucidum (a source of beta glucans), increased NK cell number and activity in some subjects (Gao 2005; Chen 2006). In addition, some researchers are studying ways to use beta glucans as vaccine adjuvants or even as vaccine delivery systems (Levitz 2015; Wang, Zhang 2016; Huang 2013).

Polysaccharide K (PSK) is a beta glucan derived from a mushroom called Coriolus versicolor. It has been studied extensively (Maehara 2012). PSK is widely used in Japan to treat a variety of cancers, but has not been adopted into mainstream clinical practice in other countries (Fritz 2015). PSK improves the ability of NK and T cells to find and destroy cancer cells, and it protects against immune dysfunction caused by cancer treatment.

A recent meta-analysis of six randomized controlled trials found that PSK (3 grams per day) in combination with chemotherapy or radiation in lung cancer patients improved immune function and helped fight cancer (Fritz 2015). In a study on patients with colorectal cancer, PSK (3 grams daily) increased the number of NK cells and improved patient five-year survival rates (Ohwada 2006). Another study concluded that taking PSK after surgery improved survival of gastric cancer patients (Oba 2007).

The data on beta glucans are compelling enough that the biotechnology industry is taking notice. One company, called Biothera Pharmaceuticals, is developing a soluble form of a yeast beta glucan named Imprime PGG (Segal 2016; Thomas 2017). The drug is being tested in combination with pembrolizumab in several phase II trials as of mid-2017 (Biothera Pharmaceuticals 2016).

Green Tea (Epigallocatechin Gallate)

The compound epigallocatechin gallate (EGCG) is abundant in green tea, Camellia sinensis (Niu, Na 2013). In one study, EGCG effectively treated neuroblastomas in mice. The authors went on to study the mechanism and found that EGCG reduced the suppressive immune cells that protect the tumor (Santilli 2013; Orentas 2013). Furthermore, EGCG enhanced T-cell response to a vaccine in a mouse model (Kang 2007).

Vitamin C

Vitamin C can improve immune system function, with effects on lymphocyte proliferation and NK cell activity (Shaik-Dasthagirisaheb 2013). Treating immature NK cells with vitamin C in the laboratory increased the number of NK cells produced (Huijskens 2015). Mice lacking the ability to manufacture vitamin C can fight tumors more effectively when they take supplemental vitamin C. The supplemental vitamin C increases NK cell activity against cancer cells (Kim 2012).

In a mouse model of human aging, supplementation with high amounts of vitamin C reversed many aspects of immune senescence (Uchio 2015). When human immune cells were treated with vitamin C in the laboratory, T cells proliferated and became more responsive (Bouamama 2017).

Garlic

Humans have explored the medical uses of garlic (Allium sativum) for thousands of years (Rivlin 2001). Modern clinical trials have begun to investigate the effects of garlic on the immune system. The effects have been examined in the laboratory in numerous studies in mice and human cells, and taken together, the data suggest garlic can inhibit inflammation caused by tumors and boost the immune system’s ability to fight the tumor (Schäfer 2014).

A 2016 review of clinical trials on the effects of garlic found that garlic stimulates and modulates immunity; can increase numbers of T, B, and NK cells; and enhance macrophage activity (Ried 2016). For instance, in one clinical trial on 120 healthy volunteers, aged garlic (2.56 grams per day) increased the number NK cells and certain types of T cells (Nantz 2012). Other trials have shown that garlic can reduce inflammatory cytokines that can contribute to tumor growth (Zeb 2012; Mozaffari-Khosravi 2012).

Sulforaphane

Sulforaphane, which is abundant in broccoli and other vegetables, reversed some aspects of immune senescence in a mouse model (Kim 2008) and increased phagocytosis by mouse macrophage-like cells in the lab (Suganuma 2011). Sulforaphane has shown beneficial effects in men with prostate cancer, including significantly increasing PSA doubling time in men with biochemical recurrence after radical prostatectomy (Cipolla 2015).

Ginseng

Ginseng (Panax ginseng) can enhance phagocytosis by macrophages, boost NK cell activity, and enhance dendritic cell maturation (Kang 2012). These three cell types are essential for immunotherapy. In healthy volunteers aged 50 to 75 years, a ginseng polysaccharide (6 grams per day) increased NK cell activity by 40% in three months (Cho 2014). In another study, ginseng extract (100 mg per day) nearly doubled NK cell activity within eight weeks (Scaglione 1996).

Ginseng may also boost response to vaccines, including cancer vaccines. In healthy humans, ginseng extract (100 mg per day) increased the antibody response to a vaccine by nearly 60% (Scaglione 1996).

Astragalus

In patients with chronic obstructive pulmonary disease, an herb called astragalus (Astragalus membranaceus) improved biomarkers of immune function (Jiang, Wang 2015). The number of NK cells in blood increased, and the number of regulatory T cells decreased. Regulatory T cells can suppress immune response to cancer cells and make immunotherapies less effective. When samples of human liver cancer were treated with astragalus extracts, the number of regulatory T cells decreased (Li 2012). These effects suggest astragalus can boost the immune system’s ability to fight cancer. In fact, in a study of a mouse model of breast cancer, astragalus dramatically decreased tumor growth by modulating molecular aspects of the immune system (Zhou 2017).

Ginger

Ginger (Zingiber officinale) root has antioxidant and anti-inflammatory effects, and it can also inhibit tumor growth in the lab (Shukla 2007). When mice with a variety of tumor types were treated with a component of ginger called 6-gingerol, a large number of tumor-fighting T cells infiltrated the tumor, including a 5-fold increase in cytotoxic T cells. The authors went on to show that those newly arrived T cells were tumor-antigen specific. Also, the number of suppressor T cells declined (Ju 2012).