Cancer Immunotherapy

Last Section Update: 02/2023

Table of Contents

1 Introduction

Summary and Quick Facts for Cancer Immunotherapy

The American Society of Clinical Oncology named immunotherapy the “clinical cancer advance of the year” for the second year running in 2017.
The goal of cancer immunotherapy is to enhance the body’s natural ability to find and destroy cancer cells. This protocol covers immunotherapy specifically, which will likely be only one facet of a cancer treatment plan.
Successful immunotherapeutic approaches boost the immune system’s natural defenses and provide it with new ways to attack cancer. Integrative interventions such as zinc, selenium, vitamin E, probiotics, enzymatically modified rice bran and beta glucans from Reishi mushrooms and other sources can enhance immune system function and may complement immunotherapies.

William Coley was an American surgeon who dedicated himself to finding a cure for cancer after losing one of his patients to the disease in 1890. He scoured hospital records and found the case of a man named Fred Stein. Mr. Stein’s sarcoma had disappeared seven years earlier after a bacterial skin infection. Coley tracked Stein down. He was still alive and cancer-free (McCarthy 2006; Murala 2010).

Coley was struck by the idea that an immune response to a bacterial infection could cure cancer. He went on to test his hypothesis by inoculating almost 1000 cancer patients with dead bacteria, with some success (McCarthy 2006).

This innovative physician is thought to have originated cancer immunotherapy, a field still blossoming today (Karbach 2012; McCarthy 2006). One hundred and twenty-five years after Coley began his research, former President Jimmy Carter began treatment for metastatic melanoma with a promising new drug called pembrolizumab (Keytruda) (Mulcahy 2015). Metastatic melanoma like Carter’s has a one-year survival rate of about 22% (Song, Zhao 2015), but after just a few months, he had no detectable tumors.

President Carter’s experience with pembrolizumab is not unique. Recent clinical trials in urinary tract and lung cancers were stopped early because the drug was working so well (Bellmunt 2017; Reck 2016). Many trials are assessing the potential of pembrolizumab in treating numerous other cancers (MCT 2017).

Pembrolizumab is just a small part of the rapidly expanding category of cancer treatments called immunotherapy. Scientists have spent years studying how the immune system fights infection and disease, and now they have found ways to build on some of those tools to fight cancer.

Cancerous tumors can suppress the immune system and evade immune cells (Rabinovich 2007). As we age, we naturally undergo a process called immune senescence, which makes us more susceptible to infection and some chronic diseases (Agarwal 2010). Successful immunotherapeutic approaches overcome some of these barriers by boosting the immune system’s natural defenses and providing it with new ways to attack cancer (ACS 2016b). Integrative interventions such as zinc, selenium, vitamin E, probiotics, enzymatically modified rice bran, and beta glucans from Reishi mushrooms and other sources can also enhance immune system function and may complement immunotherapies. The over-the-counter drug cimetidine (Tagamet) can also modulate immune function and facilitate a more robust immune response against some cancers (Pantziarka 2014).

For the first time, patients like Jimmy Carter with difficult-to-treat cancers have some hope that their disease can be effectively treated. Indeed, the American Society of Clinical Oncology named immunotherapy the “clinical cancer advance of the year” for the second year running in 2017 (ASCO 2017).

Immunotherapy research has already brought hope to many patients, and with hard work, financial investment, and solid science, many more immunotherapeutic breakthroughs are expected in the years to come.

Note: this protocol covers immunotherapy specifically, which will likely be only one facet of a cancer treatment plan. Readers should consult other relevant Life Extension protocols as well, such as Cancer Treatment: The Critical Factors, Chemotherapy, Radiation Therapy, and Cancer Surgery.

2 Background

What Does the Immune System Do?

The immune system’s goal is simple: protect the body from viruses, bacteria, malignant cells, and other dangers without damaging normal cells. Several types of immune cells work together to achieve this goal (Table 1).

Cells of the innate immune system are the body’s first line immune responders against foreign and potentially harmful substances and microbial invaders. Cells of the adaptive or acquired immune system, including T cells and B cells, attack invaders that the body has previously encountered (Chaplin 2010).

Cancer Cells and the Immune System

Cancer cells’ DNA changes as they become increasingly malignant. These changes affect the proteins on the surface of the cancer cells, which are exposed to the immune cells (Pio 2014). Most of the time, cells from the innate and adaptive immune systems recognize these surface protein changes and destroy the cancer cells (Janeway 2001b). Natural killer cells, or NK cells, are one type of immune cell responsible for detecting these changes and destroying the cancer cells (Waldhauer 2008).

However, cancer cells often acquire the ability to evade immune detection (Schreiber 2011). Cancer cells typically use two main methods for avoiding detection by the immune system. First, the cells alter the proteins on their surfaces so that immune cells can no longer recognize them as foreign (Kim, Emi 2007). Second, cancer cells alter their surrounding environment to suppress immune cell function (Menon 2016). In people suffering from immune senescence—the general decline of immune function that accompanies aging—tumors may escape immune detection more easily (Turner 2017).

Table 1: Key Cells for Immunotherapy

Branch of Immune System	Cell Type		Function
Innate	Neutrophil		Abundant white blood cell Phagocyte* that responds early to infection
	Monocyte		A large phagocyte in blood that can differentiate into a macrophage or dendritic cell in tissues
	Macrophage		A phagocyte with the primary function of ridding the body of debris and microorganisms Can also present antigens to T and B cells and stimulate other immune cells
	Dendritic cell		A phagocyte that patrols the body to identify pathogens Primary function is to present antigens to T and B cells
	Natural killer cell		A lymphocyte (white blood cell of the lymphatic system) that directly and rapidly kills tumor and virus-infected cells Releases toxic chemicals that cause the target cell to die
Adaptive	T lymphocyte (T cell)	Cytotoxic (CD8+)	Directly and rapidly kills tumor and virus-infected cells Expresses T-cell receptors that are specific for one antigen
		Helper (CD4+)	Modulates the activity of other immune cells with cytokine signaling Expresses T-cell receptors that are specific for one antigen
		Regulatory	Immunosuppressive cell; suppresses other immune cells Expresses T-cell receptors that are specific for one antigen
	B lymphocyte (B cell)		Expresses B-cell receptors that are specific for one antigen Differentiates into plasma cells that produce antibodies specific for the antigen
(Abbas 2009; Delves 2017) *A phagocyte is any type of cell that can engulf harmful invaders such as bacteria and malignant cells. After the phagocyte engulfs the invader, it may destroy it or alert other cells to the presence of invaders in the body.

3 Immunotherapy: Harnessing the Immune System to Treat Cancer

The goal of cancer immunotherapy is to enhance the body’s natural ability to find and destroy cancer cells (ACS 2016b). Immunotherapy can be either passive or active. In passive immunotherapy, general immune-enhancing strategies attempt to bolster the intrinsic immune response against cancer. This may be an effective approach for someone who is generally immunocompromised or afflicted with immune senescence. In contrast, active approaches give the immune system a new way of attacking cancer cells. Active immunotherapeutic approaches stimulate a new immune response in patients whose immune systems are capable of responding (Papaioannou 2016).

Monoclonal Antibody Therapy

Monoclonal antibodies are Y-shaped proteins produced by mature B cells. The term “monoclonal” denotes that the antibodies are made by identical immune cells that are all progeny of a unique parent cell. One of the functions of antibodies is to tag foreign invaders for elimination by the immune system (Delves 2017; Gabrilovich 2016). Each B cell produces one type of antibody, and each antibody is specific for one antigen (Janeway 2001a; Abbas 2009).

Researchers can create antibodies in the lab and develop them for clinical use (Steplewski 2015). Over the past few decades, scientists have learned how to create antibodies highly specific for tumor antigens (Saxena 2016).

Several antibodies are already used to treat cancer. Bevacizumab (Avastin) is used to treat some types of brain, colorectal, lung, and kidney cancers (NCI 2014). This antibody targets a protein called vascular endothelial growth factor (Raphael 2017). Panitumumab (Vectibix) and cetuximab (Erbitux) target the cellular receptor for epidermal growth factor and are used to treat metastatic colorectal cancer (Chen 2016; Lv 2017). Several other antibody drugs target various other cancer-specific cellular markers.

Another way antibodies are used to combat cancer is by delivering cell-killing agents, such as chemotherapy drugs or radioisotopes. Therapies that combine an antibody, which targets cancer cells, with a cell-killing drug are called antibody-drug conjugates (Thomas, Teicher 2016). Brentuximab vedotin (Adcetris) is an example of an antibody-drug conjugate. This drug targets a certain marker (called CD30) that is more common on some types of lymphoma cells than on healthy cells (Berger 2017). Ibritumomab tiuxetan (Zevalin) is another antibody-drug conjugate. It combines rituximab (Rituxan), an antibody that binds to the CD20 marker on the surface of non-Hodgkin lymphoma and chronic lymphocytic leukemia cells, with a radioactive isotope (Rizzieri 2016; Gold Standard 2017j).

While some antibodies deliver poisons to the tumor, others recruit the patient’s immune cells to the tumor in a form of passive immunotherapy (Table 2). Rituximab is an example of this approach. This antibody attracts NK cells that destroy malignant B cells. This process is called antibody-dependent cellular cytotoxicity (Wang 2015; Seidel 2013).

Some other antibodies also trigger antibody-dependent cellular cytotoxicity and have been used clinically. For instance:

alemtuzumab (Campath) targets CD52-positive chronic lymphocytic leukemia cells (Warner 2012)
daratumumab (Darzalex) targets CD38-positive multiple myeloma cells (Costello 2017)
elotuzumab (Empliciti) targets a molecule (SLAMF7) on both multiple myeloma cells and NK cells (Lonial 2015)
trastuzumab (Herceptin) is an antibody to HER2, a growth factor receptor sometimes overexpressed in breast cancer (Nahta 2003; Vu 2012). Trastuzumab was approved by the FDA in 1998 to treat human epidermal growth factor receptor-2-positive (HER2+) breast cancer. By binding to HER2, trastuzumab both blocks growth factor signaling and attracts immune cells to the cancer cells. Trastuzumab is typically used as part of a treatment course that includes chemotherapy.
Pertuzumab (Perjeta) is another antibody to HER2 that is also used in breast cancer treatment. It binds to a different part of the HER2 receptor than trastuzumab, but triggers a similar response. In some cases, trastuzumab and pertuzumab may be used together for dual HER2-targeted therapy (NCCN 2017; Prat 2013). Pertuzumab was approved by the FDA in 2012 (NCCN 2016).

There are many other ways that antibody-based therapies can kill cancer cells. Some antibodies may trigger multiple anti-cancer responses (Weiner 2010).

Blinatumomab (Blincyto) is a newer type of antibody called a bispecific T-cell engager or BiTE (Wu 2015). These compounds link two antibodies, with one binding to a marker on the patient’s T cells and the other to a particular marker on malignant B cells in a certain type of acute lymphoblastic leukemia. This results in a T-cell attack on cancer cells carrying that specific marker (Amgen 2017; Gold Standard 2017e).

Table 2: FDA-approved Monoclonal Antibodies that Engage the Immune System

Category	Name (Trade name)	Target	Cancer types
Antibody dependent cellular cytotoxicity (ADCC)	Rituximab (Rituxan)	CD20	Non-Hodgkin lymphoma, chronic lymphocytic leukemia
	Alemtuzumab (Campath)	CD52	Chronic lymphocytic leukemia, cutaneous T-cell lymphoma
	Daratumumab (Darzalex)	CD38	Multiple myeloma
	Elotuzumab (Empliciti)	SLAMF7	Multiple myeloma
	Trastuzumab (Herceptin)	HER2	Breast cancer
	Cetuximab (Erbitux)	EGFR*	Colorectal cancer, head and neck cancer
	Ofatumumab (Arzerra)	CD20	Chronic lymphocytic leukemia
BiTE	Blinatumomab (Blincyto)	CD19	Acute lymphoblastic leukemia
Checkpoint inhibitor	Ipilimumab (Yervoy)	CTLA-4	Melanoma
	Nivolumab (Opdivo)	PD-1	Melanoma, lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck cancer, Hodgkin lymphoma
	Pembrolizumab (Keytruda)	PD-1	Melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, urothelial carcinoma
	Atezolizumab (Tecentriq)	PD-L1	Urothelial carcinoma, non-small cell lung cancer
	Avelumab (Bavencio)	PD-L1	Urothelial carcinoma Merkel cell carcinoma

(Wu 2015; Li 2017; ACTIP 2013; Gold Standard 2017f; Gold Standard 2017g; Gold Standard 2017a; Gold Standard 2017h; Gold Standard 2017i; Gold Standard 2017c; Gold Standard 2017d)

*Cetuximab also blocks EGRF signaling

Immune Checkpoint Inhibitor Therapy

Normally, checkpoint proteins on the surface of T cells help them balance between attacking dangerous cells and protecting healthy cells. This system is often referred to as the “brakes” of the immune system. Manipulating this checkpoint system is one way cancer cells evade the immune system (NCI 2017a; Pardoll 2012).

Early in tumor development, these brakes on the immune system are “turned off,” and T cells are able to recognize and destroy many of the cancer cells. However, tumors can mask themselves with proteins that activate T cells’ checkpoint proteins, which turns down the immune response to the cancer cells (DFCI 2017).

Fortunately, new drugs have been developed that help stop cancer cells from activating the immune system’s checkpoints. These drugs are a form of active immunotherapy. The first checkpoint inhibitor antibody, ipilimumab (Yervoy), was approved by the Food and Drug Administration (FDA) in 2011. This drug targets a checkpoint protein called CTLA-4 (Letendre 2017). When CTLA-4 is blocked by the antibody, T cell activation can proceed (Menon 2016).

Ipilimumab has already been shown to successfully extend lifespan in patients with metastatic melanoma (Hodi 2010). Hundreds of studies of ipilimumab are planned as of mid-2017 (NIH 2017). In early trials, another CTLA-4 blocking antibody, tremelimumab, showed promise in patients with advanced melanoma (Ribas 2013). Tremelimumab received the FDA’s Orphan Drug Designation for treatment of malignant mesothelioma in 2015 (AstraZeneca 2015).

Former President Jimmy Carter was treated with a checkpoint inhibitor called pembrolizumab (Mulcahy 2015). This drug blocks a checkpoint protein called PD-1 that is found on the surface of T cells. Blocking PD-1 prevents T cells from being “turned off” (Gold Standard 2017i). In a clinical trial, pembrolizumab improved survival compared with ipilimumab in advanced melanoma patients, with a lower rate of severe toxicity (Robert 2015). Nivolumab (Opdivo) is another FDA-approved drug that blocks PD-1, allowing the immune system to attack certain cancers (Gold Standard 2017h). Pembrolizumab and nivolumab are FDA approved for several types of cancer (Table 2) and are being tested for treatment of many other types.

Other drugs also target the PD-1 pathway. One of these, atezolizumab (Tecentriq), has been approved by the FDA for patients with certain advanced lung and bladder cancers that no longer respond to standard chemotherapy (Gold Standard 2017c). Another drug, avelumab (Bavencio), has been approved for advanced cases of urinary tract cancers that no longer respond to conventional chemotherapy (Andtbacka, Agarwala 2016; Gold Standard 2017d).

Although checkpoint inhibitors have helped many cancer patients, they are not appropriate for everyone and can cause side effects including rashes, diarrhea and colitis, liver toxicity, and hypothyroidism and other endocrine abnormalities (Villadolid 2015). PD-L1 expression testing is a strategy used to determine which patients will be most likely to benefit from PD-1-targeted therapy. This test involves determining if a patient’s cancer cells express a marker called PD-L1. This marker binds and activates the PD-1 immune checkpoint, thus suppressing the immune response. If a patient’s cancer cells express a lot of PD-L1, that means the PD-1 immune checkpoint system is likely playing an important role in helping the cancer evade destruction by the immune system. Higher PD-L1 expression usually suggests a better expected response to PD-1 targeted therapy (Dang 2016). Other tests to determine the likelihood of success of immune checkpoint-targeted therapy are in development and will likely help guide targeted therapy in the future.

Cytokine Therapy

Cytokines are biochemicals that immune cells use to communicate with each other (Lee 2011). In some conditions such as asthma and rheumatoid arthritis, excessive cytokine concentrations cause inflammation, but in tumors, some cytokines can recruit and activate immune cells that can destroy cancer cells (Lee 2011; Turner 2014). Two classes of cytokines are used to treat cancer: interferons and interleukins. They play roles in the activation and proliferation of white blood cells, enhancing the immune response against cancer (NCI 2013).

One particular type of interferon is called interferon alpha. This cytokine increases the ability of T cells and dendritic cells to destroy some types of cancer cells. Three forms of interferon alpha are commercially available; they are used to treat melanoma and other cancers (Rafique 2015; Floros 2015).

The other group of cytokines used in cancer treatment is interleukins. Specifically, aldesleukin (Proleukin) is a form of interleukin-2 (IL-2) that is approved for the treatment of metastatic melanoma and a form of metastatic kidney cancer (Jiang 2016). IL-2 activates T cells and NK cells (Lee 2011; Jiang 2016). T cells and NK cells can destroy cancer cells and also release more cytokines to recruit other immune cells to the tumor (Abbas 2009; Wu 2003).

Cytokines modulate the immune response, and therefore they are excellent candidates for combination with other cancer treatments, including immunotherapies such as tumor vaccines and checkpoint inhibitors (Lee 2011; Ott 2017).

Ongoing Research on Immunotherapy

The field of cancer immunotherapy continues to expand. Some research is focused on finding new targets. New therapies are being tested to target immune cells in the tumor that aid tumor growth, such as tumor-associated macrophages (Williams 2016).

Researchers are also trying to find ways to improve antibodies currently in use. For instance, antibodies can be altered in the lab to make them more effective at inducing antibody-dependent cellular cytotoxicity or last longer in the body (Gabellier 2016; Saxena 2016).

Immunotherapy drugs are candidates for combination therapy. Passive immunotherapy approaches boost immune function, while active immunotherapies aim to eliminate the tumor’s defenses (Papaioannou 2016). Combination therapies combine these two approaches and represent one promising area of immunotherapy research. Combination therapies may also include conventional cancer therapies like chemotherapy, radiation, and targeted therapies. For instance, various combinations of cytokines and checkpoint inhibitors are being tested. Other researchers are testing the effect of combining more than one checkpoint inhibitor drug (Ott 2017). In melanoma patients, those treated with the PD-1 inhibitor nivolumab in combination with ipilimumab responded better than those treated with ipilimumab alone (Postow 2015). Checkpoint inhibitors that target the PD-1 pathway are usually considered the best candidates for the foundation of most combination therapies (Ott 2017).

So far, the immunotherapeutic approaches discussed have all been drugs. But new treatments are being developed with an approach called adoptive cell transfer. In this process, the patient’s own T cells are removed from his or her body, grown in large numbers in a laboratory, and then returned to the patient by infusion. This laboratory process can allow for selection of T cells especially capable of recognizing and attacking tumor cells. Another strategy used in adoptive cell transfer is genetic engineering to create T cells that express specific anti-tumor receptors on their surface. These new receptors allow the T cells to recognize and destroy cancer cells (Perica 2015; Rosenberg 2015).

Various adoptive cell transfer treatments are being tested in early clinical trials, with promising results (Brown 2016; Garfall 2015; Maude 2014; Locke 2017). Early trials of a chimeric antigen receptor T-cell therapy called KTE-C19 have shown promising results in diffuse large B-cell lymphoma, with an interim analysis in one trial reporting complete remission in one-third of patients after three months (AACR 2017; Locke 2017). Chimeric antigen receptor (CAR) therapy is one of the most exciting areas of adoptive cell transfer research. In CAR therapy, T cells from cancer patients are modified to develop specificity for a marker on the patient’s cancer cells. The cells are then cultured in the lab so their numbers expand before being reintroduced into the patient. One reason that CAR therapy is so promising is that the T cells can be engineered to target a wide range of markers. This flexibility makes it easier to target each cancer’s specific properties. CAR has shown success in blood cancers and appears promising in solid tumors as well. Many trials are underway, and the hope is that CAR techniques will be refined and become available to many cancer patients (NCI 2017b; Barrett 2014; Luskin 2017; Maude 2016).

4 Cancer Vaccines

When pathogens enter the body, the immune system retains a memory of the invader so a rapid immune response can be mounted in the event of a future exposure (Chaplin 2010). Vaccines take advantage of the immune system’s ability to remember antigens. Upon vaccination, the body is exposed to a specific antigen from a pathogen or, in the case of a cancer vaccine, a cancer cell. The immune system then “remembers” this antigen and can respond to it in the future (Chaplin 2010; Sayour 2017). Vaccines can be given to healthy individuals to prevent certain types of cancer (NCI 2015), and some are given to cancer patients to treat the disease (Table 3).

Vaccines designed to prevent cancer actually prevent infection with viruses that can cause cancer later in life. Infection with human papillomavirus, or HPV, can lead to cervical, vulvar, vaginal, or anal cancers (NCI 2015). Vaccines such as Gardasil and Cervarix protect against infection with HPV (Garland 2007; Harper 2004). Other vaccines can protect against hepatitis B infection, which can lead to liver cancer (Andre 1987).

Therapeutic cancer vaccines, a form of active immunotherapy, treat cancers that have already been diagnosed. The vaccine introduces a tumor-specific antigen into the body, causing an immune response (Sayour 2017). The patient’s T cells become activated and antibodies are produced. The patient’s immune system can then effectively recognize and destroy the cancer cells.

Therapeutic cancer vaccines are a promising form of immunotherapy. Two such vaccines have already been approved by the FDA (NCI 2015), and numerous others are being developed (Thomas, Prendergast 2016; Mohammed 2016). Although the vaccines being developed are promising, there is much work to be done to improve their ability to induce an immune response in patients with cancer, who are often immunocompromised or experiencing immune senescence (Thomas, Prendergast 2016).

Cell-Based Vaccines

An autologous cancer vaccine uses cells taken from the patient’s own tumor. The cells are modified before being reintroduced into the patient, so that they cannot reproduce to form more cancer, and to make them easier for the immune system to detect and attack. This modification is often accomplished by radiation (Srivatsan 2014; Mohammed 2016).

Since different tumors have different tumor antigens, one advantage of using the patient’s own cells is that antigens presented to the immune system will be present on their tumor. However, even within one tumor, different cancer cells can have a vastly different selection of tumor antigens, and a cell-based vaccine might not be effective against all cancer cells (Srivatsan 2014). Furthermore, tumor material for vaccine production is not available for all patients (Guo 2013).

Some cell-based vaccines treat patients with cancer cells derived from other people’s tumors. These are called allogeneic cancer vaccines. Allogeneic vaccines can be produced in a more standardized and cost-effective process than autologous vaccines. However, tumor antigens in an allogeneic vaccine might not match the patient’s cancer cells (Guo 2013; Srivatsan 2014).

Another approach to cancer vaccination is to remove some of the patient’s immune cells, prime them with a cancer antigen, then re-introduce the cells into the patient. The first FDA-approved therapeutic cancer vaccine, sipuleucel-T (Provenge), uses one’s own dendritic cells (Table 3) to deliver antigens back to the patient (NCI 2015).

Sipuleucel-T is created by extracting immune cells from a blood sample (Hammerstrom 2011). The cells are then exposed to a compound that stimulates immune cell function—a process that allows them to respond to a marker on many prostate cancer cells. The modified immune cells are then infused back into the patient (Kantoff 2010). Sipuleucel-T was approved in 2010 for treatment of patients with metastatic prostate cancer (NCI 2015).

Adverse effects of sipuleucel-T infusion are common but generally mild to moderate. In one randomized controlled trial, less than 1% of subjects were unable to complete treatment due to adverse effects (Kantoff 2010; Anassi 2011). Although the survival benefit of sipuleucel-T for prostate cancer patients is modest (about 4 months), scientists believe there are several ways dendritic cell vaccines can be improved (Sabado 2017; Koido 2016; Vandenberk 2015). Some studies have fused dendritic cells directly to cancer cells to enhance the immune response (Koido 2016). Other researchers are testing whether ultraviolet light, heat, or high pressure can improve dendritic cell vaccines (Vandenberk 2015).

Antigen Vaccines

Antigen vaccines use tumor-specific antigens, in the form of proteins or peptides (fragments of proteins), to induce an immune response against cancer cells (Mohammed 2016).

One peptide-based vaccine (called the WT1 peptide vaccine) has been granted orphan drug status for acute myeloid leukemia and mesothelioma. Randomized controlled trials are planned to study this vaccine for those conditions (AIL 2017). Nelipepimut-S (NeuVax) is a peptide-based vaccine that uses part of the HER2 protein to treat women with breast cancer (Mittendorf 2014). Although the vaccine alone did not work effectively, it is being tested in combination with trastuzumab for high-risk breast cancer patients (Peoples 2017).

Nucleic Acid Vaccines

Instead of delivering whole cells or peptides to the patient, nucleic acid vaccines use ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) molecules that contain the code for the tumor-specific antigen. RNA or DNA is taken up by the patient’s cells, which then manufacture the antigen and present it to immune cells. The RNA or DNA can be directly injected into the patient, or loaded into the patient’s dendritic cells before returning them to the patient. DNA may also be packaged into a benign virus for delivery (Fiedler 2016; Mohammed 2016). RNA-based vaccines are believed to be safer than DNA-based vaccines because RNA cannot cause mutations by integrating permanently into the patient’s genome (Diken 2017). In 2016, a mouse study showed that an RNA-based vaccine activated T cells and led to tumor elimination. An RNA vaccine was found to be safe in three melanoma patients, but the anti-tumor effect has not been evaluated (Kranz 2016).

Oncolytic viruses are another approach, but the mechanism is quite different from other DNA- or RNA-based vaccines. Cancer cells are susceptible to infection with viruses. Oncolytic viruses can be engineered to maximize their ability to target and kill cancer cells without harming healthy cells. They are an excellent candidate for combination with other anti-cancer therapies (Fukuhara 2016; Lawler 2016). Beyond this deadly attack on the tumor itself, cancer cells killed by oncolytic viruses release antigens that stimulate cytokine release and anti-tumor immunity (Bartlett 2013).

The most successful oncolytic virus, talimogene laherparepvec (T-VEC or Imlygic), was approved by the FDA in 2015 for treatment of melanoma (FDA 2015). This preparation is injected directly into the tumor (Andtbacka, Agarwala 2016; Lawler 2016; Andtbacka, Ross 2016). Even melanoma lesions not directly treated with T-VEC responded, lending support to the idea that this vaccine promotes a systemic anti-tumor immune response (Andtbacka, Ross 2016). With the success of T-VEC, dozens of other clinical trials are being conducted to test oncolytic viruses (Lawler 2016). For example, in a recent preliminary trial of pelareorep (Reolysin), patients with metastatic breast cancer lived seven months longer when treated with the oncolytic virus plus the chemotherapy agent paclitaxel versus paclitaxel alone (Bernstein 2017).

Vaccine Adjuvants

Vaccines are often given to patients along with adjuvants. Adjuvants are substances that increase the immune response to the vaccine. Many vaccines rely heavily on the stimulatory effect of adjuvants (Banday 2015).

Some adjuvants are derived from bacteria. Bacillus Calmette-Guérin (TheraCys or TICE BCG), for example, is a weakened form of a bacterium that does not cause disease. The HPV vaccine Cervarix contains the adjuvant monophosphoryl lipid A (Cluff 2010), which is found in some bacterial cell walls (Dubensky 2010). Aluminum-based adjuvants are also commonly incorporated into vaccines (Petrovsky 2004). The Gardasil vaccine contains a proprietary aluminum adjuvant (Garnock-Jones 2011). Cytokines are also used as adjuvants (Petrovsky 2004). Sipuleucel-T and nelipepimut-S both use granulocyte-macrophage colony stimulating factor as an adjuvant (Mittendorf 2016; Hammerstrom 2011).

Because effective adjuvants are essential for generating an immune response in cancer patients, researchers continue to search for new, safe, and potent adjuvants (Banday 2015). CpG-oligodeoxynucleotides (CpG ODNs) are short pieces of synthetic DNA that are recognized by human immune cells. These agents have been tested in several clinical trials with some encouraging effects on the immune system, but scientists are still working on ways to make them suitable for use in patients (Temizoz 2016).

Cimetidine (Tagamet), a medication used to treat gastroesophageal reflux, reduces stomach acid production by blocking histamine H2 receptors. Because histamine plays a role in cancer growth, histamine blockers are potentially therapeutic in some cancer cases. Histamine increases the number of certain types of immune cells that normally suppress immune function. So, blocking histamine with cimetidine may allow the immune system to respond more robustly (Pantziarka 2014).

In 1979, two cases were reported in which patients with metastatic cancer were treated with cimetidine—with surprising success (Armitage 1979). Since then, compelling evidence has emerged suggesting cimetidine can improve outcomes in some cancer patients. In a study of colorectal cancer patients, those treated with cimetidine experienced much less surgery-induced immune suppression (Adams 1994). Furthermore, 93% of cimetidine-treated patients were alive three years after surgery, but only 59% of the controls survived (Pantziarka 2014).

Immune function drops dangerously in many patients after surgery. Taking cimetidine at the time of surgery could benefit many patients, and a group of researchers recently called for new studies of these overlooked effects of taking cimetidine at the time of cancer surgery (Deva 2012; Pantziarka 2014).

Cimetidine’s effects on the immune system make it an excellent candidate for combination with immunotherapies, including vaccines. Cimetidine improved immune response to vaccines in mice (Wang 2008; Xie 2014; Niu, Yang 2013). When cimetidine was used in combination with a DNA vaccine, antibody production improved, tumor-fighting cytokines were produced, and cytotoxic activity increased (Wang 2008). Future studies in humans are required to see whether cimetidine’s effects on the immune system can enhance immunotherapies.

Aspirin and Cancer Immunotherapy

Aspirin is a non-steroidal anti-inflammatory drug that inhibits cyclooxygenase (COX) enzymes (Gold Standard 2017b). Regular low-dose aspirin use lowers the risk of colorectal cancer and has a favorable safety profile (Dulai 2016; Emilsson 2017).

Prostaglandin E2 (PGE2), which is produced by COX enzymes, promotes tumor growth by helping the tumor hide from the immune system (Zelenay 2016). Because aspirin reduces PGE2, aspirin treatment can theoretically give the immune system a better chance to fight the tumor, especially when other immunotherapies are used at the same time. Indeed, growing evidence supports this hypothesis (Wang, DuBois 2016).

One study found that aspirin enhanced the effects of a checkpoint inhibitor in mice. These mice, which had tumors formed by melanoma cells, were treated with an antibody to PD-1 (similar to pembrolizumab). Aspirin alone did not affect tumor size or growth. But when aspirin was used along with the checkpoint inhibitor, it dramatically improved the effect of the checkpoint inhibitor. Tumors in about one-third of the mice shrank rapidly and completely (Zelenay 2015).

These intriguing results were corroborated in another study in which a COX-2 inhibitor was combined with a checkpoint inhibitor to treat mice with melanoma or metastatic breast tumors. The two drugs worked effectively together to reduce suppressive immune cells and increase tumor-killing immune cells (Li 2016).

The safety of aspirin is already well-established and the drug is widely used. With these recent compelling results, aspirin has become an intriguing candidate for combination with immunotherapies such as checkpoint inhibitors (Buque 2016). Nevertheless, long-term, prospective, controlled trials are needed to establish the role of aspirin in the context of cancer immunotherapy. Also, even though aspirin is generally considered to have a favorable safety profile, bleeding risks should not be overlooked.

Ongoing Research on Cancer Vaccines

The vaccine approaches being developed are strikingly diverse, with DNA, protein, and cell-based approaches under investigation. Over time, one of these approaches may prove superior, but additional methods are also emerging.

Some researchers are using laser treatment of the tumor to expose tumor antigens to the immune system, a treatment referred to as laser immunotherapy (Zhou 2015). This approach was tested in advanced breast cancer patients. Both primary tumors and metastases shrank in some of the treated women (Li 2011).

Cancer vaccines can be optimized by finding the right antigen, adjuvant, and delivery method. However, the most dramatic effects on patient survival could come from finding the right combination of cancer vaccines with other therapies. Radiation primarily fights cancer by directly killing cancer cells, but scientists have recently found that radiation alters cancer cells and causes them to trigger a more robust immune response (Garnett-Benson 2015). Sipuleucel-T is one vaccine currently being tested in combination with radiation therapy (Finkelstein 2015). Another example is the combination of the oncolytic virus T-VEC and the checkpoint inhibitors ipilimumab and pembrolizumab. Preliminary data on this combination is promising (Puzanov 2016; Dummer 2017).

Table 3: FDA-approved Cancer Vaccines

Category	Name	Target	Cancer
Prevention	Gardisil and Gardasil 9	Human papilloma virus	Cervical, vaginal, vulvar, oropharyngeal, anal, and penile cancers
	Cervavix	Human papilloma virus	Cervical, vaginal, vulvar, oropharyngeal, anal, and penile cancers
	Recombivax HB	Hepatitis B virus	Liver cancer
	Engerix-B	Hepatitis B virus	Liver cancer
	Twinrix	Hepatitis B virus and hepatitis A virus	Liver cancer
	Pediarix	Hepatitis B virus, four other antigens	Liver cancer
Treatment	Sipuleucel-T (Provenge)	Dendritic cell vaccine to prostatic acid phosphatase	Prostate cancer
Treatment	Talimogene laherparepvec (T-VEC or Imlygic)	Oncolytic virus	Melanoma

(NCI 2015)

5 Factors Affecting Immune System Status

Age, lifestyle, nutrition, and health status can all affect the ability of the immune system to respond to cancer cells, even with immunotherapy. Also, the tumor itself can suppress the patient’s immune system (Schreiber 2011). Moreover, some cancer treatments can suppress the immune system as well (ACS 2015). During surgery, some cancer cells can be released, and the surgical procedure and anesthesia can suppress the responsiveness of NK cells and T cells that would otherwise track down those cancer cells (Tai 2014; Welden 2009).

Age

As people age, the immune system begins to deteriorate due to immune senescence. Some hallmarks of immune senescence are lower numbers of naïve cytotoxic T cells and weaker NK cells (Mekker 2012; Tarazona 2017).

Immune senescence has two major consequences. First, an older person’s immune system cannot protect them as well from infections and cancer. Second, the immune system may not respond as robustly to immunotherapies such as vaccines (Pera 2015). More information about general age-related immune decline is available in the Immune Senescence protocol.

Diet and Lifestyle

Maintaining a healthy weight is an important goal for lowering cancer risk (ACS 2016a). Obesity can suppress the immune system. Obese individuals do not respond to flu vaccines as well as average-weight people, and are more susceptible to infections (Sheridan 2012; Andersen 2016). Similarly, toxins in cigarette smoke and hormones released during times of stress can also weaken the immune system (Zhou 2016; Segerstrom 2004).

Eating a balanced diet, including ample fruits and vegetables, is also important in reducing cancer risk and possibly improving outcomes for cancer patients. Dietary phytochemicals can help prevent cancer, partially through effects on the immune system (Kotecha 2016). In one clinical trial, when people were given broccoli sprouts at the time of vaccination, the NK cells in their blood became more activated, ready to respond to the challenge (Muller 2016). Another study confirmed that viruses were more effectively destroyed by the immune system in people who had eaten a broccoli sprout preparation (Noah 2014).

Broccoli is just one component of a healthy diet. A growing body of evidence suggests a diet rich in vegetables, fruits, nuts, and other phytonutrients can not only fight cancer directly but also enhance the immune system’s ability to protect the body (Shahzad 2017; Song, Garrett 2015).

Exercise can have an immediate positive effect on T cells, and is being embraced as an immune senescence preventive (Cao Dinh 2017). For instance, in one study, elderly men who exercised responded better to the flu vaccine (de Araujo 2015).

The Microbiome in Cancer and Immunotherapy

The human gut microbiota comprises a large and diverse group of microorganisms. Collectively, these organisms, along with their genetic material, are referred to as the microbiome. The gut microbiome helps the digestion and metabolism of food and plays an important role in the immune response. Various factors, such as diet, stress, and medications, influence the microbiome, resulting in variable compositions between people.

Probiotics are microorganisms that may modulate the gut microbiome and, in that way, may improve health when consumed in sufficient amounts (Lesbros-Pantoflickova 2007). They can keep “bad” bacteria in check and help balance the immune system between efficient pathogen destruction and damaging inflammation (Yan 2011). Supplemental probiotics are used to treat digestive problems, including chemotherapy-induced diarrhea (Wang, Yao 2016), and can prevent infection-related complications after surgery (Sugawara 2006; Veziant 2022).

Gut Microbiome in Cancer

Various studies have shown the gut microbiome can affect anti-cancer treatments. Multiple studies examining the gut microbiome in patients with colorectal cancer have found increased bacterial diversity, compared to those without the disease. In a small study in colorectal cancer patients, eight patients received 14 billion CFUs Bifidobacterium lactis BI-04 and 7 billion CFUs Lactobacillus acidophilus NCFM daily before surgery (on average, patients took the probiotics for a month). This probiotic treatment resulted in an increase in butyrate-producing bacteria, especially Faecalibacterium and Clostridiales spp, both in the tumor microbiota and gut microbiome. Importantly, some of the types of bacteria associated with colorectal cancer microbiomes were reduced in the feces of these patients, suggesting probiotics can beneficially change the microbiome in patients with colorectal cancer (Hibberd 2017).

In prostate cancer, the intestinal microbiota has been found to influence the efficacy of androgen deprivation therapy (ADT), while specific bacteria of the intratumor microbiome were found in one study to exert beneficial or negative effects on tumor staging, grading, and characteristics (Ma 2020). In mice with prostate cancer that received a fecal microbiota transplant from prostate cancer patients, ADT therapy was ineffective, while it was effective when samples from healthy people were used (Terrisse 2022). There are significant changes in the gut microbiome of patients with ADT-resistant tumors, with increased levels of Phascolarctobacterium and Ruminococcus species (Liu 2020).

The microbiota of patients with metastatic renal cell carcinoma (mRCC) has been shown to have a lower amount of Bifidobacterium species. In one trial, mRCC patients being treated with VEGF tyrosine kinase inhibitors (TKIs) were assigned to a treatment group taking a yogurt enriched with the probiotic bacteria B. animalis or a control group that was restricted from eating yogurt or taking a probiotic. In those patients who benefited from treatment, there were significantly more Barnesiella intestinihominis and Akkermansia muciniphila strains in stool samples, and probiotic supplementation successfully increased levels of bifidobacteria (Dizman 2021).

Immunotherapy for Cancer and Gut Microbiome

The gut microbiome has also been associated with the response to immune checkpoint blockade (ICB) treatment. Specific gut microbiome compositions might predict who does and does not respond to this type of treatment. The presence of the bacterium A. muciniphila and Bacteroides species in the gut microbiome has been associated with efficacy of ICB (Routy 2018; Vetizou 2015).

ICB has been shown to have reduced efficacy in patients who receive proton pump inhibitors (PPI) or antibiotics. PPI treatment allows “bad” oral bacteria to move to the gut, limiting the efficacy of ICB (Tomita 2022). In one study in patients with non-small cell lung cancer, those who received antibiotics before ICB treatment had a lower bacterial diversity in the gut, in particular reduced levels of Ruminococcaceae UCG 13 and Agathobacter strains, which were higher in patients who had good treatment outcomes and prognosis (Hakozaki 2020). Another study that included patients with non-small cell lung cancer, melanoma, and other solid tumors also showed that ICB therapy was less effective in patients who received antibiotics before treatment. However, the use of antibiotics during ICB treatment did not affect the prognosis (Pinato 2019).

Targeting the Gut Microbiome to Improve Immunotherapy Efficacy

Probiotics. In patients with non-small cell lung cancer, treatment with the probiotic bacterial strain Clostridium butyricum MIYAIRI 588 (CBM588) within six months of starting ICB or during ICB improved progression-free and overall survival (Tomita 2020). A subsequent analysis of this study population found that this same probiotic treatment reduced the amount of harmful oral bacteria found in the guts of cancer patients who had taken PPIs (Tomita 2022). CBM588 was also tested together with the ICB combination drug nivolumab–ipilimumab in a small study in patients with metastatic renal cell carcinoma. This delayed disease progression markedly more than ICB therapy alone, and those who benefited from treatment had more B. longum and Butyricimonas faecalis strains and less Desulfovibrio spp. bacteria in their gut (Dizman 2022).

Studies are ongoing to determine which probiotic strains will be most beneficial for patients undergoing immunotherapy. A study that assessed healthy donor microbiota bacterial strains that were capable of inducing T-cell responses that may be beneficial in cancer treatment identified 11 such strains. In mouse models, these strains increased the efficacy of ICB. These 11 bacteria are of interest for further study to elaborate their immunomodulatory effects (Tanoue 2019):

Parabacteroides distasonis 82G9,
Parabacteroides gordonii 81H9,
Alistipes senegalensis 81E7,
Parabacteroides johnsonii 82F11,
Paraprevotella xylaniphila 82A6,
Bacteroides dorei 81B11,
Bacteroides uniformis JCM 5828 82G1,
Eubacterium limosum 81C1,
Ruminococcaceae bacterium cv2 82B1,
Phascolarctobacterium faecium 82G5, and
Fusobacterium ulcerans 81A6

Note that, as of early 2023, the research on probiotics in the context of immunotherapy is in its infancy. More research is needed to determine whether probiotics can reliably complement immunotherapy, and to identify the most promising strains.

Fecal microbial transplant. Another way to improve the gut microbiome is by using fecal microbial transplants (FMT), where a healthy person's gut microbiota is transplanted into a patient. Current studies are assessing whether FMT from healthy people or patients who responded to cancer immunotherapy could aid patients in whom the therapy was not effective (Chen 2019). Two small early-stage (phase I) studies assessed this in patients with metastatic melanoma who previously did not respond to ICB. The first study included 10 patients, three of whom showed a clinical response and were progression-free at six months after FMT treatment. The treatment was also associated with favorable changes in immune cell-tumor interaction, and with gene expression in the tumor microenvironment (Baruch 2021). In the second study, fecal microbiota was taken from patients who had responded to ICB therapy and transplanted into patients who had not responded. This FMT was well tolerated and showed clinical benefit in six of the 15 patients evaluated, and successfully altered their gut microbiota (Davar 2021). More research is needed to clarify the potential role of FMT in the context of cancer immunotherapy.

6 Nutrients

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. In addition, vitamin D may be helpful for reducing immune checkpoint inhibitor-induced adverse effects like colitis. In a retrospective analysis of 213 melanoma patients who were treated with immune checkpoint inhibiting drugs, it was discovered that those who took vitamin D before starting treatment had a 65% lower chance of developing colitis than those who did not take vitamin D. These results were confirmed with an additional cohort of 169 patients; vitamin D use in this group was associated with a 54% reduced risk of developing colitis.1 In this study, vitamin D use was categorized as either <1,000 IU per day, >1,000 IU per day, or no use. Therefore, this study was unable to identify the specific dosage used or determine whether higher-dose vitamin D was associated with better outcomes. The study also did not assess blood levels of 25-hydroxyvitamin D (Grover 2020).

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).

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).

7 Tracking Your Progress

While patients are being treated with immunotherapy, doctors can monitor their progress with blood tests or imaging. A range of tests have been developed or are being explored to inform patients and their doctors about whether their cancer is responding to the treatment. Early and frequent testing can make sure each patient is treated with the right therapy at the right dose.

Imaging may include computed tomography (CT) scans, x-rays, positron emission tomography (PET) scans, and magnetic resonance imaging (MRI). With these tests, doctors hope to visualize the effect of the treatment on the size of the tumor. Patients enrolled in immunotherapy clinical trials might undergo imaging tests designed to provide information on more than just the size and shape of the tumor (Juergens 2016). For instance, a variation of PET can be used to monitor immune status, and an iron oxide nanoparticle probe can be used with MRI to monitor macrophages in tumors (Iv 2015; Radu 2008).

In addition to imaging, blood-based assays can provide information on response to immunotherapy. Several blood-based biomarkers are used to indicate the current tumor burden. As tumors grow, whole cells or cellular components like DNA or proteins are released into the bloodstream. The tumor-derived material can be detected by laboratory tests. Biomarker technology is advancing just as fast as immunotherapy, and new biomarkers in development use multi-color laser imaging, protein microarrays, and high-throughput DNA sequencing to give extensive information to doctors and patients on how a drug is affecting the body (Yuan 2016).

Some common blood-based biomarkers include:

PSA

Prostate-specific antigen (PSA) is a reliable protein marker in blood for monitoring the response of prostate tumors to treatments (Kiper 2005; Fong 2009). Successful treatment will reduce PSA, and the levels may become undetectable. A rise in PSA can indicate that the therapy is not working (Wilkinson 2008; NCBI 2017).

CEA

Carcinoembryonic antigen (CEA) is a tumor marker in blood that can be used to monitor some patients, most commonly those with colorectal cancer (Das 2017). As with PSA, successful treatment will reduce CEA levels (Lech 2016; Patel 2010).

CA-125

Levels of another protein, called cancer antigen-125 (CA-125), are often monitored in blood after treatment of patients with ovarian cancer (Kobayashi 2012). If CA-125 levels drop, the treatment is effectively fighting the cancer (Gupta 2009).

CA 15-3

Response to breast cancer therapy can be monitored in blood with a tumor marker called cancer antigen 15-3 (CA 15-3) (Henry 2014).

Circulating Tumor Cells

Whole cancer cells also circulate in the blood of cancer patients and can be used to monitor response to treatment. Circulating cancer cells are rare, often fewer than 10 per milliliter of blood, but scientists have developed extremely sensitive isolation and analysis methods (Miller 2010). Circulating cancer cell analysis is not standard clinical practice but is increasingly used in laboratory and clinical studies, including studies of immunotherapies. For example, in a phase III trial of a whole-cell vaccine for melanoma patients, those without circulating cancer cells were significantly more likely to survive at least three years (Hoshimoto 2012). More information about circulating tumor cell testing is available in the Cancer Treatment: The Critical Factors protocol.

T cell counts

For patients being treated with immunotherapy, a detailed analysis of the immune cells is helpful. The total number of T cells is important, but cytotoxic T cells, which are critical to many immunotherapies, should also be monitored (Nonomura 2016; Klinger 2012).

Circulating Tumor DNA

In addition to proteins and whole cells, small amounts of tumor DNA can also be found in blood. If the tumor-specific DNA modifications are known, the amount of circulating tumor DNA can be used to monitor response to treatment (Xi 2016; Gremel 2016). One study suggests breast cancer recurrence can be detected earlier with circulating tumor DNA than with other clinical techniques (Olsson 2015). Circulating DNA biomarkers are not standard clinical practice, but are part of some ongoing clinical trials (Krishnamurthy 2017).

NK cell counts

A number of the supplements described in the Integrative Interventions section may boost the number of NK cells in blood. NK cells can destroy cancer cells directly and also facilitate the effects of many immunotherapies. For some patients, monitoring NK cell numbers can be informative (Sun 2011). Studies of antibody-dependent cellular cytotoxicity antibodies often quantify the number of NK cells in the blood and determine whether they are activated (Chow 2016).

2023

Feb: Added “The Microbiome in Cancer and Immunotherapy” as a sidebar under “Factors Affecting Immune System Status”

2020

Jul: Updated section on vitamin D in Nutrients

2017

Sept: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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Cancer Immunotherapy

Cancer Immunotherapy

1 Introduction

Summary and Quick Facts for Cancer Immunotherapy

2 Background

What Does the Immune System Do?

Cancer Cells and the Immune System

Table 1: Key Cells for Immunotherapy

3 Immunotherapy: Harnessing the Immune System to Treat Cancer

Monoclonal Antibody Therapy

Table 2: FDA-approved Monoclonal Antibodies that Engage the Immune System

Immune Checkpoint Inhibitor Therapy

Cytokine Therapy

Ongoing Research on Immunotherapy

4 Cancer Vaccines

Cell-Based Vaccines

Antigen Vaccines

Nucleic Acid Vaccines

Vaccine Adjuvants

Aspirin and Cancer Immunotherapy

Ongoing Research on Cancer Vaccines

Table 3: FDA-approved Cancer Vaccines

5 Factors Affecting Immune System Status

Age

Diet and Lifestyle

The Microbiome in Cancer and Immunotherapy

Gut Microbiome in Cancer

Immunotherapy for Cancer and Gut Microbiome

Targeting the Gut Microbiome to Improve Immunotherapy Efficacy

6 Nutrients

Vitamin D

Zinc

Enzymatically Modified Rice Bran

Pu-erh Tea & Cistanche

Curcumin

Vitamin E

Selenium

Beta Glucans

Green Tea (Epigallocatechin Gallate)

Vitamin C

Garlic

Sulforaphane

Ginseng

Astragalus

Ginger

7 Tracking Your Progress

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2017

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References

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