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Health Protocols

Cancer Immunotherapy

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

Talimogene laherparepvec (T-VEC or Imlygic)

Oncolytic virus

Melanoma

(NCI 2015)