Science Series #9: Cancer Vaccines

What are vaccines and how do they work?

Vaccines are a form of immunotherapy that allows the body to recognize pathogens and help the immune system fight against foreign cells. These are capable of preventing diseases by exposing the body’s immune system to a weakened version of the pathogen. This then enables the immune system to recognize antigens, which are surface markers of the foreign body, and create antibodies against such a threat. Most vaccines are given as a preventive measure, prior to the exposure to the virus or bacteria. After taking the vaccine, if the individual is exposed to the pathogen, the body will stimulate an immune response and will be able to fight against this organism easily due to the memory created by the vaccination. However, some types of vaccines can be therapeutic, which are usually administered after the disease and work by activating and amplifying the immune response.

(Source: Cancer Research Institute, Cancer Research UK, Vaccine Therapies for Cancer: Then and Now)

What are Cancer Vaccines?

Cancer vaccines are a form of immunotherapy that can help educate the immune system about what cancer cells “look like” so that it can recognize and eliminate them. Developing vaccines against cancer are difficult since cancer cells often resemble our normal healthy cells. Hence, instead of preventing disease, cancer vaccines target tumor-associated antigens present in the patient, allowing them to develop anti-tumor immunity.

More than a century ago, Dr. William Coley leveraged this observation to develop a rudimentary anti-cancer immune therapy consisting of heat-inactivated bacteria. How a non-specific innate immune response against bacterial products could translate into a specific anti-tumor immune response was explained subsequently by the discovery that antigen-presenting cells (APCs) (dendritic cells [DCs]) could acquire immunogenic tumor-derived peptides released during the innate immune response. These peptides could then be used to activate anti-tumor T cells with cognate receptors. This led to the hypothesis that use of tumor-derived antigens, if delivered to the immune system in a sufficiently immunogenic context (a “vaccine”), would, due to the preferential targeting of cancer cells, enable relatively safe and yet effective treatments for cancer, capable of inducing long-lasting immunity.

These cancer vaccines may halter the growth of cancer cells, prevent the redevelopment of cancer and destroy any remaining cancer cells from previous treatments.

(Source: Cancer Research Institute; Cancer Research UK; Vaccine Therapies for Cancer: Then and Now, 2021)

Types of Cancer Vaccines

Preventive Cancer Vaccines

Some cancers develop after contracting viral infections. Thus, researchers and scientists were able to develop vaccines that prevent the risk of such infections. In 2006, the Human Papilloma Virus (HPV) Vaccine was released. HPV is a large group of related viruses that has several strains and has been linked to cervical, anal, throat, vaginal, vulvar, and penile cancers. The HPV vaccine is given to young children, usually between the ages 9-12, to prevent infection by this virus, which consequently reduces the risk of the development of such cancers. This vaccine is given during preadolescence, as it is most effective during that age; its effectiveness decreases by age 18. There are currently three vaccines approved by the U.S. Food and Drug Administration (FDA) for HPV.

Cervarix: a vaccine that prevents infection by the HPV strains (HPV 16 and HPV 18) that most commonly are linked to cervical cancer.

Gardasil: a vaccine that prevents infection by HPV types 16, 18, 6, and 11.

Gardasil-19: a vaccine approved to prevent infection by HPV types 16, 18, 31, 33, 45, 52, and 58, and for the prevention of genital warts caused by HPV types 6 or 11.

In addition, the Hepatitis B virus (HBV), is linked to the development of liver cancer. Hence, the HBV vaccine, called HEPLISAV-B, was produced to protect against infection by the hepatitis B virus, and consequently lowers the risk of liver cancer.

(Source: Cancer Research Institute; American Cancer Society)

Unlike preventive cancer vaccines, therapeutic cancer vaccines are used on patients who already have cancer. Some cancer cells have their own antigens, and fortunately doctors can now identify those antigens on tumors that are not present on normal cells. Hence, such vaccines enable the immune system to recognize and destroy the cancer cells linked to those antigens. In some cases, the patient’s own tumor cells are extracted and used to create the vaccine, then are re-injected to increase the immune response against cancer cells. Often times, to help boost the immune response towards infectious diseases, substances or cells called adjuvants are added to the vaccine. The therapeutic vaccines can be classified as follows:

Peptide and Protein Based Vaccines: Peptide-based vaccines are relatively easy to manufacture, but combination with potent immune adjuvants is often needed to boost immunogenicity, and the number of people who may benefit from a given peptide vaccine is restricted by human leukocyte antigen (HLA) haplotype. Several phase 3 studies investigating early peptide-based vaccines have not demonstrated clinical benefit despite demonstrating some induction of immune responses against tumor-associated antigens. Explanations for lack of clinical benefit may lie in the properties of the peptides and adjuvants used, and early peptide vaccines may have been inherently inadequate for promoting antigen presentation and generating potent and durable anti-tumor immunity.
Overall, these studies have provided rationale for the development of improved peptides such as synthetic long peptides with optimized immunogenicity, alternative peptide- delivery platforms such as nanoparticles, and more potent vaccine adjuvants.

Cellular Vaccines: Commonly studied types of cell-based cancer vaccines include DCs loaded with tumor (neo)antigens, modified autologous cancer cells, and allogeneic tumor cell lines. In 2010, the FDA approved the Sipuleucel-T vaccine for treating prostate cancer patients. This vaccine is composed of the patient’s own dendritic cells, which are antigen presenting cells that help the immune system recognize and attack the cancer tumors. In the lab, scientists grow such dendritic sites along with cancer sites and hence, once the vaccine is injected, it will induce an immune response to attack the cancer due to the immunological memory created by the vaccine. This treatment is given usually after hormone therapy is no longer effective, or in cases where the cancer has spread to various parts of the body.

Genetic Vaccines: Viruses or plasmids can act as vectors for DNA or RNA encoding tumor-associated antigens. Viruses represent a promising platform for vaccines, as virus DNA or RNA may activate DCs by triggering pattern recognition receptors. PSA-TRICOM is a recombinant viral vaccine also used to treat advanced prostate cancer. In a Phase II clinical trial, results show that the administration of this vaccine led to extending overall survival by approximately eight months and with minimal side effects.

In contrast to the therapeutic cancer vaccines described previously, some vaccines used in the treatment of cancer do not deliver defined tumor antigens to generate anti-tumor immunity, but nevertheless, generate an immune response. The Bacillus Calmette-Guérin (BCG) vaccine is typically used to fight against tuberculosis (TB). This vaccine uses weakened bacteria to stimulate an immune response. It became the first approved immunotherapy in 1990 by the FDA and is often used as treatment of early-stage bladder cancer. BCG is put into the bladder and once it comes in contact with the bladder cancer cells, it triggers the immune response.

Another cancer vaccine that involves strategies to modify or inflame tumor cells by intratumoral administration of oncolytic viruses is Talimogene laherparepvec (T-VEC), which was approved in 2015 by the FDA to treat advanced cases of melanoma skin cancer. This vaccine is made from herpes virus, which has several strains, some of which have been linked to different cancers. The herpes virus type 1 strain is altered in the lab to enable the body to produce cytokines, which are proteins produced by the immune system important for cell signaling, mediate and regulate immunity. T-VEC is injected directly into the tumor and as more cells replicate, it causes cancer cells to burst and die. Such dying cells release new viruses and substances that can generate an immune response against cancer cells.

(Source: Cancer Research Institute; American Cancer Society; Cancer Research UK; Center for Disease Control and Prevention, 2016; Vaccines for Human Diseases, 2020; Clinical Cancer Research, 2020)

Side Effects to Cancer Vaccines

Depending on the type of vaccine administered and its target, side effects may vary. Often times, the vaccine may result in misdirected immune responses, targeting the patient’s healthy cells as well that express the same protein markers. Cancer vaccines may also cause flu-like symptoms such as: fever, chills, weakness, dizziness, nausea, muscle and joint pain, headaches, trouble breathing and high or low blood pressure. More severe side effects to cancer vaccines are allergic reactions. More specifically, the Sipuleucel-T may cause a stroke and the T-VEC vaccine could potentially lead to the development of tumor-lysis syndrome in which the content of the tumor cells are released into the bloodstream once they die. The chemicals released may cause damage to organs in the body such as the kidney, heart and liver. T-VEC could also result in Herpes Virus infection which causes pain, burning and tingling in a blister around the mouth or fingers, eye pain, weakness in the arms and legs, extreme fatigue and mental confusion.

(Source: National Cancer Institute; Cancer Research Institute)

Our Work in Cancer Vaccines

JCWO is currently developing a low cost and potentially safe and effective therapeutic vaccine for breast cancer, named ConvitVax. This therapy is based on past successful experiences of Dr. Jacinto Convit with vaccines for leprosy and cutaneous leishmaniasis. For the treatment of leprosy, he injected BCG with a Mycobacterium leprae suspension, inducing macrophage activation and subsequent destruction of the bacteria. When treating patients with cutaneous leishmaniasis, he applied the same vaccine model using pasteurized leishmania promastigotes with BCG, observing regression of the injury and local disappearance of the parasite. Based on these positive results, and the similarities observed in the immune contributions to the pathology of those diseases and breast cancer, ConvitVax, a personalized therapeutic vaccine for breast cancer was proposed, combining autologous tumor cells with BCG, and low concentrations of formalin.

Preclinical studies and a pilot human experience with ConvitVax have shown that this vaccine effectively reduces tumor growth, evidenced by an extensive tumor elimination, and induces a noticeable infiltration of antitumor-related and plasma cells in the tumor microenvironment with a possible establishment of immune memory. Additionally, this immunotherapy has exhibited a safe profile with minimal side effects. Currently, ConvitVax is approved by the FDA to begin a Phase I clinical trial. Furthermore, combination studies are being studied to potentiate the antitumor effect of the vaccine.

For more information on this work, visit JCWO’s press room and learn more about this development.

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