Principles and Potential Applications of Therapeutic Cancer Vaccines

Vaccines, preparations used to stimulate the immune response against a specific disease, have been in clinical use for more than two centuries. Currently, the principle of vaccination is being extended beyond the area of infectious diseases, e.g., cancer. Vaccination against viruses associated with increased risk of cancers (Human Papilloma Virus or hepatitis B virus) is successfully used to prevent these diseases.

Furthermore, a new type of vaccine – therapeutic vaccines – help to clear cancer in patients already suffering from it. This article reviews the basics and potential applications of therapeutic cancer vaccines.

Treating cancers with vaccines dates back to the 1910s when William Coley started experiments injecting tumors with killed bacteria. In the 1950s, Lloyd Old conducted similar experiments with the Bacillus Calmette–Guerin (BCG) vaccine first designed for tuberculosis prevention. The latter approach came out successful and eventually led to the approval of the BCG vaccine to treat early-stage bladder cancer.

Despite long-standing research, only two cancer vaccines are currently approved in the US. Besides BCG vaccine, a dendritic cell-based vaccine (Sipuleucel-T) is available to treat a certain type of prostate cancer.

In some countries, CIMAvax-EGF, a vaccine that induces an immune response against epidermal growth factor, a major regulator of cell growth, survival, and differentiation, is approved for the treatment of non-small-cell lung cancer.

Numerous clinical studies are currently testing the efficacy and safety of different cancer vaccines.

How cancer vaccines work

Although the immune system is capable of detecting and fighting cancer, cancer cells tend to evade immune surveillance. Thus, the main purpose of a cancer vaccine is to make cancer “visible” to the immune system and to enhance its response. This is achieved by introducing certain elements of the patient‘s cancer, sometimes concomitantly with immune system stimulatory molecules.

KRAS and claudin-6 as cancer vaccine targets

Cancer vaccines usually target specific elements of the patient‘s cancer. These elements are often located in certain genes commonly mutated in cancer. KRAS and claudin-6 are two examples of genes that have gained scientific interest as targets for cancer vaccines:

• KRAS gene. It’s a proto-oncogene and in a non-mutated state it plays a role in regulating cell proliferation, but mutations in this gene result in cancer development. Mutations in the KRAS gene are present in up to one-third of cancers, including those that are difficult to treat, i.e., pancreatic, colorectal, and lung cancer.
• Claudin-6. It is involved in the adhesion of cells, playing a significant role in cancer initiation and progression. Claudin-6 is inactivated in healthy cells, but in many cancers, it is expressed in high amounts or has an abnormal form. The feasibility of claudin-6 is being explored not only in cancer vaccines but also in other cancer immunotherapies, like CAR-T cells.

Types of cancer vaccines

Based on the different preparation methods, cancer vaccines are divided into four categories:

Cell-based vaccines

Most often employ dendritic cells which are immune cells digesting and presenting the elements of cancer to the T lymphocytes, the main warriors of the immune system. During the vaccine preparation process, dendritic cells are isolated from the patient and loaded with the elements taken from the patient‘s cancer.

Virus-based vaccines

Viruses can also be used as carriers of cancer elements, particularly because the immune system is adept to fight them. To make a virus-based cancer vaccine, the genes of the virus are engineered to include cancer-associated genes or genes that enhance the immune system. Small portions of cancer proteins may also be attached to the virus’ envelope.

Peptide-based vaccines

They are composed of small synthetic peptides (structures similar to proteins), identical to those that are found on cancer cells specifically or those that are much more abundant in cancer than in healthy cells.

Nucleic acids-based vaccines

They may include DNA, a molecule that encodes genetic information, or messenger RNA (mRNA), a molecule that carries the information to protein production sites. DNA cancer vaccines are closed circular DNA structures encoding cancer-associated antigens or immune system-stimulating molecules to induce a tumor-specific response.

Increasing efficacy of cancer vaccines

When given alone, cancer vaccines have limited anticancer effects. Different strategies have been used to overcome this drawback. Vaccines that produce a weak immune response (e.g., peptide-based vaccines) are often supplemented with so-called adjuvants, substances that stimulate the immune system. Also, combining cancer vaccines with standardized cancer therapies or immunotherapies has become an effective strategy for improving clinical outcomes. Interestingly, the addition of the antidiabetic drug metformin to mRNA-based vaccines potentiated their effects.

CAR T-cell therapy has revolutionized the treatment of blood cancers, but its role in other cancers remains uncertain. A recent study tested the safety and preliminary efficacy of a CAR T-cell product that targets claudin-6, together with a claudin-6-encoding mRNA vaccine. This combined treatment, called BNT211, resulted in the expansion of the transferred CAR T-cells and their higher persistence in the blood, which in turn improved tumor cell killing.

Furthermore, in a clinical study conducted at the University of Arizona Cancer Center, of 10 patients with head and neck cancer, five experienced a clinical response to the personalized cancer mRNA vaccine administered together with a checkpoint inhibitor, a type of cancer immunotherapy. Two patients had a complete response after the treatment with no detectable disease. To compare, the response rate in similar patients given checkpoint inhibitors without cancer vaccines, the response rate was approximately 15%.

So cancer vaccines are a valuable addition to the cancer treatment armamentarium. For many years, costly and complex manufacturing processes and limited anti-cancer effects were the major challenges in the wider applicability of cancer vaccines. However, experience gained with mRNA vaccines during the COVID-19 pandemic and the first results of clinical studies employing combinations of cancer vaccines with other cancer therapies allow us to expect rapid progress in this area.