Tumor antigen vaccine

Tumor antigen vaccines work the same way that viral vaccines work, by training the immune system to attack cells that contain the antigens in the vaccine. The difference is that the antigens for viral vaccines are derived from viruses or cells infected with virus, while the antigens for tumor antigen vaccines are derived from cancer cells. Since tumor antigens are antigens found in cancer cells but not normal cells, vaccinations containing tumor antigens should train the immune system to target cancer cells not healthy cells. Cancer-specific tumor antigens include peptides from proteins that are not typically found in normal cells but are activated in cancer cells or peptides containing cancer-specific mutations. Antigen-presenting cells (APCs) such as dendritic cells take up antigens from the vaccine, process them into epitopes, and present the epitopes to T-cells via Major Histocompatibility Complex proteins. If T-cells recognize the epitope as foreign, the adaptive immune system is activated and target cells that express the antigens.[1]

Cancer vaccines can be cell-based, protein- or peptide-based, or gene-based (DNA/RNA).[2]

Cell-based vaccines include tumor cells or tumor cell lysates. Tumor cells from the patient are predicted to contain the greatest spectrum of relevant antigens, but this approach is expensive and often requires too many tumor cells from the patient to be effective.[3] Using a combination of established cancer cell lines that resemble the patient’s tumor can overcome these barriers, but this approach has yet to be effective. Canvaxin, which incorporates three melanoma cell lines, failed phase III clinical trials.[3] Another cell-based vaccine strategy involves autologous dendritic cells (dendritic cells derived from the patient) to which tumor antigens are added. In this strategy, the antigen-presenting dendritic cells directly stimulate T-cells rather than relying on processing of the antigens by native APCs after the vaccine is delivered. The best known dendritic cell vaccine is Sipuleucel-T (Provenge), which only improved survival by four months. The efficacy of dendritic cell vaccines may be limited due to difficulty in getting the cells to migrate to lymph nodes and interact with T-cells.[2]

Peptide-based vaccines usually consist of cancer specific-epitopes and often require an adjuvant (for example, GM-CSF) to stimulate the immune system and enhance antigenicity.[1] Examples of these epitopes include Her2 peptides, such as GP2 and NeuVax. However, this approach requires MHC profiling of the patient because of MHC restriction.[4] The need for MHC profile selection can be overcome by using longer peptides (“synthetic long peptides”) or purified protein, which are then processed into epitopes by APCs.[4]

Gene-based vaccines are composed of the nucleic acid (DNA/RNA) encoding for the gene. The gene is then expressed in APCs and the resulting protein product is processed into epitopes. Delivery of the gene is particularly challenging for this type of vaccine.[2]

Viral vaccines usually work by preventing the spread of the virus. Similarly, cancer vaccines can be designed to target common antigens before cancer evolves if an individual has appropriate risk factors. Additional preventive applications include preventing the cancer from evolving further or undergoing metastasis and preventing relapse after remission. Therapeutic vaccines focus on killing existing tumors. While cancer vaccines have generally been demonstrated to be safe, their efficacy still needs improvement. One way to potentially improve vaccine therapy is by combining the vaccine with other types of immunotherapy aimed at stimulating the immune system. Since tumors often evolve mechanisms to suppress the immune system, immune checkpoint blockade has recently received a lot of attention as a potential treatment to be combined with vaccines. For therapeutic vaccines, combined therapies can be more aggressive, but greater care to ensure the safety of relatively healthy patients is needed for combinations involving preventive vaccines.[2]

The clinicaltrials.gov website lists over 1900 trials associated with the term “cancer vaccine”. Of these, 186 are Phase 3 trials.

A recent Trial Watch review (2015) of peptide-based vaccines summarized the results of more than 60 trials that were published in the 13 months preceding the article.[4] These trials targeted hematological malignancies (cancers of the blood), melanoma (skin cancer), breast cancer, head and neck cancer, gastroesophageal cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and colorectal cancers. The antigens included peptides from HER2, telomerase (TERT), survivin (BIRC5), and Wilms’ tumor 1 (WT1). Several trials also used “personalized” mixtures of 12-15 distinct peptides. That is, they contain a mixture of peptides from the patient’s tumor that the patient exhibits an immune response against. The results of these studies indicate that these peptide vaccines have minimal side effects and suggest that they induce targeted immune responses in patients treated with the vaccines. The article also discusses 19 clinical trials that were initiated in the same time period. These trials are targeting solid tumors, glioma, glioblastoma, melanoma, and breast, cervical, ovarian, colorectal, and non-small lung cell cancers and include antigens from MUC1, IDO1 (Indoleamine 2,3-dioxygenase), CTAG1B, and two VEGF receptors, FLT1 and KDR. Notably, the IDO1 vaccine is being tested in patients with melanoma in combination with the immune checkpoint inhibitor ipilimumab and the BRAF (gene) inhibitor vemurafenib.

The following table, summarizing information from another recent review shows an example of the antigen used in the vaccine tested in Phase 1/2 clinical trials for each of 10 different cancers:[3]

• Tumor antigen vaccine entry in the public domain NCI Dictionary of Cancer Terms
• List of cancer vaccine clinical trials at clinicaltrials.gov.

 This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms".