The landscape of cancer and immunology has gone through major scientific advances in research over the past 2 decades. The emergence of immunotherapy as a treatment option for patients diagnosed with cancer has led to improvements in patient outcomes. Patients diagnosed with certain forms of cancer can now live longer and enjoy good quality of life. Although not widely used at present, therapeutic cancer vaccines are now available for select groups of patients, such as those with early prostate cancer. In this paper, we provide a brief background and an overview of cancer vaccine therapy, current research, clinical application, and current challenges.
The interaction between immune cells and cancer cells is complex and beyond the scope of this paper. However, current advances in cellular and molecular immunology have led to a comprehensive and better understanding of the complex nature of cellular interactions and how cancer cells can escape the immune surveillance system. In results from preclinical models and some early human studies, cancer vaccines have been shown to induce both tumor and clinical responses in some patients. This body of knowledge has led to new and exciting areas of inquiry in the field of immunology and cancer. Researchers in these fields are exploring and refining how vaccines can be utilized to effectively harness the immune system to halt the growth and spread of cancer.
Therapeutic Cancer Vaccines
The use of vaccines for the treatment of diseases is not entirely new and predates the 20th century, when William B. Coley, MD, used heat-inactivated bacterial combination mixtures to treat patients with inoperable cancer. Surprisingly, some of these patients achieved durable responses.1 Historically, inactivated vaccines have been used to prevent childhood diseases such as measles, smallpox, poliomyelitis, mumps, and rubella, and in adults, tuberculosis, among many other diseases. To date, the use of vaccines to prevent diseases remains one of medical science’s greatest achievements and partly provides a foundation for current explorations and investigations for therapeutic cancer vaccine research. Although most of the current trials focus on therapeutic cancer vaccines, clinical trials are underway investigating the role of preventive cancer vaccines as well. Currently, most cancer vaccines are only available through clinical trials.
Cancer vaccines have multiple functions, including prevention of tumor cell proliferation, metastasis, and disease recurrence. Therapeutic cancer vaccines, also known as cancer vaccines, are a type of immunotherapy. However, unlike other types of immunotherapy such as checkpoint blockade and chimeric antigen T-cell therapy, which inhibits the immune system’s tolerance to tumor cells by either “releasing the brakes off” the immune system and/or by immune cell expansion (to create a tumor-free environment), vaccines work by inducing immunity against tumor-associated antigens (TAAs) and can either stimulate an immune response or enhance existing immune responses against cancer cells. In cancer, the immune system loses normal function, which leads to abnormal cell or tumor growth. These changes raise the need to identify specific tumor antigens that can be effectively targeted and the need to develop strategies to reverse the immunosuppressive mechanisms exploited by cancer cells.1-3
Cancer Vaccine Targets
The field of immunology is complex and requires fundamental knowledge of the concepts of interdependence of the body’s immune system, surveillance mechanisms, tumor suppression and evasion, and the role of tumor antigens. Tumor antigens are produced from an overexpression of proteins that are found on the surface of cancer cells and some normal cells, such as HER2 and the epidermal growth factor receptor. In general, tumor antigens are typically transported in the body by antigen-presenting cells, immune simulators, and immune modulators and are responsible for inducing or enhancing an immune response. This calls for identification of tumor targets that can be exploited by cancer vaccines.
There are 2 different types of cancer vaccine targets: TAAs and tumor-specific antigens (TSAs). TAAs, also referred to as self-antigens, are proteins that derive their immunogenic potential from their unique expression by tumor cells and are also found on some normal cells. The presence of TAAs on normal cells is a double-edged sword, as this phenomenon increases the risk of developing autoimmunity in some patients.4 In contrast, TSAs are produced in tumor cells and can stimulate an immune response and therefore can be used as surrogate tumor markers for diagnosis in some tumors. Unlike TAAs, TSAs are not expressed by normal cells.1,4,5
In general, most tumor antigens are unique to an individual patient’s tumor. This lays the foundation for personalized cancer vaccine development. From an immunology perspective, cancer vaccines can identify abnormal signatures on cancer cells and can subsequently render effective and lethal attacks.1 Other cancer vaccine targets include surface proteins on viruses, such as the human papillomavirus (HPV), Epstein-Barr virus (EBV), and the hepatitis virus.
Therapeutic cancer vaccines are generally classified into 3 major categories: cellular, protein/peptide, and gene-based vaccines.6 Cellular vaccines are modified cancer antigens or tumor-presenting cells. The GVAX vaccine, a granulocyte-macrophage colony-stimulating factor, is an example of a modified cancer vaccine (gene-transfected tumor cell vaccine), albeit with limited efficacy in patients with melanoma, and prostate and pancreatic cancers.1 Modified vaccines facilitate the transfer of antigens into immune cells, resulting in cell activation and destruction of cancer cells. Other vaccines induce endogenous degradation of cellular material. These types of vaccines are also known as autophagy modulators and are currently under investigation in different types of tumors, including liver, breast, pancreatic, lung, and colorectal cancers. However, there are no available cancer vaccines on the market that specifically target cellular degradation in these cancers.1
Proteins, also known as peptide vaccines, have been investigated in clinical trials and have been shown to induce immune responses. Unfortunately, these findings have not translated into clinical efficacy. Unlike other vaccines, peptide vaccines preserve tumor selectivity and therefore have a lower risk of autoimmunity.7 Other vaccines under investigation include lysed vaccines and DNA and RNA formulations in patients with melanoma. Vaccine adjuvants are used to enhance or promote immune responses in patients undergoing treatment with cancer vaccine therapy.
In addition, cancer vaccines can be classified according to their mechanism of action (MOA). Monovalent vaccines are those that typically induce immunity against a single known TAA. An example of a monovalent vaccine is the HPV16 vaccine. In contrast, polyvalent vaccines induce immunity against multiple TAAs and can target multiple antigens, such as HPV strains 6, 11, 16, and 18, used to prevent cervical and oropharyngeal cancers.8
Integration into Clinical Practice
Successful integration of cancer vaccine therapy into clinical practice is challenging for many reasons. First and foremost, the clinical efficacy of these vaccines has not always matched the successes that have been observed in preclinical models and/or early human trials. For more than 50 years, the Bacillus Calmette-Guerin (BCG) vaccine, a live attenuated strain of Mycobacterium bovis, has been used to treat early and asymptomatic bladder carcinoma. However, cancer researchers have not been able to clearly identify the full MOA of the BCG vaccine. Researchers speculate that it stimulates an antitumor response, which in part explains tumor regression often seen in select patients with melanoma.1 In 2010, the FDA approved sipuleucel-T (PROVENGE), an autologous dendritic cell–based vaccine and the first therapeutic cancer vaccine for patients with hormone-refractory prostate cancer who express high levels of prostatic acid phosphatase. The approval of sipuleucel-T was based on improvement in overall survival in 3 phase 3 clinical trials. Although the approval of sipuleucel-T was hailed as a milestone in the fight against prostate cancer, its clinical utility has been limited.9 Patients receiving sipuleucel-T require leukapheresis (a procedure to remove immune cells from the patients’ blood) at least 3 days prior to reinfusion. A protein is then added to the immune cells in the laboratory to help stimulate the immune cells against prostate cancer cells once the cells are reinfused into the patient. A total of 3 treatments are typically required. Like most other cancer treatments, the cost of these novel therapies can be prohibitive. The cost of 3 treatments of sipuleucel-T is approximately $100,000.00, or just over $30,000 for each infusion. Unfortunately, these costs can create unintended barriers for many patients who do not have access to adequate healthcare insurance coverage.
The hepatitis B virus (HBV) and the HPV have been broadly successful in preventing liver disease, and cervical and anal cancer, respectively, as preventive vaccines. Currently, several studies are underway investigating the efficacy of the HPV vaccine in patients with squamous-cell carcinoma of the head and neck (SCCHN). The basis of these studies partially springs from available knowledge that in oral SCCHN, the HPV and EBV viruses have been observed to be reliable and predictable epitopes for vaccine-directed therapy against E6 and E7 oncogenes. These oncogenes can therefore be used as prime targets. Unlike other cancer vaccines, the clinical efficacy of the HBV and HPV vaccines is partially attributed to the vaccines’ ability to circumvent common obstacles associated with the development of therapeutic cancer vaccines, which include low immunogenicity associated with some tumors, disease burden, and the immunosuppressive tumor microenvironment.1,10
The process of developing personalized cancer vaccines is complex and costly. With the available technological advances, trials are underway to investigate how these vaccines can be formulated and delivered in an efficient and cost-effective way to enable widespread use. The process of vaccine development may vary depending on many factors. Typically, a biopsy is performed, and a sample of the patient’s tumor is sent for pathology analysis, cytology, and DNA sequencing for mutations. Once the diagnosis is established, the patient will undergo a series of required tests, including imaging, to determine the extent of the disease and the appropriateness of vaccine therapy for the patient. Once all the required testing has been completed per disease protocol, 3 days prior to reinfusion, the patient will then undergo leukapheresis, a procedure by which immune cells—T-cells, B-cells, and natural killer cells—are removed. These cells are sent to a laboratory or manufacturing company where they are modified by adding a protein. These modified cells will be activated and will help stimulate the immune cells and unleash lethal attacks on cancer cells after they are reinfused into the patient.11
Despite significant advances in cancer vaccine research, more work is needed from both a technological and patient perspective. In general, weakened immune systems and the general immunosuppressive effects of cancer cells on the immune system have a negative impact on treatment outcomes. In clinical trials, poorer responses have been observed in patients who present with high levels of tumor mutational burden compared with those who have low levels. The number of mutations found in a tumor and antigen expression on the cancer cell dictates the viability of potential targets. These factors underscore the challenge of using cancer vaccine therapy in patients with large or advanced tumors, as a single modality treatment with vaccine therapy may not be effective. This begs the question of the feasibility of utilizing combination therapies with other cancer therapies in select patients. Overall, these are some of the important factors to consider when evaluating patients for cancer vaccine therapy to avoid needless exposure for patients. Identification of specific cancer targets across tumor types for broader use of these therapies is necessary. Strategies to reduce costs and optimize delivery of these vaccines should be implemented. Clinical trials are investigating the feasibility of combining cancer vaccine therapy with other cancer treatments such as checkpoint inhibitors, chemotherapy, and/or radiation. The goal is not only to improve survival outcomes using cancer vaccines but also to make vaccine therapy available to more patients.
Clinicians need to be aware of the role of cancer vaccine therapy and the need for appropriate patient selection.
Several clinical trials are currently investigating the use of cancer vaccines in many tumor types, including bladder, brain, breast, cervical, colorectal, kidney, lung, pancreatic, prostate, head and neck cancers, as well as leukemia, melanoma, myeloma, and many others.
- Hollingsworth RE, Jansen K. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines. 2019;4:7.
- Espinoza-Delgado I. Cancer vaccines. Oncologist. 2002;7(suppl 3):20-23.
- McArthur HL, Page DB. Immunotherapy for the treatment of breast cancer: checkpoint blockade, cancer vaccines, and future directions in combination immunotherapy. Clin Adv Hematol Oncol. 2016;14:922-933.
- Valilou SF, Rezaei N. Tumor Antigens. In: Rezaei N, Keshavarz-Fathi M, eds. Vaccines for Cancer Immunotherapy. An Evidence-Based Review on Current Status and Future Perspectives. San Diego, CA: Elsevier, Inc; 2018:61-74.
- Alatrash G, Crain AK, Molldrem JJ. Tumor-Associated Antigens. In: Socié G, Zeiser R, Blazar BR, eds. Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation. Models in Discovery and Translation. San Diego, CA: Elsevier, Inc; 2019:107-125.
- Pan RY, Chung WH, Chu MT, et al. Recent development and clinical application of cancer vaccine: targeting neoantigens. J Immunol Res. 2018; 2018:4325874.
- Avigan D, Rosenblatt J. Vaccine therapy in hematologic malignancies. Blood. 2018;131:2640-2650.
- Pils S, Joura EA. From the monovalent to the nine-valent HPV vaccine. Clin Microbiol Infect. 2015;21:827-833.
- Anassi E, Ndefo UA. Sipuleucel-T (Provenge) Injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. P T. 2011;36:197-202.
- Aggarwal C, Cohen RB, Morrow MP, et al. Immunotherapy targeting HPV16/18 generates potent immune responses in HPV-associated head and neck cancer. Clin Cancer Res. 2019;25:110-124.
- Berinstein NL, Berinstein JA. Therapeutic Cancer Vaccines. In: Plotkin S, Orenstein W, Offit P, eds. Vaccines. San Diego, CA: Elsevier, Inc; 2013. Chapter 42.