Authors: Jean-Claude Bystryn, MD, Sandra R. Reynolds, PhD
Source:Oncology 19(1):97-108, 2005
- Currently, there is no available therapy that prolongs survival in widely metastatic melanoma.
- For resected disease, treatment with interferon alfa-2b has only limited effectiveness and is associated with potentially severe toxicities.
- Theoretically, cancer vaccines can permit selective destruction of melanoma cells. Cancer vaccines are receiving increasing attention as a potential treatment for this disease.
Rationale for a Melanoma Vaccine
- The progression of melanoma can be delayed by stimulation of certain immune factors which can be activated by vaccines.
- The influence of immune factors on melanoma is shown by the following observations:
- In vivo stimulation of immune factors can result in partial regression of 15-20% of primary melanoma lesions as well as rare, but dramatic complete response of advanced lesions, without harming normal melanocytes.
- Vaccines can markedly increase resistance to melanoma in animal models. Murine B16 melanoma is invariable fatal within 6-8 weeks when injected into mice; however, almost all mice pre-immunized with a melanoma vaccine survive, and this protection is specific to melanoma.
Tumor Regression vs. Absence of Progression
- Immunization of mice has shown that although treatment with vaccine does not always result in tumor regression, it can result in mice that appear clinically healthy and gain weight despite having large amounts of tumor burden that would otherwise kill non-immunized mice.
- This finding implies that clinical vaccine trials may result in improved survival due to delay in tumor growth, and the correct endpoint for study should be lack of tumor progression rather than rates of tumor regression.
- Observations supporting the hypothesis that immune mechanisms are important in slowing melanoma progression include:
- The presence of unique melanoma antigens in larger amounts in melanoma than in melanocytes and the ability to stimulate antibody response in patients with melanoma
- Infiltration of lymphocytes in melanoma patients treated with vaccines
- Correlation of improved clinical outcomes with the presence of immune response
What Is Required for Melanoma Vaccines to Be Effective
- Tumor vaccines must have several key properties, the two most important being:
- The vaccine must contain antigens that stimulate a tumor-protective response.
- Some of these antigens must be present in the patient’s own tumor.
- Other requirements to make a vaccine effective and practical include:
- Safety of use
- Well-characterized composition
- Reproducible manufacturing
Challenges in the Design of Melanoma Vaccines
- Selection of Antigens Used to Prepare the Vaccine
- This is the most critical issue in preparing melanoma vaccines.
- Although a number of melanoma-specific antigens have been identified, it is not known which of these can stimulate adequate tumor-protective immunity
- Antigenic Heterogeneity
- The relative expression of various melanoma antigens varies significantly from patient to patient, making it difficult to choose a single antigen to be used in all patients.
- Autologous vaccines can be prepared from an individual patient’s own tumor; however, it is possible that the antigens used to prepare the vaccine would not be present in the residual tumor in the patient.
- Antigen Modulation
- Over time, the pattern of antigens expressed by tumor cells can change.
- This can affect the ability of a vaccine to produce an immunologic response if the antigens used to produce the vaccine are no longer present in sufficient quantities in the tumor by the time the vaccine is given.
- HLA Restriction
- Some tumor-related immune responses are human leukocyte antigen (HLA) restricted, that is only patients with a particular type of HLA peptide can bind to the vaccine antigen and produce an immune response.
- There are a large number of HLA molecules with varying expression among individuals; therefore, even an effective vaccine may work only in a small percentage of individuals due to HLA variability.
- HLA-Unrelated Heterogeneity in Immune Responses
- Individuals vary in their ability to produce immune responses, even if they have the same HLA phenotype.
- This can further limit the proportion of patients who will mount adequate anti-tumor immune responses.
- Number of Antigens Required to Induce Effective Protective Immunity
- It is unknown whether a single antigen or multiple antigens are needed to stimulate sufficient anti-tumor immunity to destroy the tumor
- In theory, a larger number of antigens should result in improved immune generation; however, this comes at the cost of decreases specificity of the vaccine.
- Polyvalent vaccines contain a large number of different tumor-associated antigens.
- The large number of antigens increases the chances that the antigen will be expressed by the patient’s tumor and will be an antigen that is able to stimulate an anti-tumor immune response.
- Targeting a large number of antigens also decreases the changes that a melanoma cell will be able to downregulate a particular antigen to avoid an immune-mediated attack.
Constructing Polyvalent Cancer Vaccines
- Three strategies are currently available to construct polyvalent cancer vaccines:
- Nonpurified or Cellular Vaccines
- Traditionally, cancer vaccines are constructed using whole tumor cells or non-purified extract from these cells.
- Tumor cells can be genetically modified to express cytokines (such as GM-CSF) that increase the ability to produce an immune response.
- Although autologous vaccines theoretically allows a vaccine to more closely resemble the actual tumor in a patient, this does not always occur, is costly, and requires large tumors that provide enough tissue to manufacture the vaccine.
- The biggest advantage of non-purified or cellular vaccines is that they are more likely to contain relevant antigens than purified vaccines; however, only a small portion of the vaccine is relevant to the targeted tumor. The majority of the vaccine is irrelevant and potentially may even be detrimental.
- Vaccines Prepared From Pure, Defined Antigens
- Identification of melanoma-associated antigens can be performed by melanoma-associated antibodies or T cells.
- HLA affinity of these antigens can be improved by substituting specific amino acids in the antigen through molecular engineering techniques.
- Pure antigen vaccines are easily characterized, can be reproducibly manufactured, and contain little irrelevant contaminating material.
- However, it is unknown which are the optimal antigens to produce the strongest immunity response.
- In addition, the majority of purified antigen vaccines utilize antigens based on HLA-A0201 which is the most common HLA type; however, less than half of all patients who develop melanoma express this HLA phenotype.
- The above two factors mean that purified vaccines can be used only in a minority of melanoma patients and are therefore less likely to be clinically effective compared to nonpurified vaccines.
- Vaccines Prepared From Partially Purified Tumor Antigens
- Partially purified vaccines attempts to enrich cellular elements most likely to contain tumor antigens and deplete irrelevant material from melanoma tumor extracts
- This approach attempts to retain the most critical elements required for vaccine effectiveness while being much purer than vaccines prepared from whole extracts.
- Two examples of this approach which are currently in clinical trials are:
- Polyvalent vaccines prepared from antigens shed by melanoma
- Vaccines constructed from autologous heat shock proteins (HSP). HSP’s function as chaperones for peptide transport within cells including normal self-peptides as well as tumor antigen-derived peptides.
- Immune responses produced by tumor antigens are generally weak.
- The use of adjuvants with cancer vaccines can enhance immune responses through a wide variety of mechanisms including:
- Modification of physical or biochemical properties of the antigen
- Use of emulsions or bacterial extracts such as Freund’s adjuvant, BCG, QS21, or Detox
- Use of immunomodulators such as IL-2, IFN-gamma, and GM-CSF
- Coupling antigens to strong immunogenic molecules such as hapten
- Binding antigen to the surface of inert beads that are immunostimulating
- Use of recombinant techniques to express antigen on non-pathogenic viruses
- Transfecting tumor cells to express molecules that increase their immunogenicity
- One of the most effective approaches is to present the antigen on dendritic cells which are potent inducers of T-cell immunity. A variety of methods are used to achieve this; however, it is unclear which method is the most effective.
- Another promising approach is to encapsulate the vaccine into liposomes together with a small amount of immunomodulators to increase the immune response; the liposome greatly prolongs the half-life of the cytokine, increasing the immune stimulation.
Clinical Trials of Melanoma Vaccines
- In several thousand patients that have been treated with melanoma vaccines, little toxicity has been seen.
- Most toxicity seen has been due to the use of an adjuvant rather than the vaccine itself.
- Most common toxicities are reactions at the injection site which are worse with when more toxic adjuvants are used.
- Other toxicities include lymphadenopathy, chills, fevers, and infections.
- Two potentially severe but theoretical side effects are:
- Enhancement of tumor growth if the vaccine induces the wrong type of immune response. This has been seen in animal models but reported in few vaccine-treated patients.
- Induction of autoimmunity, particularly against normal melanocytes. Some cases of vitiligo or uveitis have been seen with the use of melanoma vaccines.
- Despite these toxicities, vaccines are clearly less toxic than current FDA-approved treatments such as IFN-alpha2b.
- Immunologic activity is the most common endpoint currently used to assess the activity of cancer vaccines.
- This endpoint is important because cancer vaccines cannot work without stimulating immune responses; however, the type of responses measured and how they are measured vary from vaccine to vaccine, making comparisons among of immunologic activity among different vaccines difficult.
- In addition, it is unclear what clinical relevance the different types of vaccine-induced immune responses have.
- The frequency and magnitude of the immune response normally increases with time and the number of immunizations; however, excessive immunizations can sometimes lead to immune tolerance.
- Both cellular and humoral immunity can be induced by cancer vaccines and it is unclear which is more important in protective immunity or which is the proper endpoint to use.
- Correlations between vaccine-induced immune response and improved clinical outcome have been observed in multiple studies.
- Molecular Markers
- Molecular markers of melanoma can be present in the blood and included melanoma cells as well as individual proteins and antigens
- Several of these markers have been correlated with melanoma stage and may reflect tumor load.
- Treatment with melanoma vaccines has been shown to result in decrease in some of the markers in treated patients, and a decrease in these markers has been correlated with improved clinical outcome in several studies
- Clinical Trial Results
- Two large studies comparing patients treated with melanoma vaccine compared to historical controls showed improved outcomes with use of the vaccine:
- Morton et al. found 5-year overall survival of 107 patients was 39% in patients treated with whole-cell vaccine compared to 19% in a matched-pair control group
- Bystryn et al. found overall survival of 94 patients with stage IV melanoma was 2 to 4 times longer than matched historical controls. 35% of patients with resected, non-visceral disease treated with the vaccine survived 5 years compared to 13% of historical controls.
- Two randomized, controlled trials have shown improved results with vaccine-immunized patients over control patients
- Bystryn et al. used polyvalent, shed-antigen melanoma vaccine in stage III disease in 38 patients and found the recurrence-free survival to be over twice as long as patients treated with placebo vaccine.
- The Southwest Oncology Group used Melacine, a vaccine prepared from lysate of two melanoma cell lines enhanced with the adjuvant Detox, in 689 resected stage II melanoma patients and found no difference in recurrence-free survival between the two groups. However, in a planned subset analysis of patients who were HLA-A2 negative or C3-positive, relapse free survival was improved in the vaccine-treated group.
- Canvaxin is an irradiated, whole-melanoma-cell, polyvalent vaccine which has been shown to improve recurrence-free and overall survival in stage III and IV melanoma patients in case-control studies. This vaccine is currently in two large-scale phase III trials with results still pending.
- However, several trials of melanoma vaccine have shown no improvement in outcomes including a vaccine made from purified ganglioside GM-2 as well as two large randomized trials using vaccines prepared from viral lysates of melanoma.
Indications for Melanoma Therapy With Vaccines
- Melanoma vaccines are still experimental and none has been approved by the FDA; therefore, these vaccines can only be administered in the context of a clinical trial.
- No standard criteria exist of determining whether a patient will be eligible for a melanoma vaccine trial. However, generally, patients most likely to be treated with vaccines are those with resected disease with a high risk of recurrence (such as stage IIB and III patients) or patients with stage IV disease, either resected or with a limited tumor load.
- Contraindications to vaccine therapy include widely disseminated disease, known allergies to vaccine components, concurrent administration of immunosuppressive agents, or underlying medical conditions that would preclude the use of melanoma vaccines.
Melanoma Prevention With Vaccines
- Individuals at high risk for melanoma can be identified with some degree of accuracy and include patients with certain genetic backgrounds, skin type, history of sun exposure, or dysplastic nevi.
- In animal models, prophylactic treatment of melanoma vaccines can prevent this cancer and is often more effective than treatment of established melanoma tumor.
- It may prove possible to use these vaccines to prevent melanoma and may ultimately be easier than treating patients who already have the disease.
The above article represents a good overview of the current state of melanoma vaccines. The rationale underlying these vaccines is well described as are the significant obstacles in producing a successful vaccine. These obstacles cannot be understated. It is clear that while melanoma vaccines have been shown to be effective in animal models and able to produce immune responses in clinical trials, the results of most randomized trials with melanoma have thus far been disappointing. Although the article emphasized the few positive randomized melanoma vaccine trials, the majority of phase III trials with these vaccines have failed to show improvement with the use of these vaccines. Clearly, much more needs to be learned about the optimal way to stimulate adequate immune response to eradicate this tumor. Despite these challenges, cancer vaccines remain an extremely intriguing option for cancer treatment. The potential for treatment specifically targeting melanoma cells with little toxicity is strong with these vaccines, and significant research should be invested in this promising technology.