Q J Med 1999; 92: 299-307
© 1999 Association of Physicians
Review |
Vaccine therapy for cancer—fact or fiction?
From the CRC Department of Medical Oncology, University of Glasgow, Glasgow, UK
Dr T.R.J. Evans, CRC Department of Medical Oncology, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD. e-mail: trjelv{at}udcf.gla.ac.uk
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Introduction |
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 Top Introduction Principles of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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In the 1890s, William B. Coley started to treat cancer patients with inoculations of bacterial extracts (Coley's toxins) to activate general systemic immunity, some of which might be directed against the tumour.1,2 Subsequent efforts to enhance our understanding of the molecular basis of immune recognition and immune regulation of cancer cells have led to the identification of potential new targets on tumour cells, and the potential to create potent, specific cancer vaccines. In this review, we discuss the principles of tumour immunity, the tumour antigens that can be recognized by the immune system, the different types of vaccines that have been evaluated, and the potential clinical applications of these approaches.
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Principles of tumour immunity |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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Unlike most vaccines for infectious agents, the goal of cancer vaccination is therapeutic and this can be achieved by activating immune responses against tumour antigens. The immune response can be crudely divided into either antibody responses or T-cell responses. Antibodies recognize and bind to conformational determinants on cell surface proteins, and can kill the cell by either antibody-dependent cellular cytotoxicity or complement-mediated cell lysis. Conversely, T cells recognize small proteins presented on the cell surface on major histocompatibility (MHC) antigens, and T-cell activation requires a co-stimulatory signal which is usually present on the cell surface of antigen-presenting cells. However, attempts to exploit the immune system as a therapeutic strategy in cancer treatment have to overcome the host's inability to develop effective endogenous immunity against cancer. Several mechanisms have been proposed to explain this phenomenon, including generation of tumour variants lacking certain tumour antigens,3–5 loss of MHC expression,6–9 downregulation of the antigen processing mechanism10 and also expression of inhibitory molecules which may promote escape from immune surveillance including TGFß11 and Fas ligand.12 A further significant contributor to escape from immune surveillance is the induction of tolerance of mature T cells either by anergy or physical deletion.13,14 The development of antigen-specific T-cell anergy appears to be an early event in the tumour-bearing host,15 and in mice tumour systems, antigenic tumour cells can grow progressively in immunocompetent hosts without inducing either acute or memory T-cell responses.16,17 Activity of T cells not only requires an antigen-specific signal delivered through the T-cell receptor with the appropriate peptide/MHC complex, but also requires a second antigen non-specific or `co-stimulatory' signal delivered by specialized antigen-presenting cells. T-cell co-stimulatory pathways determine whether T-cell receptor complex engagement results in functional activation or clonal anergy.18,19 Engagement of the T-cell receptor in the absence of a co-stimulatory signal results in T cells that fail to develop full effector function, and become anergic, even if both signals are presented in subsequent encounters with antigen.20
Cancer patients and tumour-bearing mice have impaired delayed-type hypersensitivity, decreased lymphocyte lytic function and a decreased lymphocyte proliferation response,21 and may have diminished T-cell functions in vitro that correlate with specific alterations in the T-cell signal transduction pathways.22–27 The notion is that tumours are poor stimulators of immune responses and may be capable of actively inducing tolerance. The goal of cancer vaccination is therefore to breakdown tolerance or activate T cells that have escaped tolerance.
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Tumour antigens |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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The rational design of a cancer vaccine depends upon the identification of tumour antigens that can be targeted by the immune system, as well as strategies in antigen presentation to overcome tolerance. Tumour antigens can be classified into various categories based on their pattern of expression: (a) unique tumour antigens expressed exclusively in the tumour from which they were identified; (b) shared tumour-specific antigens which are expressed in many tumours but not in normal adult tissues; and (c) tumour-associated differentiation antigens (TADA). That is, antigens normally expressed in the tissue from which the tumour has arisen, but inappropriately expressed by the tumour. Furthermore, oncogene products, tumour-suppressor gene products, and viral antigens in virus-associated tumours are also candidates for targeting by the immune system.
Unique tumour antigens
True tumour antigens are uncommon in humans, as those described in mice are probably provided by retroviral antigens. However, a number of antigens derived from the products of gene mutations have been identified in melanoma, including a peptide derived from a mutation in the cyclin-dependent kinase 4 gene that can disrupt the cell-cycle regulation exerted by the tumour suppressor gene p16, INK4a,28 and a product of a mutation in the ß-catenin gene which may play a role in melanoma progression.29 However, these unique antigens can not be used as targets in the design of generic cancer vaccines.
Shared tumour-specific antigens
The majority of shared tumour antigens isolated from mice and human tumours are reactivation of genes not normally expressed in adult tissues but activated in some tumours.30 The best characterized example of shared tumour-specific antigens in humans is the MAGE gene family. Boon and colleagues cloned the tumour-specific antigen named MAGE-1, which encodes the tumour-rejection antigen MZ2-E, recognized by autologous CD8+ cytotoxic T lymphocytes.31,32 This antigen is expressed on many melanomas as well as other types of tumours, but not on normal tissues, with the exception of testis. Two other MAGE genes (MAGE-2 and MAGE-3) have been identified.33 Given the shared and selective expression in tumours, these antigens are promising candidates for antigen-specific cancer vaccines.
Tumour-associated differentiation antigens (TADA)
Although it would be expected that T cells specific for self-antigens would be functionally tolerant, the majority of T cells from melanoma patients recognize nonmutated peptides derived from melanocyte-specific differentiation antigens, most commonly from melanosome proteins. Examples include tyrosinase, an MHC class II-restricted melanoma antigen recognized by CD4+ T cells,34,35 Melan A/MART1 and gp100/Pmel17.36,37
Oncogene and tumour suppressor gene products
The dominant transforming oncogenes most often associated with human neoplasia are members of the ras family that are mutated at high frequency in certain tumour types, including cancers of the thyroid, colon, pancreas, lung (non-small-cell) and in acute myeloid leukaemia.38 The ras family of genes consists of three functional genes—k-ras, N-ras and H-ras, which encode very similar proteins with molecular masses of about 21 kDa. Mutations which constitutively activate the ras-induced signal transduction pathway occur at codons 12,13 or 61 of ras genes,39 and mutations of the ras protein can be recognized by antibodies and T-cells in both healthy individuals and cancer patients.40–42
Mutations in the p53 tumour suppressor gene are among the most common genetic alterations found in human cancers.43,44 Cytotoxic T-cell response can be generated against tumours with a mutant p53 protein following vaccination with a synthetic peptide designed to correspond to the MHC class I epitope generated from the particular p53 mutated protein.45,46 However, cancer vaccines aimed at a specific p53 mutation would be impractical in clinical practice, as any single p53 mutation is present in a very small proportion of human cancers. Vaccination against wild-type p53 could potentially have broader application, as it would work against any tumour overexpressing p53 without accurately defining the precise mutation. Indeed, vaccination with wild-type p53 recombinants is as effective in protecting animals against tumour challenge as vaccination with mutant p53 recombinants.47
An additional oncogene that is a potential target for vaccine design is the HER2/neu proto-oncogene. Although no mutations of these gene have been found, amplification and overexpression of the gene have been demonstrated in a variety of human tumours, including breast, ovarian, uterus, lung and colon cancers,48 and overexpression correlates with aggressiveness of malignancy and poor prognosis in breast and ovarian cancers.48,49 The HER/2/neu-derived peptides can elicite a cytotoxic T lymphocyte response by primary in vitro immunization in culture systems.50 Moreover immune manipulation of this oncogene product with a monoclonal anti-receptor antibody can effectively prevent the development of tumours in a transgenic mouse model overexpressing the rat neu oncogene in mammary epithelial cells.51
Virus-associated tumour antigens
Specific viruses have been implicated in the aetiology of a number of human cancers, raising the possibility that viral antigens could be exploited as tumour-associated antigens for the purpose of vaccine design. The hepatitis B virus is closely associated with hepatocellular carcinoma, although the cause-and-effect relationship is unproven.52–54 In addition to the possibilities of developing a therapeutic vaccine, this is an opportunity to introduce prophylactic hepatitis B vaccination in high-risk areas in a cancer prevention strategy.55
The role of human papillomaviruses (HPVs) in the development of cervical carcinoma has been well documented, with HPV DNA detected in more than 90% of these tumours predominantly of the HPV16 and HPV18 genotypes. The majority of cervical cancer cells express the E6 and E7 antigen and CTL responses have been observed in vitro in patients with HPV-associated cervical lesions.56,57 This raises the possibility of designing therapeutic vaccines against these antigens.
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Vaccine design: cell-based or antigen-specific? |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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Historically, the initial cancer therapeutic vaccines were cell-based, that is, the approach was to use the tumour cells themselves as a source of antigen. Indeed, this approach has potential advantages in that the vast majority of tumour rejection antigens remain unknown. However, for this approach to be effective, it must generate a stronger immune response to the tumour-associated antigens than to the expressed self-antigen within the tumour. Therefore the development of immune tolerance during tumour development would be a potential drawback of this approach, and a further disadvantage is the poor expression of both MHC and co-stimulatory molecules by cancer cells.
Early clinical studies, for example in melanoma, used vaccines consisting of tumour cells mixed with adjuvants such as BCG58 or DETOX.59 Subsequently, genetic modification of these cell-based vaccines has been evaluated in an attempt to overcome the disadvantages of poor MHC and co-stimulatory molecule expression by cancer cells. A number of cytokine genes can augment host antitumour immunity against transplanted tumour cells, including IL-1, IL-2, IL-4, 
-interferon, IL-6, IL-7, TNF-
, and GM-CSF (granulocyte-macrophage colony-stimulating factor) (reviewed in reference 60). Of these, the most potent appears to be GM-CSF,61 which is also a crucial factor in differentiation of precursors to dendritic cells, which are powerful antigen-presenting cells.62
A number of studies have also been reported where the gene transfer of the co-stimulatory molecule B7 results in the rejection of tumour cells expressing MHC I and MHC II,63–65 and B7 can also prevent anergy.66 Other co-stimulatory molecules such as B7-2 and GL-1 have also been identified.67–69 Similar anti-tumour immune responses have been reported when HLA genes and co-stimulatory molecules are transfected into tumour cells. Presentation of TADAs by MHC molecules are necessary for immune recognition of TADAs. Non-immunogenic animal tumours which lack MHC class I expression can be rendered immunogenic when MHC expression is restored following gene transfer.6,7,70–73 Similar enhanced anti-tumour immune response can occur after transfection of MHC class II molecules.74,75
In several of the early studies, autologous tumour cells were used as cell-based vaccines. However this approach would be highly individualized and labour-intensive, and therefore relatively impractical for use in clinical studies. Given that many tumour antigens are shared rather than unique, an alternative approach is to use an allogeneic cell-based vaccine, that is standard tumour cell lines derived from other patients. This has the advantages of being more practical for use in clinical practice, and as `foreign' material, may also amplify the immune response. Indeed, there is evidence that tumour antigens are presented by host bone-marrow-derived cells rather than by the vaccinated tumour cells,76 and so MHC compatability between patient and tumour is not necessary for function of an allogeneic vaccine.
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Cancer vaccines: antigen-specific |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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The notion of directing the immune response towards a selected antigen should give potentially greater control of the immune response. However tumour-associated antigens have not been identified for most tumours, and where these have been identified, they may not be the most potent antigens involved in the rejection of that particular tumour, so that vaccine design may be suboptimal. Peptide vaccines, viral vaccines, bacterial vaccines and nucleic DNA vaccines are all mechanisms that can be used to activate immune responses against a specific antigen.
Most of the peptide vaccines have used MHC-class-I-restricted antigenic peptides. Examples include an HLA-A1-restricted MAGE-3 peptide in metastatic melanoma,77 and an HLA-2-restricted gp100 peptide synthetic analogue, also in melanoma.78 Indeed 42% of 31 patients treated with this vaccine plus IL-2 had objective responses.78 Whether this combination is superior to IL-2 alone remains to be determined. Furthermore although peptide vaccines require loading of MHC molecules on to antigen-presenting cells (APCs) in vivo, administration of peptide without targeting activating APCs can potentially load MHC molecules on non-professional APCs, resulting in induction of tolerance rather than activating an immune response.79,80
Genes encoding specific tumour antigens can also be introduced into the viral genome by standard techniques to create recombinant viral vaccines. Recombinant vaccinia,81–83 adenovirus84 and fowlpox85 vaccines have been evaluated in preclinical models as cancer vaccines. Preliminary results of clinical trials with recombinant vaccinia vaccines expressing CEA86 or HPV E6 or E787 in humans have shown that these vaccines can induce an immune response, although it is too early to evaluate their clinical efficacy. Furthermore, recombinant bacterial vaccines have potential as cancer vaccines. Several bacteria including Salmonella,88,89 BCG90,91 and Listeria monocytogenes92 are potentially infective by the enteric route (raising the possibility of an oral vaccine) and can also target antigens to professional APCs. Listeria monocytogenes has the additional advantage of being able to `live' in the cytoplasm of the cell and thus target protein antigens to the cellular arm of the immune response. A recombinant Listeria monocytogenes vaccine that secretes a tumour-specific antigen can protect mice against lethal challenge with colon or renal cancer cells that express the antigen, and can also induce regression of established tumours (colon and renal cancers and melanoma) in animal models by an antigen-specific T-cell-dependent mechanism.93,94 However, these recombinant viral vaccines have yet to be evaluated in clinical trials.
Naked DNA vaccines can also induce tumour-antigen-specific immunity. Direct injection of plasmid DNA into mouse muscle or skin, without any transfection agent, results in the expression of the gene product and can stimulate an immune response.95,96 Furthermore, intramuscular injection of plasmid DNA encoding influenza A nucleoprotein in mice results in the generation of specific CTLs and protection from a subsequent challenge with a heterologous strain of influenza A virus.97 DNA vaccines could potentially be used as immunotherapy of malignant disease by re-injection of plasmid DNA encoding tumour-specific antigens. However, DNA vaccination has poorer efficacy than vaccination with recombinant viruses.98 Numerous strategies have attempted to induce improved immune responses over intramuscular injection of DNA, including transdermal99 or mucosal100 delivery, gene-gun delivery of DNA-coated gold beads100 and DNA-liposome complexes.101 The feasibility, safety and therapeutic potential of the latter has been demonstrated in a small study in patients with melanoma.101 Encapsulation of plasmid DNA in poly (DL-lactide-co-glycolide) microparticles can protect plasmid DNA against degradation after oral administration, and can induce immune responses.102 This approach has potential in developing cancer vaccines that can be administered orally.
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Cancer vaccines: potential clinical applications |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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Many of the early clinical studies have evaluated cancer vaccines in melanoma, although most of these clinical observations have been on a small number of patients. In an early study in patients with metastatic melanoma (n=80), treatment with vaccinia melanoma cell lysates was reported to give an improved overall survival after 2 years follow-up, although this was in comparison with historical controls.103 Other studies have suggested a survival benefit in stage II patients,104 in stage IIIA and stage IV patients treated with a polyvalent melanoma cell vaccine,105 and in stage II patients treated with a polyvalent melanoma vaccine.106 However none of these vaccines were evaluated in a randomized phase III study, and the survival benefit was extrapolated from comparison with historical matched patients. The interim analysis from a phase III study in surgically-resected stage II melanoma randomizing to either vaccinia melanoma oncolysate vaccine or placebo vaccinia virus vaccine showed no survival advantage after a mean follow-up of 42 months, although retrospective subset analysis did suggest a significant survival benefit in favour of the vaccine in clinical stage I patients.107 Until these various vaccine approaches have been evaluated in randomized phase III studies against standard therapy, their activity in advanced disease or in the adjuvant setting remains speculative, although the results from these phase II studies are encouraging and have confirmed the safety of this approach.
Several clinical studies have attempted to exploit the expression of CEA by colonic carcinoma cells in the design of therapeutic vaccines. A recombinant vaccinia—CEA vaccine (rV-CEA)—can elicit a specific CTL response which is MHC-restricted.108 A murine monoclonal anti-idiotype antibody, which mimics a specific epitope on CEA, has been evaluated in 12 patients.110 This study demonstrated that the vaccine was capable of breaking `immune tolerance' to CEA in patients with CEA-positive tumours, and although toxicity was limited to mild fever and chills, all patients had disease progression after 4–13 dosages. A phase I study of rV-CEA in 17 patients confirmed that the vaccine was well tolerated, with toxicity limited to mild local and systemic reactions comparable to those seen with vaccinia alone.109 However, most of these patients with advanced colorectal cancer had tumour progression demonstrated by clinical and radiological assessment or by CEA levels.109 It is likely that cancer vaccines, like other forms of cancer immunotherapy, will have most anti-tumour impact in minimal disease states. Interestingly, a phase I study in 20 patients using an autologous-tumour-cell vaccine modified by Newcastle disease virus has confirmed the safety of the vaccine (mild fever in 4/20 patients) when used adjuvantly after surgical resection of the tumour,111 and is likely to be evaluated in a large randomized clinical trial.
A phase I/II study of a recombinant vaccinia virus expressing the E6 and E7 proteins of HPV16 and 18 (TA-HPV) has been evaluated in eight patients with late-stage cervical cancer.87 There were no clinically significant side-effects and immune responses were observed,87 and this strategy warrants further evaluation not only in advanced cervical cancer but also in pre-invasive malignancy.
Sialyl-Tn (STn) is a carcinoma-associated core-region carbohydrate antigen of epithelial mucin, and its expression is associated with a poor prognosis in colon,112 gastric,113 ovarian,114 and breast cancer.115 In a phase I study in patients with metastatic breast cancer, immunization with a synthetic STn linked to keyhole limpet haemocyanin (KLH) and given with an immunological adjuvant (DETOX-B) gave rise to the development of specific IgM and IgG antibodies in all patients, and 2 of the 13 patients treated in this study had a documented partial response.116 Measurable tumour responses were also recorded using this vaccine in a randomized phase II study in patients with metastatic breast cancer. The vaccine was well tolerated apart from erythema and granuloma formation at the injection sites, and the humoral immune responses to the antigen were augmented by low-dose cyclophosphamide.117 This vaccine will shortly be evaluated in a multi-centre randomized phase III study as maintenance therapy in patients with metastatic breast cancer who have responded to chemotherapy.
The notion that the immune system can be activated by cancer vaccines to attack and reject established tumours is a fact. Early clinical evaluation of these vaccines suggests that they are well tolerated with minimal toxicity, although the optimal vaccine design has yet to be designed. Further clinical trials are required to determine the activity of cancer vaccines in (a) advanced disease, (b) in the adjuvant setting to delay or prevent disease recurrence and to prolong overall survival, (c) as maintenance therapy after chemotherapy, and (d) as potential enhancers of the sensitivity of tumours to standard cytotoxic chemotherapy agents. The notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realms of fiction.
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Acknowledgments |
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The authors would like to thank Fiona Conway for typing the manuscript.
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References |
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TopIntroductionPrinciples of tumour immunityTumour antigensVaccine design: cell-based or...Cancer vaccines: antigen...Cancer vaccines: potential...References |
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