This classification, however, is imperfect because many antigens thought to be tumor-specific turned out to be expressed on some normal cells as well. The modern classification of tumor antigens is based on their molecular structure and source. Accordingly, they can be classified as; [ citation needed ]. Any protein produced in a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of the concerned gene.
Mutation of protooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumor and thus such abnormal proteins are called tumor-specific antigens. Examples of tumor-specific antigens include the abnormal products of ras and p53 genes.
In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens. Other examples include tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens , cancer-testis antigens and vascular or stromal specific antigens. Tissue differentiation antigens are those that are specific to a certain type of tissue. Mutant protein antigens are likely to be much more specific to cancer cells because normal cells shouldn't contain these proteins.
Normal cells will display the normal protein antigen on their MHC molecules, whereas cancer cells will display the mutant version.
Some viral proteins are implicated in forming cancer oncogenesis , and some viral antigens are also cancer antigens. Cancer-testis antigens are antigens expressed primarily in the germ cells of the testes , but also in fetal ovaries and the trophoblast. Some cancer cells aberrantly express these proteins and therefore present these antigens, allowing attack by T-cells specific to these antigens.
Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response.
An example of such a protein is the enzyme tyrosinase , which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells. Oncofetal antigens are another important class of tumor antigens. These proteins are normally produced in the early stages of embryonic development and disappear by the time the immune system is fully developed.
Thus self-tolerance does not develop against these antigens. Abnormal proteins are also produced by cells infected with oncoviruses , e. Cells infected by these viruses contain latent viral DNA which is transcribed and the resulting protein produces an immune response. In addition to proteins, other substances like cell surface glycolipids and glycoproteins may also have an abnormal structure in tumor cells and could thus be targets of the immune system.
Furthermore, CTLs play an important role in the rejection of transplanted organs and tissues 10 , analogous to tumors as foreign or abnormal human cells invading the host. Thus, although monoclonal antibodies have clearly shown therapeutic efficacy in certain cancers e. The class I MHC antigen processing pathway acting as an internal surveillance mechanism to detect any abnormal or foreign protein synthesized in the cell.
Tumor antigens encoded in the endogenous DNA of the tumor cell, or encoded in a DNA plasmid or viral vector vaccine taken up by an APC, are synthesized and cleaved by the 26S proteasome into fragments that are transported by TAP, the transporter associated with antigen processing, into the endoplasmic reticulum, where they are loaded onto newly synthesized class I MHC molecules that transport them to the cell surface for recognition by the T cell receptor.
DCs express high levels of costimulatory molecules, such as CD80 and CD86, which can make the difference between turning off the CTL precursor and activating it. In addition, a number of regulatory mechanisms that dampen the immune response are exploited by tumors to escape immunosurveillance. Major hurdles in developing cancer vaccines include: identification of antigens that focus the exquisite specificity of the immune system on cancer cells without harming normal cells; development of methods to induce an immune response sufficient to eradicate the tumor, in the face of self-tolerance to many tumor antigens; and overcoming mechanisms by which tumors evade the host immune response.
An extensive listing of the known tumor-associated antigens is available, and more are being discovered These categories and the two major strategies used to identify tumor antigens are described in Approaches to tumor antigen discovery.
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To specifically target tumors, antigens must be expressed only in tumor cells. Peptides derived from common ras mutations bind to specific MHC molecules and can generate tumor-specific immune responses 30 , Because the mutations are necessary for generation and maintenance of the neoplastic phenotype, they are expressed by all of the tumor cells and cannot be lost. However, only a short segment of the amino acid sequence encompassing the mutation or fusion breakpoint is actually unique, and this region may not be presented by many common HLA molecules. Another type of tumor antigen unique to cancer cells are antigens with tumor-specific posttranslational modifications, exemplified by MUC1, which shows altered glycosylation in cancer cells, creating neoantigenic sites by exposing protein sequences normally masked by glycosylation 1 , 7.
To overcome this problem, investigators have searched for whole proteins either not highly expressed in adult tissues, such as carcinoembryonic antigen CEA 32 , 33 ; overexpressed in cancer cells, such as nonmutated portions of p53 34 ; or uniquely expressed in expendable tissues. The disadvantage is that self-tolerance may limit responses to these normal host proteins. Expression of these proteins can also be lost if they are not essential for malignancy, allowing tumor escape. The vaccine strategies used against cancer depend on how well defined the target antigens are and whether there are conserved antigens that are shared among tumors of the same type in many individuals.
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We will discuss the rationale for, and experience with, some of the most widely studied approaches Table 1. The richest source of rejection antigens is the tumor itself. However, use of autologous tumor cell vaccines is cumbersome and not amenable to large-scale vaccine production, and tumor samples are often unavailable. Approaches using allogeneic or generic cell lines as vaccines are more widely applicable. Tumor cells engineered to secrete a number of different cytokines have been shown to protect mice from challenge with the same tumor type These acquire, process, and present antigen to T cells.
A number of genetically modified autologous or allogeneic tumor cell vaccines have been tested in clinical trials 38 — Studies in patients with advanced prostate cancer 38 and metastatic malignant melanoma 39 used irradiated autologous tumor cells transduced with a retroviral vector expressing GM-CSF, resulting in one partial response in 21 melanoma patients, although extensive inflammatory infiltrate with necrosis and fibrosis of tumor was seen in 11 of 16 melanoma patients biopsied In another phase I trial, among 14 patients with resectable pancreatic cancer vaccinated with GM-CSF—transduced allogeneic pancreatic cancer cell lines after surgery 40 , three patients remained disease free at 23 months.
A number of other genetically altered autologous and allogeneic tumor cell vaccines expressing IL-2, IL-4, B7. Elucidation of the crystal structure of the MHC and of the peptides bound to it 45 and discovery of anchor-residue sequence motifs accounting for binding specificity of peptides to MHC molecules 46 has provided the visual and mechanistic answer to how T cells recognize antigens in the form of short peptides. The observation that short peptide segments 8—10 amino acids fit into a groove in the MHC molecule, combined with knowledge of the amino acid sequences of tumor epitopes, prompted the use of peptides as therapeutic agents in the treatment of cancer.
These observations were followed by cloning of the first human tumor-associated antigen and identification of its nonamer peptide sequence Several strategies have been developed both to improve immunogenicity and to steer the immune system toward desired types of responses. Also, peptides have been loaded onto autologous DCs for administration, as described below. However, individual peptides will be useful only in patients with appropriate HLA molecules capable of presenting that peptide.
Modification of the amino acid sequence of epitopes, commonly referred to as epitope enhancement, can improve the efficacy of vaccines through several means: a increasing affinity of peptide for MHC molecules 4 , 48 , 49 ; b increasing TCR triggering 32 , 33 , 50 ; or c inhibiting proteolysis of the peptide by serum peptidases 4 , 6 , Whenever the peptide sequence is altered, it is important to demonstrate that the T cells induced still recognize the native peptide sequence. There is precedent for epitope-enhanced peptides showing greater efficacy in clinical trials 49 see below.
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Another approach is to deliver the peptide with adjuvants containing cytokines, chemokines, costimulatory molecules, or other immunomodulators that amplify and direct the immune response 4. Other synergistic combinations have been described in animal models 4. Another approach to target DCs is to use ex vivo—generated DCs that have been preincubated pulsed with the peptide of interest.
The best-studied clinical model of peptide vaccination is malignant melanoma. The various immunologic monitoring methods employed are listed in Table 2. Each has advantages and disadvantages, but none has been shown to provide a surrogate marker for tumor prevention or regression. Rosenberg and colleagues evaluated vaccination with native gp peptide — and found that it produced only low levels of T cell reactivity in two of eight melanoma patients analyzed, whereas an epitope-enhanced gp gM peptide generated strong T cell reactivity in 10 of 11 patients immunized Nevertheless, only a single objective clinical response was reported.
In the adjuvant setting, Smith et al.
The impact of age was striking Immunization with tyrosinase peptide has been significantly less effective despite epitope enhancement. The use of peptide vaccines may be additionally complicated by the choice of adjuvants. Most studies used IFA, but in the study by Schaed et al. The importance of epitope enhancement is supported by the promising results of vaccination with the epitope-enhanced carcinoembryonic antigen CEA peptide FLT3 ligand—expanded DCs were pulsed with this peptide to immunize patients with advanced colorectal cancer.
Despite the small sample sizes and the variable populations treated, some principles emerge. Immunization with native peptide sequences is often insufficient to generate reactive T cells and clinical responses in most patients. Epitope-enhanced peptides can generate T cell responses but not always clinical tumor responses. Adjuvants, including cytokines and costimulatory molecules, improve the immunogenicity of peptide vaccination.
Paradoxically, combining peptide vaccination with IL-2 significantly reduced detection of specific T cells in blood, but nearly half the patients showed objective cancer regressions 49 , possibly due to IL-2—induced innate immunity combined with vaccine immunity. In a new approach, blockade of the negative regulatory molecule CTLA-4 showed promise when combined with vaccination with gM in melanoma patients.
Human Tumor Antigens and Cancer Immunotherapy
Three of 14 patients treated had objective tumor regressions although at the cost of development of autoimmune disease, including bowel, liver, and pituitary dysfunction Blockade of other negative regulatory pathways has shown promise in animal models 4 , 16 , A number of trials utilizing recombinant viruses expressing tumor antigens such as CEA or PSA, some with immunostimulatory cytokines, have been reported or are in progress 63 , Adenovirus, vaccinia, and avipox vectors have been used.
The high prevalence of antiviral neutralizing antibodies may limit use of these vectors, especially for multiple doses, except for fowlpoxes e. Possible resistance due to prior systemic immunity to poxviruses can potentially be overcome by mucosal immunization, because systemic immunization is poor at inducing mucosal immunity, but mucosal immunization can induce both systemic and mucosal immunity Immunodominance is also problematic. Stronger immune responses may be induced against viral vector antigens than against weaker tumor antigens.
The potency of these vectors may be enhanced by the addition of genes for immunostimulatory molecules or cytokines 66 , Such vectors are entering clinical trials. These vectors can also be used to express antigens in DCs, as described below. Intramuscular injections of naked DNA expression plasmids have been shown to generate immune responses 68 , Such DNA vaccines introduce tumor antigen genes into DCs for endogenous processing and presentation to CTLs in draining lymph nodes or into other cells for cross-presentation by DCs, without the need for a viral vector Figure 2.
Thus, problems of competition from viral vector epitopes, reduced efficacy due to prior immunity to the viral vector, and potential dangers associated with a live virus are avoided. Constitutive, tissue, or tumor-specific promoters may be used for selective expression. Approaches to antitumor vaccination. B DCs can be directly loaded by incubation with tumor protein lysates or peptides with sequences based on expressed tumor antigens, or by viral gene transfer vectors expressing TAAs.