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• W2068862486 abstract "The demonstration that naturally induced tumors in rodents were largely nonimmunogenic and disappointing results from clinical studies were responsible for the notion that tumors are not sufficiently distinct from normal tissue to activate the immune system and led to the inevitable conclusion that immunological intervention in cancer is futile (25Hewitt H Blake E Walder A A critique of the evidence for active host defense against cancer, based on person studies of 27 murine tumors of spontaneous origin.Cancer. 1976; 33: 241-259Crossref Scopus (378) Google Scholar). In a seminal work, van Pel and Boon have shown that a protective immune response can be generated against a “nonimmunogenic” murine tumor, providing the first experimental evidence that lack of immunogenicity could be due to the tumor's inability to activate the immune system rather then the absence of tumor antigens (72van Pel A Boon T Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis.Proc. Natl. Acad. Sci. USA. 1982; 79: 4718-4722Crossref PubMed Scopus (125) Google Scholar). This observation, subsequently confirmed and extended to other rodent nonimmunogenic tumor models, has shown that by proper manipulation—otherwise called vaccination—the tumor antigens present in nonimmunogenic tumors can be “exposed” to the immune system to generate an immune response capable of eradicating the tumor. If this conclusion can be extrapolated to human cancer—and I see no reason why it cannot—all forms of cancer should be susceptible to immunological intervention; namely, all forms of cancer contain tumor antigens that can be targeted for immunotherapy. The recognition that tumors could after all be sufficiently “foreign” to be recognized by the immune system has reinvigorated the efforts to identify and isolate tumor antigens (6Boon T van der Bruggen P Human tumor antigens recognized by T lymphocytes.J. Exp. Med. 1996; 183: 725-729Crossref PubMed Scopus (766) Google Scholar, 56Rosenberg S.A A new era for cancer immunotherapy based on the genes that encode cancer antigens.Immunity. 1999; 10: 281-287Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). This review will focus on what makes a tumor antigen a good or not-so-good target for immunotherapy. Tumor antigens can be classified according to the type of immune response they elicit: humoral, cellular, CD4+ (T helper), or CD8+ cytotoxic T lymphocyte (CTL) responses. As will be discussed below, the fact that a tumor antigen elicits a tumor-specific immune response does not necessarily mean that the immune response will cause the rejection of the tumor in vivo. Thus, from a vaccination standpoint, the question is which tumor antigen can or is better at inducing a clinically beneficial response. We refer to such antigens as “tumor rejection antigens.” Tumor-rejection antigen is therefore an operational term describing how well an immune response elicited against a tumor antigen will impact on tumor growth. Tumor antigens can be poor, intermediate, or strong tumor rejection antigens, describing quantitatively the impact of the immune response on tumor growth. The extent to which an antigen is a tumor rejection antigen is also a function of the immunization protocol. A weak tumor rejection antigen can record as a strong tumor rejection antigen by using an effective vaccination protocol, such as protocols that favor the induction of CTL responses and the Th-1 subset of CD4+ T cell responses (see below). It is therefore not surprising if different studies reach divergent conclusions as to whether a tumor antigen is or is not a tumor rejection antigen (54Ramarathinam L Sarma S Maric M Zhao M Yang G Chen L Liu Y Multiple lineages of tumors express a common tumor antigen, P1A, but they are not cross-protected.J. Immunol. 1995; 155: 5323-5329PubMed Google Scholar, 55Rosato A Zambon A Milan G Ciminale V D'Agostino D.M Macino B Zanovello P Collavo D CTL response and protection against P815 tumor challenge in mice immunized with DNA expressing the tumor-specific antigen P815A.Hum. Gene Ther. 1997; 8: 1451-1458Crossref PubMed Scopus (38) Google Scholar, 7Brandle D Bilsborough J Rülicke T Uyttenhove C Boon T Van den Eynde B.J The shared tumor-specific antigen encoded by mouse gene P1A is a target not only for cytolytic T lymphocytes but also for tumor rejection.Eur. J. Immunol. 1998; 28: 4010-4019Crossref PubMed Scopus (56) Google Scholar). The take-home message is that the potency of a tumor rejection antigen is a relative value that can be assessed only by comparing tumor antigens using the same vaccination protocol. Historically, it was thought that tumor immunity is best mediated by antibodies. Hence, extensive efforts were devoted to the development of serological approaches for identifying antigens expressed on the surface of tumor cells, which are recognized by antibodies from cancer patients (46Old L.J Cancer immunology, the search for specificity—G.H.A. Lowes memorial lecture.Cancer Res. 1981; 41: 361-375PubMed Google Scholar). Disappointing results from early clinical vaccination trials, animal studies indicating the importance of the cellular arm in the antitumor immune response, and new insights into immunological mechanisms have refocused the attention on the cellular response arm of the immune response as the mediator of tumor immunity. The seminal work of Boon and his colleagues, first introducing the methodology of isolating tumor antigens recognized by CTL (14De Plaen E Lurquin C Van Pel A Mariame B Szikora J.P Wölfel T Sibille C Chomez P Boon T Immunogenic (tum−) variants of mouse tumor P815. Cloning of the gene of tum− antigen P91A and identification of the tum− mutation.Proc. Natl. Acad. Sci. USA. 1988; 85: 2274-2278Crossref PubMed Scopus (212) Google Scholar) and then isolating the first human antigen recognized by CTL from melanoma patients (70van der Bruggen P Traversari C Chomez P Lurquin C De Plaen E Van den Eynde B Knuth A Boon T A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.Science. 1991; 254: 1643-1647Crossref PubMed Scopus (3041) Google Scholar), represents yet another important milestone in the annals of contemporary cancer immunotherapy. There are three good reasons why tumor antigens recognized by CTL would make effective tumor rejection antigens. (1) The major histocompatibility complex (MHC) class I processing pathway ensures that CTL are able to recognize subtle changes in the repertoire of antigens expressed by most (MHC class I–expressing) somatic cells (67Townsend A Bodmer H Antigen recognition by class I-restricted T lymphocytes.Annu. Rev. Immunol. 1989; 7: 601-624Crossref PubMed Scopus (1099) Google Scholar). (2) Murine studies using antibody depletion or adoptive transfer of T cell subsets have shown that the CD8+ CTL arm of the immune response, alone or sometime in combination with CD4+ T cells, constitutes the primary antitumor effector arm of the adaptive immune response. (3) Perhaps the most compelling evidence stems from the frequent correlation seen between tumor progression and loss of histocompatibility leukocyte antigen (HLA) class I expression in cancer patients (20Garrido F Ruiz-Cabello F Cabrera T Perez-Villar J.J Lopez-Botet M Duggan-Keen M Stern P.L Implications for immunosurveillance of altered HLA class I phenotypes in human tumors.Immunol. Today. 1997; 18: 89-95Abstract Full Text PDF PubMed Scopus (677) Google Scholar, 26Hicklin D.J Marincola F.M Ferrone S HLA class I antigen downregulation in human cancers.Mol. Med. Today. 1999; in pressGoogle Scholar), strongly suggesting that progressing tumors in cancer patients must have elaborate means of escaping an apparently effective MHC class I–restricted immune response. It is, however, becoming clear that the CD4+ T cell response also plays an essential role in tumor rejection. The primary role of CD4+ T cells, specifically, the Th-1 subset, is to enhance the induction and/or extend the persistence of CD8+ CTL in vivo (18Frasca L Piazza C Piccolella E CD4+ T cells orchestrate both amplification and deletion of CD8+ T cells.Crit. Rev. Immunol. 1998; 18: 569-594Crossref PubMed Google Scholar, 78Zajac A.J Murali-Krishna K Blattman J.N Ahmed R Therapeutic vaccination against chronic viral infection, The importance of cooperation between CD4+ and CD8+ T cells.Curr. Opin. Immunol. 1998; 10: 444-449Crossref PubMed Scopus (105) Google Scholar, 66Toes R.E.M Ossendorp F Offringa R Melief C.J.M CD4+ T cells and their role in antitumor immune responses.J. Exp. Med. 1999; 189: 753-756Crossref PubMed Scopus (454) Google Scholar). CD4+ T cells have also been ascribed a direct effector function (27Hu J Kindsvogel W Busby S Bailey M.C Shi Y.-Y Greenberg P.D An evaluation of the potential to use tumor-associated antigens at targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues.J. Exp. Med. 1993; 177: 1681-1690Crossref PubMed Scopus (60) Google Scholar, 35Levitsky H.I Lazenby A Hayashi R.J Pardoll D.M In vivo priming of two distinct antitumor effector populations. The role of MHC class I expression.J. Exp. Med. 1994; 179: 1215-1224Crossref PubMed Scopus (181) Google Scholar, 48Overwijk W.M Lee D.S Surman D.R Irvine K.R Touloukian C.E Chan C.-C Carroll M.W Moss B Rosenberg S.A Restifo N.P Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice. Requirement for CD4+ T lymphocytes.Proc. Natl. Acad. Sci. USA. 1999; 96: 2982-2987Crossref PubMed Scopus (342) Google Scholar), but their contribution relative to other effector arms has not yet been fully elucidated. Clearly, tumor antigens capable of eliciting CD4+ T cell responses will also function as important tumor rejection antigens, and their incorporation into effective tumor vaccination protocols is absolutely essential. And what about humoral tumor antigens? Humoral responses do not appear to play an important role in protective tumor immunity. Tumor-reactive antibodies occur with high frequency in cancer patients but do not correlate with disease state (15Disis M.L Cheever M.A Oncogenic proteins as tumor antigens.Curr. Opin. Immunol. 1996; 8: 637-642Crossref PubMed Scopus (114) Google Scholar). Vaccination of mice with tumors can elicit tumor-specific humoral responses that are not protective (53Qin Z Richter G Schüler T Ibe S Cao X Blankenstein T B cells inhibit induction of T cell-dependent tumor immunity.Nat. Med. 1998; 4: 627-630Crossref PubMed Scopus (333) Google Scholar). Thus, humoral tumor antigens would make poor tumor rejection antigens and under some circumstances could even prevent the establishment of a T cell–based antitumor response (59Rowley D.A Stach R.M A first or dominant immunization. I. Suppression of simultaneous cytolytic T cell responses to unrelated alloantigens.J. Exp. Med. 1993; 178: 835-840Crossref PubMed Scopus (25) Google Scholar). Yet, monoclonal antibody therapy can exert a significant therapeutic benefit in murine models and in cancer patients, suggesting that humoral tumor antigens could function as tumor rejection antigens (23Hara I Takechi Y Houghton A.N Implicating a role for immune recognition of self in tumor rejection, passive immunization against the Brown locus protein.J. Exp. Med. 1995; 182: 1609-1614Crossref PubMed Scopus (168) Google Scholar, 24Herlyn D Birebent B Advances in cancer vaccine development.Ann. Med. 1999; 31: 66-78Crossref PubMed Scopus (33) Google Scholar). Interestingly, in a recent study, the protective effects of DNA vaccination against an idiotype expressed on a murine B cell lymphoma could be largely attributed to humoral but not cellular immunity (63Syrengelas A.D Levy R DNA vaccination against the idiotype of a murine B cell lymphoma mechanism of tumor protection.J. Immunol. 1999; 162: 4790-4795PubMed Google Scholar). Thus, at present the prospects of using humoral tumor antigens in cancer vaccine formulations is “down but not out.” New and vastly improved methods for isolating tumor antigens recognized by the humoral response have reinvigorated the efforts to develop antibody-based treatments to cancer (60Sahin U Türeci Ö Pfreundschuh M Serological identification of human tumor antigens.Curr. Opin. Immunol. 1997; 9: 709-716Crossref PubMed Scopus (275) Google Scholar). Whether effective tumor rejection antigens are unique patient-specific antigens or correspond to normal gene products shared among many patients is of enormous practical value. Identification and isolation of tumor rejection antigens from each patient is currently not an option. If nonmutated shared antigens can function as tumor rejection antigens, common “off-the-shelf” reagents could be used to treat many cancer patients. While the notion that tumor antigens encoding CTL epitopes will make good tumor rejection antigens is compelling, a tumor antigen encoding a CTL epitope is not necessarily a potent tumor rejection antigen. Three examples will illustrate this point. P1A is a murine prototype of a nonmutated shared tumor antigen recognized by tumor-specific CTL (69Van den Eynde B Lethé B Van Pel A De Plaen E Boon T The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice.J. Exp. Med. 1991; 173: 1373-1384Crossref PubMed Scopus (272) Google Scholar). P1A was isolated from the P185 mastocytoma cell line by virtue of the fact that tumor cells which lost P1A antigen (as well as other tumor antigens) escaped tumor rejection in vivo (68Uyttenhove C Maryanski J Boon T Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression.J. Exp. Med. 1983; 157: 1040-1052Crossref PubMed Scopus (221) Google Scholar). P1A is expressed in several unrelated tumors including Meth A sarcoma and J558 plasmacytoma (54Ramarathinam L Sarma S Maric M Zhao M Yang G Chen L Liu Y Multiple lineages of tumors express a common tumor antigen, P1A, but they are not cross-protected.J. Immunol. 1995; 155: 5323-5329PubMed Google Scholar) and immunization of mice with each tumor elicits P1A-specific CTL. Nevertheless, cross-protection among the P1A-expressing tumors is weak and could be demonstrated only when the P1A-expressing tumor cells were also engineered to express B7-1 (54Ramarathinam L Sarma S Maric M Zhao M Yang G Chen L Liu Y Multiple lineages of tumors express a common tumor antigen, P1A, but they are not cross-protected.J. Immunol. 1995; 155: 5323-5329PubMed Google Scholar, 7Brandle D Bilsborough J Rülicke T Uyttenhove C Boon T Van den Eynde B.J The shared tumor-specific antigen encoded by mouse gene P1A is a target not only for cytolytic T lymphocytes but also for tumor rejection.Eur. J. Immunol. 1998; 28: 4010-4019Crossref PubMed Scopus (56) Google Scholar). It would appear, therefore, that P1A is at best a weak tumor rejection antigen. MART-1/Melan A is a human melanocyte–specific antigen that is recognized by CTL from melanoma patients. Tumor infiltrating lymphocytes (TIL) from nine out of ten patients exhibited CTL activity against MART-1, but only four TILs exhibited activity against another tumor-associated antigen, gp100 (32Kawakami Y Eliyahu S Sakaguchi K Robbins P.F Rivoltini L Yannelli J.R Appella E Rosenberg S.A Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes.J. Exp. Med. 1994; 180: 347-352Crossref PubMed Scopus (761) Google Scholar). Yet, upon adoptive transfer of TIL to patients, tumor regression was correlated with TIL, which recognized gp100 and not MART-1 (33Kawakami Y Eliyahu S Jennings C Sakaguchi K Kang X Southwood S Robbins P.F Sette A Appella E Rosenberg S.A Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression.J. Immunol. 1995; 154: 3961-3968PubMed Google Scholar). Furthermore, vaccination with the dominant MART-1 peptide administered in adjuvant generated significant increases in MART-1-specific CTL, yet no clinical responses were seen (30Jaeger E Bernhard H Romero P Ringhoffer M Arand M Karbach J Ilsemann C Hagedorn M Knuth A Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptides in vivo, implications for tumor vaccines with melanoma-associated antigens.Int. J. Cancer. 1996; 66: 162-169Crossref PubMed Scopus (232) Google Scholar, 12Cormier J.N Salgaller M.L Prevette T Barracchini K.C Rivoltini L Restifo N.P Rosenberg S.A Marincola F.M Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART-1/melan A.Cancer J. 1997; 3: 37-44Google Scholar). Notwithstanding the preliminary nature of such phase I clinical studies, MART-1/Melan A is a dominant antigen recognized by CTL in melanoma patients, yet it does not exhibit properties of a tumor rejection antigen. In a recent study, vaccination of melanoma patients with an anchor residue–modified gp100 derived peptide stimulated strong CTL responses in most patients, yet no clinical responses were seen. Interestingly, patients who also received IL-2 exhibited reduced CTL activities but experienced a dramatic increase in clinical responses. Clearly, there was no simple correlation between the measured CTL responses and clinical responses in this particular case (57Rosenberg S.A Yang J.C Schwartzentruber D.J Hwu P Marincola F.M Topolian S.L Restifo N.P Dudley M.E Schwartz S.L Spiess P.J et al.Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.Nat. Med. 1998; 4: 321-327Crossref PubMed Scopus (1682) Google Scholar). At the heart of the matter is the growing appreciation that the biological impact of a CTL response is not only a function of the experimentally determined magnitude of the immune response, but it is also, and perhaps even more so, a function of the avidity of the CTL to their targets. Several studies have shown that whereas low-avidity CTL can be readily detected by standard immunological assays, only high-avidity CTL exert biological function in vivo in viral (61Speiser D.E Kyburz D Stübi U Hengartner H Zinkernagel R.M Discrepancy between in vitro measurable and in vivo virus neutralizing cytotoxic T cell reactivities.J. Immunol. 1992; 149: 972-980PubMed Google Scholar, 1Alexander-Miller M.A Leggatt G.R Berzofsky J.A Selective expansion of high or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy.Proc. Natl. Acad. Sci. USA. 1996; 93 (a): 4102-4107Crossref PubMed Scopus (458) Google Scholar, 19Gallimore A Dumrese T Hengartner H Zinkernagel R.M Rammensee H.G Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides.J. Exp. Med. 1998; 187: 1647-1657Crossref PubMed Google Scholar) or tumor (Zeh 3rd et al., 1999) models. Thus, perhaps the single most important parameter that determines the potency of a tumor rejection antigen is the avidity of the cognate T cells that can be activated and marshaled against the progressing tumor. Two assumptions are necessary to complete this argument. The first assumption is that tolerance to self-antigen is incomplete. Antigens presented by thymic antigen-presenting cells (APC) cause the clonal deletion of autoreactive T cells (central tolerance), whereas the response to peripherally expressed antigens with no access to the thymus varies from physical elimination or functional anergy to complete “ignorance” (peripheral tolerance). If self-antigens induce tolerance by causing the functional or physical elimination of all autoreactive T cells, self-antigens could not be tumor antigens, let alone tumor rejection antigens. This, however, does not appear to be the case. As a rule, tolerogenic responses are limited to the inactivation of high-avidity but not low-avidity T cells. The threshold is determined by the properties of the APC and epitope density. Tolerogenic responses to self are calibrated to eliminate only the high-avidity T cells capable of reacting to physiologically relevant amounts of antigen presented by somatic cells. Thus, low-avidity autoreactive T cells, which are not capable of recognizing self-antigens under normal conditions, persist in the circulation. The presence of such low-avidity anti-self T cells has been amply documented in animal studies (49Poindexter N.J Landon C Whiteley P.J Kapp J.A Comparison of the T cell receptors on insulin-specific hybridomas from insulin transgenic and nontransgenic mice.J. Immunol. 1992; 149: 38-44PubMed Google Scholar, 9Cibotti R Cabaniols J.P Pannetier C Delarbre C Vergnon I Kanellopoulos J.M Kourilsky P Public and private Vβ T cell receptor repertoires against hen egg white lysozyme (HEL) in non-transgenic versus HEL transgenic mice.J. Exp. Med. 1994; 180: 861-872Crossref PubMed Scopus (171) Google Scholar, 45Oehen S.U Ohashi P.S Burki K Hengartner H Zinkernagel R.M Aichele P Escape of thymocytes and mature T cells from clonal deletion due to limiting tolerogen expression levels.Cell. Immunol. 1994; 158: 342-352Crossref PubMed Scopus (53) Google Scholar, 74von Herrath M.G Dockter J Oldstone M.B.A How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model.Immunity. 1994; 1: 231-242Abstract Full Text PDF PubMed Scopus (285) Google Scholar, 50Poplonski L Vukusic B Pawling J Clapoff S Roder J Hozumi N Wither J Tolerance is overcome in beef insulin-transgenic mice by activation of low-avidity autoreactive T cells.Eur. J. Immunol. 1996; 26: 601-609Crossref PubMed Scopus (36) Google Scholar, 40Morgan D.J Kreuwel H.T.C Fleck S Levitsky H.I Pardoll D.M Sherman L.A Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity.J. Immunol. 1998; 160: 643-651PubMed Google Scholar). It is therefore conceivable that a spectrum of autoreactive T cells are present in the mature T cell population, ranging from high-avidity T cells corresponding to antigens that have been completely “ignored” to very low-avidity T cells directed against antigens that have triggered effective tolerance. The second assumption, which constitutes the underlying rationale for using nonmutated self-antigens as tumor rejection antigens, is that through vaccination low-avidity anti-self T cells can be activated and marshaled to eradicate tumors. Conceivably, activation of such low-avidity T cells will be less efficient and more difficult to achieve than activation of high-avidity T cells, and hence the corresponding antigens will score as weak tumor rejection antigens. The key is the effectiveness of the vaccination protocol required to activate the low-avidity T cells in order to compensate for their relative weakness in recognizing their tumor targets. That low-avidity T cells corresponding to a self-transgene can be activated to impact on tumor growth has been demonstrated in the elegant studies by 40Morgan D.J Kreuwel H.T.C Fleck S Levitsky H.I Pardoll D.M Sherman L.A Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity.J. Immunol. 1998; 160: 643-651PubMed Google Scholar. The potency of a tumor rejection antigen is also dictated by the frequency of cognate T cells in the mature T cell population and, as suggested from viral models, the TCR diversity of the responding population (Busch et al., 1998; 11Cooper S Erickson A.L Adams E.J Kansopon J Weiner A.J Chien D.Y Houghton M Parham P Walker C.M Analysis of a successful immune response against hepatitis C virus.Immunity. 1999; 10: 439-449Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar). Conceivably, a high frequency of responding T cells can offset their low avidity, and their activation in the course of vaccination would elicit an effective antitumor response. Naturally, both frequency and diversity of the responding T cells will be reduced by tolerance. The overall implications are that mutated-self, tumor-specific antigens will make effective tumor rejection antigens, whereas shared tumor antigens corresponding to nonmutated tissue-spe cific gene products will make weak tumor rejection antigens. Fortunately, as will be discussed below, this is not as simple as that and there is a gray area that can be exploited for cancer vaccination. Guided by the principle that the potency of tumor rejection antigens is foremost a function of cognate T cell avidity, the current list of human tumor antigens was divided into four groups shown in Figure 1. Group I. Group I antigens represent tumor antigens that have arisen as a result of somatic mutations in normal gene products. The mutations in this group of antigens are incidental to the oncogenic process reflecting the genetic instability of tumor cells. Tumor antigens in this group will be therefore patient specific, not expected to trigger tolerance, and should make potent tumor rejection antigens. One caveat is that tumors could tolerize the immune system against antigens expressed on the tumor cells. In one study, tumor antigen–specific CD4+ T cell anergy was established in tumor-bearing mice (62Staveley-O'Carroll K Sotomayor E Montgomery J Borrello I Hwang L Fein S Pardoll D Levitsky H Induction of antigen-specific T cell anergy, an early event in the course of tumor progression.Proc. Natl. Acad. Sci. USA. 1998; 95: 1178-1183Crossref PubMed Scopus (583) Google Scholar), yet in other studies no impairment of tumor antigen–specific (CD8+) T cell responses was observed (76Wick M Dubey P Koeppen H Siegel C.T Fields P.E Chen L Bluestone J.A Schreiber H Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.J. Exp. Med. 1997; 186: 229-238Crossref PubMed Scopus (180) Google Scholar, 52Prevost-Blondel A Zimmermann C Stemmer C Kulmburg P Rosenthal F.M Pircher H Tumor-infiltrating lymphocytes exhibiting high ex vivo cytolytic activity fail to prevent murine melanoma tumor growth in vivo.J. Immunol. 1998; 161: 2187-2194PubMed Google Scholar, 44Ochsenbein A.F Klenerman P Karrer U Ludewig B Pericin M Hengartner H Zinkernagel R.M Immune surveillance against a solid tumor fails because of immunological ignorance.Proc. Natl. Acad. Sci. USA. 1999; 96: 2233-2238Crossref PubMed Scopus (390) Google Scholar). We have not seen evidence that in vitro stimulation of CTL against a “self” tumor-associated antigen, carcinoembryonic antigen (CEA), is significantly blunted in cancer patients as compared to healthy individuals (43Nair S.K Hull S Coleman D Gilboa E Lyerly H.K Morse M.A Induction of carcinoembryonic antigen (CEA)-specific CTL responses in vitro using autologous dendritic cells loaded with CEA peptide or CEA RNA in patients with metastatic malignancies expressing CEA.Int. J. Cancer. 1999; in pressGoogle Scholar). Thus, whether or to what extent progressing tumors impact negatively on tumor-specific immunity is yet unresolved, but it clearly merits more investigation. Unique tumor antigens recognized by CTL have been isolated from tumor-bearing mice and from cancer patients. Mut-1 was the first murine tumor antigen recognized by CTL isolated from the spontaneously induced Lewis lung carcinoma line (36Mandelboim O Berke G Fridkin M Feldman M Eisenstein M Eisenbach L CTL induction by a tumor-associated antigen octapeptide derived from a murine lung carcinoma.Nature. 1994; 369: 67-71Crossref PubMed Scopus (239) Google Scholar). The Mut-1 epitope was generated by a point mutation in the connexin 37 protein generating a novel H-2Kb-restricted epitope. Immunization of mice with Mut-1 peptide elicit CTL that recognize the tumor of origin and can lead to the regression of established metastases in tumor-bearing mice (37Mandelboim O Vadai E Fridkin M Katz-Hillel A Feldman M Berke G Eisenbach L Regression of established murine carcinoma metastases following vaccination with tumor-associated antigen peptides.Nat. Med. 1995; 11: 1179-1183Crossref Scopus (144) Google Scholar). Tumor antigens resulting from point mutations in normal gene products recognized by CTL from cancer patients have been also identified, although they represent a small fraction of the human tumor antigens isolated so far (6Boon T van der Bruggen P Human tumor antigens recognized by T lymphocytes.J. Exp. Med. 1996; 183: 725-729Crossref PubMed Scopus (766) Google Scholar, 56Rosenberg S.A A new era for cancer immunotherapy based on the genes that encode cancer antigens.Immunity. 1999; 10: 281-287Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar). Nevertheless, as will be discussed below, experimental bias in the methodology of isolating human tumor antigens may be responsible for underrepresentation of this group of antigens. Group II. Group II antigens correspond to tumor-specific antigens (antigens expressed in tumor cells but not in normal tissue), which nevertheless could be shared among cancer patients. This group of antigens is further subdivided into two subgroups. One subgroup consists of antigens that have arisen as a result of mutations related to the oncogenic process and hence are conceivably shared among some of the patients. For example, mutated or translocated oncogens could provide new epitopes and serve as tumor rejection antigens. Indeed, vaccination of mice with peptides spanning mutations in p53 or ras elicit CTL, but evidence that vaccination with mutated or translocated oncogens will provide effective tumor immunity is lacking (15Disis M.L Cheever M.A Oncogenic proteins as tumor antigens.Curr. Opin. Immunol. 1996; 8: 637-642Crossref PubMed Scopus (114) Google Scholar). This is not surprising, since the likelihood that a mutation will generate a potent epitope was estimated to be" @default.
• W2068862486 created "2016-06-24" @default.
• W2068862486 creator A5068892519 @default.
• W2068862486 date "1999-09-01" @default.
• W2068862486 modified "2023-10-15" @default.
• W2068862486 title "The Makings of a Tumor Rejection Antigen" @default.
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