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Tumour immunology
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Tumour immunology Editorial overview Thierry Boon and Benoit Van den Eynde Current Opinion in Immunology 2003, 15:129–130 This review comes from a themed issue on Tumour immunology Edited by Thierry Boon and Benoit Van den Eynde 0952-7915/03/$ – see front matter ß 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0952-7915(03)00010-4
Thierry Boon and Benoit Van den Eyndey Ludwig Institute for Cancer Research and Cellular Genetics Unit, Universite´ de Louvain, Brussels, Belgium e-mail: [email protected] y e-mail: [email protected]
Thierry Boon and Benoit Van den Eynde are involved in the identification of tumour antigens recognised by T cells and in the use of such antigens for cancer immunotherapy.
Following the identification of tumour-specific antigens recognised on human tumours by autologous T lymphocytes, a large number of smallscale therapeutic vaccination trials have been carried out. Many of these trials have concentrated on the therapeutic vaccination of melanoma patients, using as vaccine either antigens encoded by cancer germline genes or melanocytic differentiation antigens. Several antigen modalities have been used, such as antigenic peptides and proteins (with and without adjuvant), recombinant viruses bearing antigen-coding sequences and dendritic cells pulsed with peptides. These clinical studies have fully confirmed the expectation that these vaccinations would not cause serious side-effects. The regression of relatively large tumour masses has been observed in some patients, indicating the potential of such vaccinations even in the face of a large tumour burden. However, regression occurs only in a minority of the treated patients. Why do most vaccinated patients fail to show tumour regression after vaccination? One possibility is that the vaccination has failed to elicit a T-cell response that is adequate, either quantitatively or functionally. Another possibility, not mutually exclusive with the first, is that a number of tumours and their stroma have features that hamper or even completely prevent the action of T lymphocytes. Such features might include the impaired permeability of tumour microvessels to T lymphocytes, defective antigen-presentation mechanisms in the tumour cells, or the secretion of T-cell inhibitory factors, such as TGF-b, by the tumour. For the comparison of different antigens and vaccination modalities, it is reasonable to focus on the evaluation of the quality of T-cell response elicited by the vaccine. This, however, is a very difficult problem. At present we do not know what the quantitative and functional requirements which enable a T-cell response to produce tumour regression are. It would be very convenient to have easy ‘surrogate endpoints’ that predict clinical success, such as the presence of antibodies, which is used to evaluate vaccines against viruses or bacteria. But the choice of appropriate surrogate endpoints requires compelling evidence that they accurately predict clinical efficacy. So we have no alternative but to start with our initial hypothesis: the vaccine elicits a T-cell response and these T cells initiate, and possibly carry through, a tumour rejection process. Therefore, we should evaluate this T-cell response as well as we can, until we observe that some aspect of it — either quantitative or functional — correlates with clinical success. Coulie and van der Bruggen [1] review the evaluation of T-cell responses in vaccinated cancer patients. It is clear that T-cell responses against vaccine
www.current-opinion.com
Current Opinion in Immunology 2003, 15:129–130
130 Tumour immunology
antigens are observed in a number of patients, although as yet there is no solid evidence for the correlation of clinical and T-cell responses. The approaches are constantly being improved, however, and such a correlation may soon emerge. Among the most interesting attempts to improve the efficacy of anti-cancer vaccinations are those that involve dendritic cells. There is now a very large body of evidence to suggest that dendritic cells play a crucial role in the generation of T-cell responses. At the same time, the field is extremely complex: many different types of dendritic cells have been reported; some seem to immunise whereas others appear to tolerize. Schuler, SchulerThurner and Steinman [2] provide a very thorough review of the dendritic cell vaccination effort. There is no doubt that strong T-cell responses have been observed in some patients vaccinated with dendritic cells. It is perhaps worth mentioning here a point of logic: a crucial physiological role of dendritic cells in spontaneous immunisations does not necessarily imply that vaccination with antigen-pulsed or gene-pulsed dendritic cells will be superior to other vaccination modalities. Equally, if some other modality proved equal or superior, this would in no way question the role of dendritic cells in immune physiology. With respect to the current efforts to elicit tumour regression by T cells, it is important to realise that the antivaccine T cells might only initiate the immune process leading to regression. Epitope spreading might occur after a minor attack of the tumour by the anti-vaccine T cells, and a second wave of more effective T cells could thus be generated. Other immune effectors might intervene and processes other than the direct killing of tumour cells could operate. Blankenstein and Qin [3] review the effect of IFN-g in tumour transplantation immunity and inhibition of chemical carcinogenesis, and describe the remarkable anti-angiogenic effect of IFN-g as well as its ability to induce a collagen shell. Both processes might be very important for tumour destruction and containment. In the past, the prospects of therapeutic vaccination against cancer have often been linked to the existence of T-cell based immunosurveillance. For a good reason: both were thought to depend on the presence of tumour rejection antigens on human tumours. This conceptual alliance is now obsolete as the presence of tumour-specific antigens on most if not all human tumours is now safely demonstrated. For the therapeutic vaccination
Current Opinion in Immunology 2003, 15:129–130
effort that is now in progress it is far from clear whether the previous occurrence of a partly effective immunosurveillance process against the tumour that is being treated increases or decreases the chances of success. On the one hand, the immunosurveillance process, which failed to eliminate the tumour completely, might have selected immunoresistant tumour variants or might have induced the lymphocytes directed against the tumour antigens into a state of anergy. On the other hand, it may well be that in those patients in which anti-cancer vaccination produces tumour regression, the elimination of the tumour is achieved mainly by a pre-existing pool of anti-tumoural T lymphocytes that has been re-awakened following a minor attack on the tumour by T cells elicited by the vaccine. A clear indication of the in vivo efficacy of anti-tumour T cells has emerged from recent clinical studies of adoptive transfer [4–6]. These studies demonstrated the in vivo persistence of transferred T cells, their preferential localisation to tumour sites and their clinical efficacy. In a study involving melanocytic differentiation antigens, tumour regressions were associated with signs of autoimmune destruction of melanocytes, including not only vitiligo but also uveitis [5]. These results confirm the capability of T cells to induce tumour regression and argue in favour of selecting tumour antigens that have a high degree of tumour specificity.
References 1.
Coulie PG, van der Bruggen P: T-cell responses of vaccinated cancer patients. Curr Opin Immunol 2003, 15: in press.
2.
Schuler G, Schuler-Thurner B, Steinman RM: Use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003, 15: in press.
3.
Blankenstein T, Qin Z: The role of IFN-c in tumour transplantation immunity and inhibition of chemical carcinogenesis. Curr Opin Immunol 2003, 15: in press.
4.
Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD: Adoptive T cell therapy using antigen-specific CD8þ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 2002, 99:16168-16173.
5.
Dudley ME, Wunderlich J, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM et al.: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002, 298:850-854.
6.
Dre´ no B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S, Cassidanus A, Lemarre P, Billaudel S, Labarrie`re N et al.: Randomized trial of adoptive transfer of melanoma tumour-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother 2002, 51:539-546.
www.current-opinion.com
Tumour immunology Editorial overview Thierry Boon and Benoit Van den Eynde Current Opinion in Immunology 2003, 15:129–130 This review comes from a themed issue on Tumour immunology Edited by Thierry Boon and Benoit Van den Eynde 0952-7915/03/$ – see front matter ß 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0952-7915(03)00010-4
Thierry Boon and Benoit Van den Eyndey Ludwig Institute for Cancer Research and Cellular Genetics Unit, Universite´ de Louvain, Brussels, Belgium e-mail: [email protected] y e-mail: [email protected]
Thierry Boon and Benoit Van den Eynde are involved in the identification of tumour antigens recognised by T cells and in the use of such antigens for cancer immunotherapy.
Following the identification of tumour-specific antigens recognised on human tumours by autologous T lymphocytes, a large number of smallscale therapeutic vaccination trials have been carried out. Many of these trials have concentrated on the therapeutic vaccination of melanoma patients, using as vaccine either antigens encoded by cancer germline genes or melanocytic differentiation antigens. Several antigen modalities have been used, such as antigenic peptides and proteins (with and without adjuvant), recombinant viruses bearing antigen-coding sequences and dendritic cells pulsed with peptides. These clinical studies have fully confirmed the expectation that these vaccinations would not cause serious side-effects. The regression of relatively large tumour masses has been observed in some patients, indicating the potential of such vaccinations even in the face of a large tumour burden. However, regression occurs only in a minority of the treated patients. Why do most vaccinated patients fail to show tumour regression after vaccination? One possibility is that the vaccination has failed to elicit a T-cell response that is adequate, either quantitatively or functionally. Another possibility, not mutually exclusive with the first, is that a number of tumours and their stroma have features that hamper or even completely prevent the action of T lymphocytes. Such features might include the impaired permeability of tumour microvessels to T lymphocytes, defective antigen-presentation mechanisms in the tumour cells, or the secretion of T-cell inhibitory factors, such as TGF-b, by the tumour. For the comparison of different antigens and vaccination modalities, it is reasonable to focus on the evaluation of the quality of T-cell response elicited by the vaccine. This, however, is a very difficult problem. At present we do not know what the quantitative and functional requirements which enable a T-cell response to produce tumour regression are. It would be very convenient to have easy ‘surrogate endpoints’ that predict clinical success, such as the presence of antibodies, which is used to evaluate vaccines against viruses or bacteria. But the choice of appropriate surrogate endpoints requires compelling evidence that they accurately predict clinical efficacy. So we have no alternative but to start with our initial hypothesis: the vaccine elicits a T-cell response and these T cells initiate, and possibly carry through, a tumour rejection process. Therefore, we should evaluate this T-cell response as well as we can, until we observe that some aspect of it — either quantitative or functional — correlates with clinical success. Coulie and van der Bruggen [1] review the evaluation of T-cell responses in vaccinated cancer patients. It is clear that T-cell responses against vaccine
www.current-opinion.com
Current Opinion in Immunology 2003, 15:129–130
130 Tumour immunology
antigens are observed in a number of patients, although as yet there is no solid evidence for the correlation of clinical and T-cell responses. The approaches are constantly being improved, however, and such a correlation may soon emerge. Among the most interesting attempts to improve the efficacy of anti-cancer vaccinations are those that involve dendritic cells. There is now a very large body of evidence to suggest that dendritic cells play a crucial role in the generation of T-cell responses. At the same time, the field is extremely complex: many different types of dendritic cells have been reported; some seem to immunise whereas others appear to tolerize. Schuler, SchulerThurner and Steinman [2] provide a very thorough review of the dendritic cell vaccination effort. There is no doubt that strong T-cell responses have been observed in some patients vaccinated with dendritic cells. It is perhaps worth mentioning here a point of logic: a crucial physiological role of dendritic cells in spontaneous immunisations does not necessarily imply that vaccination with antigen-pulsed or gene-pulsed dendritic cells will be superior to other vaccination modalities. Equally, if some other modality proved equal or superior, this would in no way question the role of dendritic cells in immune physiology. With respect to the current efforts to elicit tumour regression by T cells, it is important to realise that the antivaccine T cells might only initiate the immune process leading to regression. Epitope spreading might occur after a minor attack of the tumour by the anti-vaccine T cells, and a second wave of more effective T cells could thus be generated. Other immune effectors might intervene and processes other than the direct killing of tumour cells could operate. Blankenstein and Qin [3] review the effect of IFN-g in tumour transplantation immunity and inhibition of chemical carcinogenesis, and describe the remarkable anti-angiogenic effect of IFN-g as well as its ability to induce a collagen shell. Both processes might be very important for tumour destruction and containment. In the past, the prospects of therapeutic vaccination against cancer have often been linked to the existence of T-cell based immunosurveillance. For a good reason: both were thought to depend on the presence of tumour rejection antigens on human tumours. This conceptual alliance is now obsolete as the presence of tumour-specific antigens on most if not all human tumours is now safely demonstrated. For the therapeutic vaccination
Current Opinion in Immunology 2003, 15:129–130
effort that is now in progress it is far from clear whether the previous occurrence of a partly effective immunosurveillance process against the tumour that is being treated increases or decreases the chances of success. On the one hand, the immunosurveillance process, which failed to eliminate the tumour completely, might have selected immunoresistant tumour variants or might have induced the lymphocytes directed against the tumour antigens into a state of anergy. On the other hand, it may well be that in those patients in which anti-cancer vaccination produces tumour regression, the elimination of the tumour is achieved mainly by a pre-existing pool of anti-tumoural T lymphocytes that has been re-awakened following a minor attack on the tumour by T cells elicited by the vaccine. A clear indication of the in vivo efficacy of anti-tumour T cells has emerged from recent clinical studies of adoptive transfer [4–6]. These studies demonstrated the in vivo persistence of transferred T cells, their preferential localisation to tumour sites and their clinical efficacy. In a study involving melanocytic differentiation antigens, tumour regressions were associated with signs of autoimmune destruction of melanocytes, including not only vitiligo but also uveitis [5]. These results confirm the capability of T cells to induce tumour regression and argue in favour of selecting tumour antigens that have a high degree of tumour specificity.
References 1.
Coulie PG, van der Bruggen P: T-cell responses of vaccinated cancer patients. Curr Opin Immunol 2003, 15: in press.
2.
Schuler G, Schuler-Thurner B, Steinman RM: Use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003, 15: in press.
3.
Blankenstein T, Qin Z: The role of IFN-c in tumour transplantation immunity and inhibition of chemical carcinogenesis. Curr Opin Immunol 2003, 15: in press.
4.
Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD: Adoptive T cell therapy using antigen-specific CD8þ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 2002, 99:16168-16173.
5.
Dudley ME, Wunderlich J, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM et al.: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002, 298:850-854.
6.
Dre´ no B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S, Cassidanus A, Lemarre P, Billaudel S, Labarrie`re N et al.: Randomized trial of adoptive transfer of melanoma tumour-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother 2002, 51:539-546.
www.current-opinion.com