- Email: [email protected]
DC-based cancer immunotherapy: the sequel
COMMENT I M M U N O L O G Y TO D AY
DC-based cancer immunotherapy: the sequel Previously, I reviewed studies on a promising new approach to cancer immunotherapy that was based on advances in our understanding of the immune response to tumours1. This indicated that, although cancer immunotherapy was popularly associated with the use of monoclonal antibodies to target tumours (Ômagic bulletsÕ), the most effective immune response for tumour clearance is the generation of cytotoxic T cells (CTLs)2,3. Thus, the major question for cancer immunotherapy was Ôhow can an effective antitumour CTL response be elicited?Õ. The surprisingly universal answer that emerged from several different studies was that this required the stimulation of T cells by a specific antigen-presenting cell Ð the dendritic cell (DC)1Ð4. These studies showed that this could be achieved by loading DCs with tumour antigens ex vivo using various methods, including simply fusing them to tumour cells1,3,5. The latter studies were particularly exciting as they showed effective responses not just against primary tumours but also against secondary metastases and, moreover, showed both CD41 and CD81 T-cell and natural killer-based antitumour responses1,5. However, three outstanding questions remained concerning the clinical use of DCbased cancer immunotherapy: First, did it work in humans and, especially, in cases where tumour-specific antigens had not been characterized? Second, would it work in cancers where the immune system appeared to be suppressed or otherwise ÔtolerizedÕ to the tumours? Third, would there be an autoimmune response to normal tissues as an associated complication? These questions have been answered by a number of studies6Ð9 and the time for DC-based cancer immunotherapy has arrived. The first question had in fact been partially answered by earlier human clinical studies that successfully treated B-cell lymphoma10 and prostate cancer11 using DCs pulsed with idiotypic protein and prostate-specific membrane antigen peptides, respectively. These studies have been extended by a clinical pilot
study on the treatment of melanoma patients with DCs pulsed with multiple melanomaspecific antigen peptides and with tumour lysates derived from biopsy material6. The successful use of uncharacterized tumour lysate to load DCs with tumour-specific antigens showed that defined tumour antigens were not required and suggests that DC-based cancer immunotherapy8 should be applicable in most types of cancer where biopsy material is available. Interestingly, the trials using tumour lysates to load DCs with tumour antigens showed a higher success rate, albeit with limited patient numbers6. This would be consistent with the presentation of several tumour antigens on both major histocompatibility complex (MHC) class I and class II molecules, allowing stimulation of both CD81 and CD41 effector T cells1,6. The second question is essentially posed by the conventional viewpoint that tumour growth requires evasion of the Ôimmune surveillanceÕ that normally deals with cells that develop potentially neoplastic mutations12; although this view might be incorrect. It is generally accepted that a good tumour model for Ôimmunological unresponsivenessÕ is the induction of immunity against the human MUC1 carcinoma antigen in MUC1 transgenic mice13. Even when immunized with irradiated MUC11 tumour cells, these transgenic mice are unresponsive to MUC1 (Refs 7, 13); however, immunization with fusion hybrids of DCs and MUC11 tumour cells induced a potent immune response against MUC1 (Ref. 7). Interestingly, from a therapeutic standpoint, immunization with the fusions resulted in rejection of established metastases7. This reversal of ÔtoleranceÕ to MUC1 by the use of antigenloaded DCs is supported by the demonstration of MUC1-specific immune responses in chimpanzees immunized with DCs loaded with a MUC1-derived peptide8. However, perhaps the most surprising feature of these studies was the lack of an autoimmune response against normal tissues in mice immunized with the DCÐtumour cell fusions7. This lack of autoimmune response to normal tissues in animals immunized with DCÐtumour fusion hybrids5,7 is consistent with the similar lack of autoimmune complications in all the DC-based cancer immunotherapy studies reported to date5Ð11
and answers the third outstanding question. Although this lack of an autoimmune response might appear surprising considering the dogma that the immune system is designed to distinguish ÔselfÕ from ÔnonselfÕ, it is entirely consistent with the paradigms of Ôinnate immunityÕ14 and the Ôdanger modelÕ15. Both these paradigms suggest that the immune system makes a Ôvalue judgementÕ of what is ÔdangerousÕ, be it self or nonself, and give cells of the DC lineage a central role in the recognition of Ôdangerous self and nonselfÕ16. This central role for DCs would explain the promising clinical trials using DCbased cancer immunotherapy and poses an interesting question of if/how tumour antigens can be recognized as ÔdangerousÕ by DCs in the normal functioning of the immune system. One possibility, suggested by the use of tumour stress proteins as cancer vaccines in animal models1,3,16, is that cells of the DC/macrophage lineage take up, process and present stress protein-chaperoned tumour antigens and thus elicit effective CTL responses3,17,18. This suggestion is supported by studies showing that the immunogenicity of tumour cell lines is directly related to their expression and release of the stress protein, heat shock protein 70 (Hsp70)9. As it is unlikely that tumours would produce and release stress proteins (unless subjected to radiation or chemotherapeutic stress), it is tempting to suggest that, contrary to the conventional dogma of immune surveillance, the immune system might actually be ÔblindÕ to tumours. This is entirely consistent with the extremely high incidence of cancer as a disease and reinforces the importance of investigating the applicability of DC-based cancer immunotherapy. Camilo A.L.S. Colaco Quadrant Healthcare, Maris Lane, Cambridge, UK CB2 2SY. References 01 Hart, I. and Colaco, C. (1997) Nature 388, 627Ð628 02 Lanzavecchia, A. (1993) Science 260, 937Ð944 03 Pardoll, D. (1998) Nat. Med. 4, 525Ð531 04 Young, J.W. and Inaba, K. (1996) J. Exp. Med. 183, 7Ð11 05 Gong, J., Chen, D., Kashiwaba, M. and Kufe, D. (1997) Nat. Med. 3, 558Ð561
A P R I L Vo l . 2 0
1 9 9 9 No.4
197
COMMENT I M M U N O L O G Y T O D AY
06 Nestle, F.O., Alijagic, S., Gilliet, M. et al.
10 Hsu, F.J., Benike, C., Fagnoni, F. et al. (1996)
(1998) Nat. Med. 4, 328Ð332
Nat. Med. 2, 52Ð58
07 Gong, J., Chen, D., Kashiwaba, M. et al. (1998)
11 Murphy, G., Tjoa, B., Ragde, H., Kenny, G.
Proc. Natl. Acad. Sci. U. S. A. 95, 6279Ð6283 08 Barratt-Boyes, S.M., Kao, H. and Finn, O.J.
and Boynton, A. (1996) Prostate 29, 371Ð380 12 Burnet, F.M. (1970) Prog. Exp. Tumour Res. 13,
(1998) J. Immunother. 21, 42Ð48
1Ð27
09 Melcher, A. Todryk, S., Hardwick, N., Ford,
13 Rowse, G.J., Tempero, R.M., VanLith, M.L.,
M., Jacobson, M. and Vile, R.G. (1998) Nat.
Hollingsworth, M.A. and Gendler, S.J. (1998)
Med. 4, 581Ð587
Cancer Res. 58, 315Ð321
14 Janeway, C.A. (1992) Immunol. Today 13, 11Ð15 15 Matzinger, P. (1994) Annu. Rev. Immunol. 12, 991Ð1045 16 Colaco, C. (1998) Immunol. Today 19, 50 17 Tamura, Y., Peng, P., Liu, K., Daou, M. and Srivastava, P.K. (1997) Science 278, 117Ð120 18 Suto, R. and Srivastava, P.K. (1995) Science 269, 1585Ð1588
book review When Cells Die: A Comprehensive Evaluation of Apoptosis and Programmed Cell Death
ISBN 0 471 16569 7
edited by R.A. Lockshin, Z. Zakeri and J.L. Tilly, Wiley-Liss, 1998. £70.00 (ix 1 504 pages)
It is now clear that apoptosis and programmed cell death are major players in organism development and homeostasis. In addition, there is evidence indicating that the cellular programmes controlling apoptosis are deregulated in many diseases and, in some of them, this is the principal effector mechanism. The past years have seen a tremendous explosion in the number of published studies focusing on apoptosis and programmed cell death, however, our understanding of apoptosis is still incomplete. It is conceivable that the identification of the intracellular pathways implicated in this process will increase our understanding of the growing list of diseases that involve apoptosis, and will offer hope for the development of innovative therapies. When Cells Die attempts to convey the excitement and breadth of the field, providing a framework for interpreting many of the
studies that are currently being published. Inevitably in a multiauthored book, there are some variations in the level of detail and depth of discussion. The book starts with two very comprehensive sections that review the evolutionary origin of apoptosis and the basic machinery involved in triggering the process of apoptotic cell death but, despite discussing important questions and providing original interpretations of experimental data, the result is often too speculative and could have been made clearer, particularly for readers outside the field. The most intriguing sections of the book discuss the regulation of immune responses by apoptosis and the role of apoptosis in AIDS, autoimmunity, AlzheimerÕs disease and other neurodegenerative disorders Ð I found these chapters excellent and of outstanding interest. Overall, the book is well referenced and indexed, and contains several useful diagrams and flowcharts. Despite its five-section layout, the book has a certain degree of duplication of information, mostly in the description of the basic mechanisms of apoptosis and the intracellular transducers of apoptotic signals, although this could help readers outside the field to better understand this complex process (repetita iuvant). In summary, keeping this criticism in mind, When Cells Die is impressively documented and provides a valuable update in a rapidly evolving field. I believe that this book has the potential to attract clinicians, in addition to researchers in the field, since it would help them to face new challenges that will probably open revolutionary therapeutic strategies for a wide spectrum of diseases.
0167-5699/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.
A P R I L 198
1 9 9 9 Vo l . 2 0
No.4
Would I purchase When Cells Die? The answer is a qualified yes. Giuseppe Famularo Dept of Experimental Medicine, LÕAquila and San Camillo Hospital, Rome, Italy.
Diary If you would like your conference or course to be included in our comprehensive Diary section, send details to the Editorial Office at: Elsevier Trends Journals, 68 Hills Road, Cambridge, UK CB2 1LA. Tel: 144 1223 311114 • Fax: 144 1223 321410 E-mail: [email protected] If you let us know, then we’ll spread the news.
DC-based cancer immunotherapy: the sequel Previously, I reviewed studies on a promising new approach to cancer immunotherapy that was based on advances in our understanding of the immune response to tumours1. This indicated that, although cancer immunotherapy was popularly associated with the use of monoclonal antibodies to target tumours (Ômagic bulletsÕ), the most effective immune response for tumour clearance is the generation of cytotoxic T cells (CTLs)2,3. Thus, the major question for cancer immunotherapy was Ôhow can an effective antitumour CTL response be elicited?Õ. The surprisingly universal answer that emerged from several different studies was that this required the stimulation of T cells by a specific antigen-presenting cell Ð the dendritic cell (DC)1Ð4. These studies showed that this could be achieved by loading DCs with tumour antigens ex vivo using various methods, including simply fusing them to tumour cells1,3,5. The latter studies were particularly exciting as they showed effective responses not just against primary tumours but also against secondary metastases and, moreover, showed both CD41 and CD81 T-cell and natural killer-based antitumour responses1,5. However, three outstanding questions remained concerning the clinical use of DCbased cancer immunotherapy: First, did it work in humans and, especially, in cases where tumour-specific antigens had not been characterized? Second, would it work in cancers where the immune system appeared to be suppressed or otherwise ÔtolerizedÕ to the tumours? Third, would there be an autoimmune response to normal tissues as an associated complication? These questions have been answered by a number of studies6Ð9 and the time for DC-based cancer immunotherapy has arrived. The first question had in fact been partially answered by earlier human clinical studies that successfully treated B-cell lymphoma10 and prostate cancer11 using DCs pulsed with idiotypic protein and prostate-specific membrane antigen peptides, respectively. These studies have been extended by a clinical pilot
study on the treatment of melanoma patients with DCs pulsed with multiple melanomaspecific antigen peptides and with tumour lysates derived from biopsy material6. The successful use of uncharacterized tumour lysate to load DCs with tumour-specific antigens showed that defined tumour antigens were not required and suggests that DC-based cancer immunotherapy8 should be applicable in most types of cancer where biopsy material is available. Interestingly, the trials using tumour lysates to load DCs with tumour antigens showed a higher success rate, albeit with limited patient numbers6. This would be consistent with the presentation of several tumour antigens on both major histocompatibility complex (MHC) class I and class II molecules, allowing stimulation of both CD81 and CD41 effector T cells1,6. The second question is essentially posed by the conventional viewpoint that tumour growth requires evasion of the Ôimmune surveillanceÕ that normally deals with cells that develop potentially neoplastic mutations12; although this view might be incorrect. It is generally accepted that a good tumour model for Ôimmunological unresponsivenessÕ is the induction of immunity against the human MUC1 carcinoma antigen in MUC1 transgenic mice13. Even when immunized with irradiated MUC11 tumour cells, these transgenic mice are unresponsive to MUC1 (Refs 7, 13); however, immunization with fusion hybrids of DCs and MUC11 tumour cells induced a potent immune response against MUC1 (Ref. 7). Interestingly, from a therapeutic standpoint, immunization with the fusions resulted in rejection of established metastases7. This reversal of ÔtoleranceÕ to MUC1 by the use of antigenloaded DCs is supported by the demonstration of MUC1-specific immune responses in chimpanzees immunized with DCs loaded with a MUC1-derived peptide8. However, perhaps the most surprising feature of these studies was the lack of an autoimmune response against normal tissues in mice immunized with the DCÐtumour cell fusions7. This lack of autoimmune response to normal tissues in animals immunized with DCÐtumour fusion hybrids5,7 is consistent with the similar lack of autoimmune complications in all the DC-based cancer immunotherapy studies reported to date5Ð11
and answers the third outstanding question. Although this lack of an autoimmune response might appear surprising considering the dogma that the immune system is designed to distinguish ÔselfÕ from ÔnonselfÕ, it is entirely consistent with the paradigms of Ôinnate immunityÕ14 and the Ôdanger modelÕ15. Both these paradigms suggest that the immune system makes a Ôvalue judgementÕ of what is ÔdangerousÕ, be it self or nonself, and give cells of the DC lineage a central role in the recognition of Ôdangerous self and nonselfÕ16. This central role for DCs would explain the promising clinical trials using DCbased cancer immunotherapy and poses an interesting question of if/how tumour antigens can be recognized as ÔdangerousÕ by DCs in the normal functioning of the immune system. One possibility, suggested by the use of tumour stress proteins as cancer vaccines in animal models1,3,16, is that cells of the DC/macrophage lineage take up, process and present stress protein-chaperoned tumour antigens and thus elicit effective CTL responses3,17,18. This suggestion is supported by studies showing that the immunogenicity of tumour cell lines is directly related to their expression and release of the stress protein, heat shock protein 70 (Hsp70)9. As it is unlikely that tumours would produce and release stress proteins (unless subjected to radiation or chemotherapeutic stress), it is tempting to suggest that, contrary to the conventional dogma of immune surveillance, the immune system might actually be ÔblindÕ to tumours. This is entirely consistent with the extremely high incidence of cancer as a disease and reinforces the importance of investigating the applicability of DC-based cancer immunotherapy. Camilo A.L.S. Colaco Quadrant Healthcare, Maris Lane, Cambridge, UK CB2 2SY. References 01 Hart, I. and Colaco, C. (1997) Nature 388, 627Ð628 02 Lanzavecchia, A. (1993) Science 260, 937Ð944 03 Pardoll, D. (1998) Nat. Med. 4, 525Ð531 04 Young, J.W. and Inaba, K. (1996) J. Exp. Med. 183, 7Ð11 05 Gong, J., Chen, D., Kashiwaba, M. and Kufe, D. (1997) Nat. Med. 3, 558Ð561
A P R I L Vo l . 2 0
1 9 9 9 No.4
197
COMMENT I M M U N O L O G Y T O D AY
06 Nestle, F.O., Alijagic, S., Gilliet, M. et al.
10 Hsu, F.J., Benike, C., Fagnoni, F. et al. (1996)
(1998) Nat. Med. 4, 328Ð332
Nat. Med. 2, 52Ð58
07 Gong, J., Chen, D., Kashiwaba, M. et al. (1998)
11 Murphy, G., Tjoa, B., Ragde, H., Kenny, G.
Proc. Natl. Acad. Sci. U. S. A. 95, 6279Ð6283 08 Barratt-Boyes, S.M., Kao, H. and Finn, O.J.
and Boynton, A. (1996) Prostate 29, 371Ð380 12 Burnet, F.M. (1970) Prog. Exp. Tumour Res. 13,
(1998) J. Immunother. 21, 42Ð48
1Ð27
09 Melcher, A. Todryk, S., Hardwick, N., Ford,
13 Rowse, G.J., Tempero, R.M., VanLith, M.L.,
M., Jacobson, M. and Vile, R.G. (1998) Nat.
Hollingsworth, M.A. and Gendler, S.J. (1998)
Med. 4, 581Ð587
Cancer Res. 58, 315Ð321
14 Janeway, C.A. (1992) Immunol. Today 13, 11Ð15 15 Matzinger, P. (1994) Annu. Rev. Immunol. 12, 991Ð1045 16 Colaco, C. (1998) Immunol. Today 19, 50 17 Tamura, Y., Peng, P., Liu, K., Daou, M. and Srivastava, P.K. (1997) Science 278, 117Ð120 18 Suto, R. and Srivastava, P.K. (1995) Science 269, 1585Ð1588
book review When Cells Die: A Comprehensive Evaluation of Apoptosis and Programmed Cell Death
ISBN 0 471 16569 7
edited by R.A. Lockshin, Z. Zakeri and J.L. Tilly, Wiley-Liss, 1998. £70.00 (ix 1 504 pages)
It is now clear that apoptosis and programmed cell death are major players in organism development and homeostasis. In addition, there is evidence indicating that the cellular programmes controlling apoptosis are deregulated in many diseases and, in some of them, this is the principal effector mechanism. The past years have seen a tremendous explosion in the number of published studies focusing on apoptosis and programmed cell death, however, our understanding of apoptosis is still incomplete. It is conceivable that the identification of the intracellular pathways implicated in this process will increase our understanding of the growing list of diseases that involve apoptosis, and will offer hope for the development of innovative therapies. When Cells Die attempts to convey the excitement and breadth of the field, providing a framework for interpreting many of the
studies that are currently being published. Inevitably in a multiauthored book, there are some variations in the level of detail and depth of discussion. The book starts with two very comprehensive sections that review the evolutionary origin of apoptosis and the basic machinery involved in triggering the process of apoptotic cell death but, despite discussing important questions and providing original interpretations of experimental data, the result is often too speculative and could have been made clearer, particularly for readers outside the field. The most intriguing sections of the book discuss the regulation of immune responses by apoptosis and the role of apoptosis in AIDS, autoimmunity, AlzheimerÕs disease and other neurodegenerative disorders Ð I found these chapters excellent and of outstanding interest. Overall, the book is well referenced and indexed, and contains several useful diagrams and flowcharts. Despite its five-section layout, the book has a certain degree of duplication of information, mostly in the description of the basic mechanisms of apoptosis and the intracellular transducers of apoptotic signals, although this could help readers outside the field to better understand this complex process (repetita iuvant). In summary, keeping this criticism in mind, When Cells Die is impressively documented and provides a valuable update in a rapidly evolving field. I believe that this book has the potential to attract clinicians, in addition to researchers in the field, since it would help them to face new challenges that will probably open revolutionary therapeutic strategies for a wide spectrum of diseases.
0167-5699/99/$ – see front matter © 1999 Elsevier Science. All rights reserved.
A P R I L 198
1 9 9 9 Vo l . 2 0
No.4
Would I purchase When Cells Die? The answer is a qualified yes. Giuseppe Famularo Dept of Experimental Medicine, LÕAquila and San Camillo Hospital, Rome, Italy.
Diary If you would like your conference or course to be included in our comprehensive Diary section, send details to the Editorial Office at: Elsevier Trends Journals, 68 Hills Road, Cambridge, UK CB2 1LA. Tel: 144 1223 311114 • Fax: 144 1223 321410 E-mail: [email protected] If you let us know, then we’ll spread the news.