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Progress in human tumour immunology and immunotherapy

Nature volume 411, pages 380–384 (2001)Cite this article

Abstract

Studies of the administration of interleukin-2 to patients with metastatic melanoma or kidney cancer have shown that immunological manipulations can mediate the durable regression of metastatic cancer. The molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with anti-tumour activity can be raised in cancer-bearing patients. Highly avid anti-tumour lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies. Current studies are aimed at understanding the mechanisms that enable the cancer to escape from immune attack.

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Figure 1: Complete regression of a large liver metastasis from kidney cancer in a patient treated with IL-2.

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References

  1. Hewitt, H. B., Blake, E. R. & Walder, A. S. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br. J. Cancer 33, 241(1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Woglom, W. H. Immunity to transplantable tumors. Cancer Res. 4, 129(1929).

    Google Scholar 

  3. Rosenberg, S. A. (ed.) Principles and Practice of the Biologic Therapy of Cancer (Lippincott, Philadelphia, 2000).

    Google Scholar 

  4. Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).

    Article  CAS  PubMed  Google Scholar 

  5. Rosenberg, S. A., Yang, J. C., White, D. E. & Steinberg, S. M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2. Ann. Surg. 228, 307–319 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fyfe, G. et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high dose proleukin interleukin-2 therapy. J. Clin. Oncol. 13, 688–696 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Atkins, M. B. et al. High-dose recombinant interleukin-2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Rosenberg, S. A. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10, 281–287 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Boon, T., Coulie, P. G. & Van den Eynde B. Tumor antigens recognized by T cells. Immunol. Today 18, 267–268 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Hunt, D. F. et al. Characterization of peptides bound to the Class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255, 1261–1263 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Cox, A. L. et al. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 264, 716–719 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Kawashima, I., Hudson, S. J. & Tsai, V. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. Hum. Immunol. 59, 1–14 (1989).

    Article  Google Scholar 

  13. Chen, Y. T., Scanlan, M. J. & Sahin, U. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc. Natl Acad. Sci. USA 94, 1914–1918 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, R. -F., Wang, X., Atwood, A. L., Topalian, S. L. & Rosenberg, S. A. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. Science 284, 1351–1354 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Lowy, D. R. & Schiller, J. T. in Cancer Principles & Practice of Oncology 6th edn (eds DeVita, V. T., Hellman, S. & Rosenberg, S. A.) 3189–3195 (Lippincott, Philadelphia, 2001).

    Google Scholar 

  16. Stoler, D. L. et al. The onset and extend of genomic instability in sporadic colorectal tumor progression. Proc. Natl Acad. Sci. USA 26, 15121–15126 (1999).

    Article  ADS  Google Scholar 

  17. Landsteiner, K. & Chase, M. W. Experiments on transfer of cutaneous sensitivity to simple compounds. Proc. Soc. Exp. Biol. Med. 49, 688 (1942).

  18. Klein, E. & Sjogren, H. O. Humoral and cellular factors in homograft and isograft immunity. Cancer Res. 20, 452 (1960).

  19. Old, L. J., Boyse, E. A. & Clarke, D. A. Antigenic properties of chemically induced tumors. Ann. NY Acad. Sci. 101, 80 (1962).

    Article  ADS  CAS  Google Scholar 

  20. Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and interleukin-2 or high dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Muul, L. M., Spiess, P. J., Director, E. P. & Rosenberg, S. A. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J. Immunol. 138, 989–995 (1987).

    CAS  PubMed  Google Scholar 

  22. Itoh, K., Platsoucas, D. C. & Balch, C. M. Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas: activation by interleukin 2 and autologous tumor cells and involvement of the T cell receptor. J. Exp. Med. 168, 1419–1441 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Rosenberg, S. A. et al. Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. Preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).

    Article  CAS  PubMed  Google Scholar 

  24. Rosenberg, S. A. et al. Treatment of patients with metastatic melanoma using autologous tumor-infiltrating lymphocytes and interleukin-2. J. Natl Cancer Inst. 86, 1159–1166 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Papadopoulos, E. B. et al. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 17, 1185–1191 (1994).

    Article  Google Scholar 

  26. Rosenberg, S. A. et al. Immunologic and therapeutic evaluation of a synthetic tumor associated peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med. 4, 321–327 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Walter, E. A. et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333, 1038–1044 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Yee, C., Gilbert, M. J. & Riddell, S. R. Isolation of tyrosinase-specific CD8+ and CD4+ T cell clones from the peripheral blood of melanoma patients following in vitro stimulation with recombinant vaccinia virus. J. Immunol. 157, 4079–4086 (1996).

    CAS  PubMed  Google Scholar 

  29. Dudley, M. E., Ngo, L. T., Westwood, J., Wunderlich, J. R. & Rosenberg, S. A. T cell clones from melanoma patients immunized against an anchor-modified gp100 peptide display discordant effector phenotypes. Cancer J. Sci. Am. 6, 69–77 (2000).

    CAS  Google Scholar 

  30. Rosenberg, S. A. Gene therapy for cancer. J. Am. Med. Assoc. 268, 2416–2419 (1992).

    Article  CAS  Google Scholar 

  31. Rosenberg, S. A. et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J. Natl Cancer. Inst. 90, 1894–1900 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Marshall, J. L. et al. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J. Clin. Oncol. 23, 3963–3973 (2000).

    Google Scholar 

  33. Eder, J. P. et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin. Cancer Res. 5, 1632–1638 (2000).

    Google Scholar 

  34. Marshall, J. L. et al. Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J. Clin. Oncol. 17, 332–337 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Restifo, N. P., Ying, H., Hwang, L. & Leitner, W. W. The promise of nucleic acid vaccines. Gene Ther. 2, 89–92 (2000).

    Article  CAS  Google Scholar 

  36. Wang, R. et al. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 282, 476–480 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Dallal, R. M., Mailliard, R. & Lotze, M. T. in Principles and Practice of the Biologic Therapy of Cancer 3rd edn (ed. Rosenberg, S. A.) 705–721 (Lippincott, Philadelphia, 2000).

    Google Scholar 

  38. Gong, J. et al. Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity. J. Immunol. 3, 1705–1711 (2000).

    Article  Google Scholar 

  39. Parkhurst, M. R. et al. Improved induction of melanoma reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A* 0210 binding residues. J. Immunol. 157, 2539–2548 (1996).

    CAS  PubMed  Google Scholar 

  40. Rosenberg, S. A. et al. Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J. Immunol. 163, 1690–1695 (1999).

    CAS  PubMed  Google Scholar 

  41. Marincola, F. M. in Principles and Practice of the Biologic Therapy of Cancer 3rd edn (ed. Rosenberg, S. A.) 601–617 (Lippincott, Philadelphia, 2000).

    Google Scholar 

  42. Kawakami, Y. et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl Acad. Sci. USA 91, 3515–3519 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kawakami, Y. et al. Identification of a human melanoma antigen recognized by tumor infiltrating lymphocytes associated with in vivo tumor rejection. Proc. Natl Acad. Sci. USA 91, 6458–6462 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brichard, V. et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 178, 489–495 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, R. F., Robbins, P. F., Kawakami, Y., Kang, X. Q. & Rosenberg, S. A. Identification of a gene encoding a melanoma tumor antigen recognized by HLA-A31-restricted tumor-infiltrating lymphocytes. J. Exp. Med. 181, 799–804 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, R. -F., Appella, E., Kawakami, Y., Kang, X. & Rosenberg, S. A. Identification of TRP-2 as a human tumor antigen recognized by cytotoxic T lymphocytes. J. Exp. Med. 184, 2207–2216 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Salazar-Onfray, F. et al. Synthetic peptides derived from the melanocyte-stimulating hormone receptor MC1R can stimulate HLA-A2-restricted cytotoxic T lymphocytes that recognize naturally processed peptides on human melanoma cells. Cancer Res. 57, 4348–4355 (1997).

    CAS  PubMed  Google Scholar 

  48. Van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  49. Visseren, M. J. et al. Identification of HLA-A*0201-restricted CTL epitopes encoded by the tumor-specific MAGE-2 gene product. Int. J. Cancer 73, 125–130 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Gaugler, B. et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J. Exp. Med. 179, 921–930 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Panelli, M. C. et al. A tumor-infiltrating lymphocyte from a melanoma metastasis with decreased expression of melanoma differentiation antigens recognizes MAGE-12. J. Immunol. 4382–4392 (2000).

  52. Boel, P. et al. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2, 167–175 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Van Den Eynde, B. et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J. Exp. Med. 182, 689–698 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Jager, E., Chen, Y. T. & Drijfhout, J. W. Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J. Exp. Med. 187, 265–270 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, R. -F. et al. A breast and melanoma-shared tumor antigenic peptides translated from different open reading frames. J. Immunol. 161, 3596–3606 (1998).

    CAS  Google Scholar 

  56. Robbins, P. F. et al. A mutated B-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Chiari, R. et al. Two antigens recognized by autologous cytolytic T lymphocytes on a melanoma result from a single point mutation in an essential housekeeping gene. Cancer Res. 22, 5785–5792 (1999).

    Google Scholar 

  58. Wolfel, T. et al. A p16INK4A-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Mandruzzato, S., Brasseur, F. & Andry, G. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J. Exp. Med. 186, 785–793 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gueguen, M., Matard, J. J. & Gaugler, B. An antigen recognized by autologous CTLs on a human bladder carcinoma. J. Immunol. 160, 6188–6194 (1998).

    CAS  PubMed  Google Scholar 

  61. Brandle, D., Brasseur, F. & Weynants, P. A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma. J. Exp. Med. 183, 2501–2508 (1996).

    Article  CAS  PubMed  Google Scholar 

  62. Butterfield, L. H. et al. Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein. Cancer Res. 59, 3134–3142 (1999).

    CAS  PubMed  Google Scholar 

  63. Vonderheide, R. H., Hahn, W. C., Schultze, J. L. & Nadler, L. M. The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity 10, 673–679 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Vissers, J. L. et al. The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes. Cancer Res. 59, 5554–5559 (1999).

    CAS  PubMed  Google Scholar 

  65. Jerome, K. R. et al. Cytotoxic T-lymphocytes derived from patients with breast adenocarcinoma recognize an epitope present on the protein core of a mucin molecule preferentially expressed by malignant cells. Cancer Res. 51, 2908–2916 (1991).

    CAS  PubMed  Google Scholar 

  66. Tsang, K. Y., Zaremba, S. & Nieroda, C. A. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J. Natl Cancer Inst. 87, 982–990 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Theobald, M. B. J., Dittmer, D., Levine, A. J. & Sherman, L. A. Targeting p53 as a general tumor antigen. Proc. Natl Acad. Sci. USA 92, 11993–11997 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ioannides, C. G. et al. T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. Cell Immunol. 151, 225–234 (1993).

    Article  PubMed  Google Scholar 

  69. Li, K. et al. Tumour-specific MHC-class-II-restricted responses after in vitro sensitization to synthetic peptides corresponding to gp100 and annexin II eluted from melanoma cells. Cancer Immunol. Immunother. 47, 32–38 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Chaux, P. et al. Identification of MAGE-3, epitopes presented by HLA-DR molecules to CD4+ T lymphocytes. J. Exp. Med. 189, 767–777 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Topalian, S. L. et al. Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene. Proc. Natl Acad. Sci. USA 91, 9461–9465 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zeng, G. et al. Identification of CD4+ T cell epitopes from NY-ESO-1 presented by HLA-DR molecules. J. Immunol. 165, 1153–1159 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Pieper, R. et al. Biochemical identification of a mutated human melanoma antigen recognized by CD4+ T cells. J. Exp. Med. 189, 757–766 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, R. -F., Wang, X. & Rosenberg, S. A. Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4+ T cells. J. Exp. Med. 189, 1659–1667 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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    Steven A. Rosenberg

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Rosenberg, S. Progress in human tumour immunology and immunotherapy. Nature 411, 380–384 (2001). https://doi.org/10.1038/35077246

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