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Immunotherapy: past, present and future

Harnessing the immune system to treat chronic infectious diseases or cancer is a major goal of immunotherapy. Among others, impediments to this aim include host failure to identify tumor antigens, tolerance to self and negative immunoregulatory mechanisms. But with recent progress, active and passive immunotherapy are proving themselves as effective therapeutic strategies.

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References

  1. Boon, T., Cerottini, J.-C., Van den Eynde, B., van der Bruggen, P. & Van Pel, A. Tumor antigens recognized by T lymphocytes. Ann. Rev. Immunol. 12, 337–365 (1994).

    Article  CAS  Google Scholar 

  2. Pardoll, D.M. Spinning molecular immunology into successful immunotherapy. Nat. Rev. Immunol. 2, 227–238 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Berzofsky, J.A., Ahlers, J.D. & Belyakov, I.M. Strategies for designing and optimizing new generation vaccines. Nat. Rev. Immunol. 1, 209–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Srivastava, P.K. Immunotherapy of human cancer: lessons from mice. Nat. Immunol. 1, 363–366 (2000).

    CAS  PubMed  Google Scholar 

  7. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  PubMed  Google Scholar 

  8. Jones, P.T., Dear, P.H., Foote, J., Newberger, M.S. & Winter, G. Replacing the complementarity determining regions in a human antibody with those from a mouse. Nature 321, 522–525 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Waldmann, T.A. Monoclonal antibodies in diagnosis and therapy. Science 252, 1657–1662 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer 1, 118–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Gura, T. Magic bullets hit the target. Nature 417, 584–586 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Ehrlich, P. On immunity with special reference to cell life: Croonian lecture. In The Collected Papers of Paul Ehrlich, Vol. II: Immunology and Cancer Research (ed. Himmelweir, B.) 148–192 (Pergammon, London, England, 1956).

    Google Scholar 

  13. Coley, W. Further observations upon the treatment of malignant tumors with the toxins of erysipelas and bacillus prodigious with a report of 160 cases. Johns Hopkins Hosp. Bull. 7, 157–162 (1896).

    Google Scholar 

  14. Krackhardt, A.M. et al. Identification of tumor-associated antigens in chronic lymphocytic leukemia by SEREX. Blood 100, 2123–2131 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 92, 11810–11813 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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  CAS  PubMed  Google Scholar 

  17. Gilboa, E. The makings of a tumor rejection antigen. Immunity 11, 263–270 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Robbins, P.F. & Kawakami, Y. Human tumor antigens recognized by T cells. Curr. Opin. Immunol. 8, 626–636 (1996).

    Article  Google Scholar 

  19. Lynch, R.G., Graff, R.J., Sirisinha, S., Simms, E.S. & Eisen, H.N. Myeloma proteins as tumor-specific transplantation antigens. Proc. Natl. Acad. Sci. USA 69, 1540–1544 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Stevenson, G.T., Elliott, E.V. & Stevenson, F.K. Idiotypic determinants on the surface of immunoglobulin of neoplastic lymphocytes; a therapeutic target. Fed. Proc. 36, 2268–2271 (1977).

    CAS  PubMed  Google Scholar 

  21. Miller, R.A., Maloney, D.G., Warnke, R. & Levy, R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N. Engl. J. Med. 306, 517–522 (1982).

    Article  CAS  PubMed  Google Scholar 

  22. Syrengelas, A., Chen, T. & Levy, R. DNA immunization induces protective immunity against B-cell lymphoma. Nat. Med. 2, 1038–1041 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Bendandi, M. et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat. Med. 5, 1171–1177 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Rosenberg, S.A. & White, D.E. Vitiligo in patients with melanoma: normal tissue antigens can be targets for immunotherapy. J. Immunother. 19, 8–14 (1996).

    Article  Google Scholar 

  25. Ramshaw, I.A. & Ramsey, A.J. The prime-boost strategy: exciting prospects for improved vaccination. Trends Immunol. Today 21, 163–165 (2000).

    Article  CAS  Google Scholar 

  26. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1999).

    Article  Google Scholar 

  27. Labeur, M.S. et al. Generation of tumor immunity by bone marrow derived dendritic cells correlates with dendritic cell maturation stage. J. Immunol. 162, 168–175 (1999).

    CAS  PubMed  Google Scholar 

  28. Dubois, S., Mariner, J., Waldmann, T.A. & Tagaya, Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Dranoff, G. et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl. Acad. Sci. USA 90, 3539–3543 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shimizu, K., Thomas, E.K., Geidlin, M. & Mule, J.J. Enhancement of tumor lysate and peptide-pulsed dendritic cell-based vaccines by the addition of foreign helper protein. Cancer Res. 61, 2618–2624 (2001).

    CAS  PubMed  Google Scholar 

  31. Srivastava, P.K. Roles of heat-shock proteins in innate and adaptive immunity. Nat. Rev. Immunol. 2, 185–194 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Parkhurst, M.R. et al. Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified HLA-A 0201 binding residues. J. Immunol. 157, 2539–2548 (1996).

    CAS  PubMed  Google Scholar 

  33. Sarobe, P. et al. Enhanced in vitro potency and in vivo immunogenicity of a CTL epitope from hepatitis C virus core protein following amino acid replacement at secondary HLA-A2 binding positions. J. Clin. Invest. 102, 1239–1248 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. La Rosa, et al. Enhanced immune activity cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries. Blood 97, 1776–1786 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Slansky, J.E. et al. Enhanced antigen-specific anti-tumor immunity with altered peptide ligands that stabilize the MITC-peptide-TCR complex. Immunity 13, 529–538 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Melero, I. et al. Monoclonal antibodies against the 4-IBB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682–688 (1977).

    Article  Google Scholar 

  37. Rosenberg, S.A. et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 271, 907–913 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Atkins, M.D. 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 

  39. Ahlers, J.D., Dunlop, N., Alling, D.W., Nara, P.L. & Berzofsky, J.A. Cytokine-in-adjuvant steering of the immune response phenotype to HIV-1 vaccine constructs: GM-CSF and TNFα synergize with IL-12 to enhance induction of CTL. J. Immunol. 158, 3947–3958 (1997).

    CAS  PubMed  Google Scholar 

  40. Lenardo, M.J. Fas and the art of lymphocyte maintenance. J. Exp. Med. 183, 721–724 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Shevach, E.M. Regulatory T cells in autoimmunity. Ann. Rev. Immunol. 18, 423–449 (2000).

    Article  CAS  Google Scholar 

  42. Waldmann, T.A. & Tagaya, Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Ann. Rev. Immunol. 17, 19–49 (1999).

    Article  CAS  Google Scholar 

  43. Zhang, X., Sun, S., Hwang, I., Tough, D.F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Ku, C.C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Waldmann, T.A., Dubois, S. & Tagaya, Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14, 105–110 (2001).

    CAS  PubMed  Google Scholar 

  46. Chambers, C.A., Kuhns, M.S., Egen. J.G. & Allison, J.P. CTLA-4 mediated inhibition in regulation of T-cell responses: mechanisms and manipulation in tumor immunotherapy. Ann. Rev. Immunol. 19, 565–594 (2001).

    Article  CAS  Google Scholar 

  47. Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. Immunology 163, 5211–5218 (1999).

    CAS  Google Scholar 

  48. Onizuka, S. et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res. 59, 3128–3133 (1999).

    CAS  PubMed  Google Scholar 

  49. Sutmuller, R.P.M. et al. Synergism of cytotoxic T lymphocyte–associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J. Exp. Med. 194, 823–832 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Terabe, M. et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat. Immunol. 1, 515–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N. Engl. J. Med. 313, 337–342 (1985).

  52. Queen, C. et al. A humanized antibody that binds to the interleukin-2 receptor. Proc. Natl. Acad. Sci. USA 86, 10029–10033 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Ann. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  54. El-Gabalawy, H.S. & Lipsky, P.E. Why we do not have a cure for rheumatoid arthritis? The scientific basis of rheumatology. Arthritis Res. 4 (suppl. 3), S297–S301 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  55. McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16, 2825–2833 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Maloney, D.G. et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84, 2457–2466 (1994).

    CAS  PubMed  Google Scholar 

  57. Baselga, J., Norton, L., Albanell, J., Kim, Y.-M. & Mendelsohn, J. Recombinant humanized anti-HER2 antibody (Herceptin™) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58, 2825–2831 (1998).

    CAS  PubMed  Google Scholar 

  58. Coiffier, B. Rituximab in combination with CHOP improves survival in elderly patients with aggressive non-Hodgkin's lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Slamon, D.J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Waldmann, T.A. et al. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood 82, 1701–1712 (1993).

    CAS  PubMed  Google Scholar 

  61. Clynes, R., Tekechi, Y., Moroi, Y., Houghton, A. & Ravetch, J.V. Fc receptors are required in passive and active immunity to melanoma. Proc. Natl. Acad. Sci. USA 95, 652–656 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Clynes, R.A., Towers, T.L., Presta, L.G. & Ravetch, J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Kreitman, R.J. et al. Phase I trial of recombinant immunotoxin anti-Tac (Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol. 18, 1622–1636 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Kreitman, R.J. et al. Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood 94, 3340–3348 (1999).

    CAS  PubMed  Google Scholar 

  65. Witzig, T.E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab for patients with relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 20, 2453–2463 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Waldmann, T.A. et al. Radioimmunotherapy of interleukin-2Rα expressing adult T-cell leukemia with yttrium-90-labeled anti-Tac. Blood 86, 4063–4075 (1995).

    CAS  PubMed  Google Scholar 

  67. Kaminski, M. et al. Radioimmunotherapy with iodine 131I Tositumomab for relapsed or refractory B-cell non-Hodgkin's lymphoma: updated results and long- term follow-up of the University of Michigan experience. Blood 96, 1259–1266 (2000).

    CAS  PubMed  Google Scholar 

  68. Press, O.W. et al. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346, 336–340 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Axworthy, D.B. et al. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity. Proc. Natl. Acad. Sci. USA 97, 1802–1807 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Press, O.W. et al. A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood 98, 2535–2543 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Zhang, M. et al. Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the α-emitting radionuclide, bismuth 213. Blood 100, 208–216 (2002).

    Article  CAS  PubMed  Google Scholar 

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Waldmann, T. Immunotherapy: past, present and future. Nat Med 9, 269–277 (2003). https://doi.org/10.1038/nm0303-269

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