image

image
image
image
image
image
image
image

Immunotherapy may be the next great hope for cancer treatment. While monoclonal antibodies, cytokines, and vaccines have individually shown some promise, it is likely that our best strategy to combat cancer will be to attack on all fronts. Clearly, different strategies demonstrate benefit in different patient populations. It may be that the best results are obtained with vaccines in combination with a variety of antigens, or vaccine and antibody combinations. Nonspecific and specific immunotherapy combinations may be another potent strategy. The effect of any of the aforementioned strategies in combination with more traditional cancer therapies is another avenue, as we have seen some benefit in terms of duration with cytokines and chemotherapy.

Through these concerted efforts, our ultimate achievable goal may be a durable anti-tumor immune response that can be maintained over the course of a patient's lifespan.

Slide Libraryrequires Adobe Acrobat for viewing


References

  1. Old LJ. Immunotherapy for cancer. Sci Am. 1996; 275:136-143.
  2. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop. 1991;262:3-11.
  3. Berkow R, Beers MH. Cancer and the immune system. In: The Merck Manual of Medical Information. Whitehouse Station, NJ; Merck Research Laboratories. 1997: 792-794.
  4. Zeir M, Hartschuh W, Wiesel M, Lehnert T, Ritz E. Malignancy after renal transplantation. Am J Kidney Dis. 2002;39:E5.
  5. Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol. 1990;29:545-550.
  6. Guyton AC, Hall JE, eds. Immunity, allergy, blood groups, and transfusion. In: Human Physiology and Mechanisms of Disease. 6th ed. Philadelphia, PA: W.B. Saunders Company; 1997:291-293.
  7. Guyton AC, Hall JE, eds. Resistance of the body to infection: II. Immunity and Allergy. In: Textbook of Medical Physiology. 10th ed. Philadelphia, PA: W.B. Saunders Company, 2000;408-410.
  8. Ward RL, Hawkins NJ, Coomber D, Disis ML. Antibody immunity to the HER-2/neu oncogenic protein in patients with colorectal cancer. Hum Immunol. 1999;60:510-515.
  9. Pandolfino MC, Viret C, Gervois N, et al. Specificity, T cell receptor diversity and activation requirements of CD4+ and CD8+ clones derived from human melanoma-infiltrating lymphocytes. Eur J Immunol. 1992;22:1795-1802.
  10. Proescholdt MA, Merrill MJ, Ikejiri B, et al. Site-specific immune response in implanted gliomas. J Neurosurg. 2001;95:1012-1019.
  11. Yotnda P, Mintz P, Grigoriadou K, Lemonnier F, Vilmer E, Langlade-Demoyen P. Analysis of T cell defects in the specific immune response against acute lymphoblastic leukemia cells. Exp Hematol. 1999;27:1375-1383.
  12. Bagot M, Nikolova M, Schirm-Chabanette F, Wechsler J, Boumsell L, Bensussan A. Crosstalk between tumor T lymphocytes and reactive T lymphocytes in cutaneous T cell lymphomas. Ann NY Acad Sci. 2001;941:31-38.
  13. Echchakir H, Bagot M, Dorothee G, et al. Cutaneous T cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis. J Invest Dermatol. 2000;115:74-80.
  14. Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol. 2001;167:2972-2978.
  15. Radoja S, Frey AB. Cancer-induced defective cytotoxic T lymphocyte effector function: another mechanism how antigenic tumors escape immune-mediated killing. Mol Med. 2000;6:465-479.
  16. Kobayashi H, Wood M, Song Y, Appella E, Celis E. Defining promiscuous MHC class II helper T cell epitopes for the HER-2/neu tumor antigen. Cancer Res. 2000;60:5228-5236.
  17. Guilloux Y, Viret C, Gervois N, et al. Defective lymphokines production by most CD8+ and CD4+ tumor-specific T cell clones derived from human melanoma-infiltrating lymphocytes in response to autologous tumor cells in vitro. Eur J Immunol. 1994;24:1966-1973.
  18. Kiessling R, Wasserman K, Horiguchi S, et al. Tumor-induced immune dysfunction. Cancer Immunol Immunother. 1999;48:353-362.
  19. Salih HR, Nussler V. Commentary: Immune escape versus tumor tolerance: how do tumors evade immune surveillance? Eur J Med Res. 2001;6:323-332.
  20. Schiffman K, Rinn K, Disis ML. Delayed type hypersensitivity (DTH) response to recall antigens does not accurately reflect immune competence in advanced stage cancer patients. Breast Cancer Research and Treatment. 2002; in press.
  21. Knutson KL, Schiffman K, Disis ML. Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T cell immunity in cancer patients. J Clin Invest. 2001;107:477-484.
  22. Green MC, Murray JL, Hortobagyi GN. Monoclonal antibody therapy for solid tumors. Cancer Treat Rev. 2000;26:269-286.
  23. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6:443-446.
  24. Anderson DR, Grillo-Lopez A, Varns C, Chambers KS, Hanna N. Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma. Biochem Soc Trans. 1997; 25:705-708.
  25. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83;435-445.
  26. Kreitman RF, Wilson WH, Bergeron K, et al. Efficacy of anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy cell leukemia. N Engl J Med. 2001;345:241-247.
  27. Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000;27:17-24.
  28. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15:450-454.
  29. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol. 1993;121:1121-1132.
  30. Deans JP, Kalt L, Ledbetter JA, Schieven GL, Bolen JB, Johnson P. Association of 75/80-kDa phosphoproteins and the tyrosine kinases Lyn, Fyn, and Lck with the B cell molecule CD20. Evidence against involvement of the cytoplasmic regions of CD20. J Biol Chem. 1995;270:22632-22638.
  31. Hainsworth JD, Burris HA 3rd, Morrissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000;95:3052-3056.
  32. Hainsworth JD. Monoclonal antibody therapy in lymphoid malignancies. Oncologist. 2000;5:376-384.
  33. Solal-Celigny P. Rituximab as first-line monotherapy in low-grade follicular lymphoma with a low tumor burden. Anticancer Drugs. 2001;12:S11-S14.
  34. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001;19:389-397.
  35. Press OW, Leonard JP, Coiffier B, Levy R, Timmerman J. Immunotherapy of non-Hodgkin's lymphomas. Hematology. 2001;Jan:221-240.
  36. Martin IG, Cutts SG, Birbeck K, Gray S, Quirke P. Expression of the 17-1A antigen in gastric and gastroesophageal junction adenocarcinomas: a potential immunotherapeutic target? J Clin Pathol. 1999;52:701-704.
  37. Haller DG. Update of clinical trials with edrecolomab: a monoclonal antibody therapy for colorectal cancer. Semin Oncol. 2001;28:25-30.
  38. Pegram MD, Slamon DJ. Combination therapy with trastuzumab and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol. 1999;26:89-95.
  39. Baselga J. Phase I and II clinical trials of trastuzumab. Ann Oncol. 2001;12:S49-S55.
  40. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER-2 for metastatic breast cancer that overexpresses HER-2. N Engl J Med. 2001;344:783-792.
  41. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER-2 monoclonal antibody in women who have HER-2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648.
  42. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719-726.
  43. Dorval T, Palangie T, Jouve M, et al. Treatment of metastatic melanoma with recombinant interferon alfa-2b. Invest New Drugs. 1987;5:S61-S63.
  44. Sertoli MR, Bernego MG, Ardizzoni A, et al. Phase II trial of recombinant alfa-2b interferon in the treatment of metastatic skin melanoma. Oncology. 1989;46:96-98.
  45. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
  46. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High and low-dose interferon alfa-2b in high risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-2458.
  47. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of an intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19:2370-2380.
  48. Eggermont AM. The current EORTC Melanoma Cooperative Group adjuvant trial programme on malignant melanoma: prognosis versus efficacy, toxicity, and costs. Melanoma Res. 1997;7:S127-S131.
  49. Quesada JR, Hersh EM, Manning J, et al. Treatment of hairy cell leukemia with recombinant alfa-interferon. Blood. 1986;68:493-497.
  50. Foon KA, Maluish AE, Abrams PG, et al. Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Therapeutic and immunologic results. Am J Med. 1986;80:351-356.
  51. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomized, multicenter trial of interferon alfa n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. Lancet. 1995;345:1392-1397.
  52. Ohnishi K, Ohno R, Tomonaga M, et al. A randomized trial comparing interferon-alfa with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906-916.
  53. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13:688-696.
  54. Rosenberg SA, Yang YC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA. 1994;271:907-913.
  55. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;Feb:S55-S57.
  56. Lissoni P, Barni S, Tancini G, et al. Clinical response and survival in metastatic renal carcinoma during subcutaneous administration of interleukin-2 alone. Arch Ital Urol Androl. 1997;69:41-47.
  57. Tourani JM, Lucas V, Mayeur D, et al. Subcutaneous recombinant interleukin-2 (rIL-2) in outpatients with metastatic renal cell carcinoma. Results of a multicenter SCAPP1 trial. Ann Oncol. 1996;7:525-528.
  58. Negrier S, Maral J, Drevon M, Vinke J, Escudier B, Philip T. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am. 2000;6:S93-S98.
  59. Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2000;18:1614-1621.
  60. Atkins MB, Roberston MJ, Gordon M, et al. Phase I evaluation of intravenous recombinant human interleukin-12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409-417.
  61. Lee P, Wang F, Kuniyoshi J, et al. Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol. 2001;19:3836-3847.
  62. Lee P, Wang F, Kuniyoshi J. Slingluff CL Jr, Yamshchikov G, Neese P, et al. Phase 1 trial of a melanoma vaccine with gp100 (280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes. Clin Cancer Res. 2001;7:3012-3024.
  63. Lee KH, Wang E, Nielson MB, et al. Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol. 1999;163:6292-6300.
  64. Weber JS, Hua FL, Spears L, Marty V, Kuniyoshi C, Celis E. A phase I trial of an HLA-A1 restricted MAGE-3 epitope peptide with incomplete Freund's adjuvant in patients with resected high-risk melanoma. J Immunother. 1999;22:431-440.
  65. Wang F, Bade E, Kuniyoshi C, et al. Phase I trial of a MART-1 peptide vaccine with incomplete Freund's adjuvant for resected high-risk melanoma. Clin Cancer Res. 1999;5:2756-2765.
  66. Knutson KL, Schiffman K, Disis ML. Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T cell immunity in cancer patients. J Clin Invest. 2001;104:477-484.
  67. Bendandi M, Gocke CD, Kobrin CB, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999;5:1171-1177.
  68. Kusumoto M, Umeda S, Ikubo A, et al. Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF. Cancer Immunol Immunother. 2001;50:373-381.
  69. Jaffee EM, Hruban RH, Biedrzycki B, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 20001;19:145-156.
  70. Hsueh EC, Famatiga E, Gupta RK, Qi K, Morton DL. Enhancement of complement-dependent cytotoxicity by polyvalent melanoma cell vaccine (CancerVax): correlation with survival. Ann Surg Oncol. 1998;5:595-602.
  71. Hanna MG Jr., Hoover HC Jr, Vermorken JB, Harris JE, Pinedo HM. Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise. Vaccine. 2001;19:2576-2582.
  72. Schneider T, Gerhards R, Kirches E, Firsching R. Preliminary results of active specific immunization with modified tumor cell vaccine in gliobastoma multiforme. J Neurooncol. 2001;53:39-46.
  73. von Mehren M, Arlen P, Gulley J, et al. The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res. 2001;7:1181-1191.
  74. Marshall JL, Hoyer RJ, Toomey MA, 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. 2000;18:3964-3973.
  75. Conry RM, Khazaeli MB, Saleh MN, et al. Phase I trial of a recombinant vaccinia virus encoding carcinoembryonic antigen in metastatic adenocarcinomas: comparison of intradermal versus subcutaneous administration. Clin Cancer Res. 1999;5:2330-2337.
  76. Mincheff M, Tchakarov S, Zoubak S, et al. Naked DNA and adenoviral immunizations for immunotherapy of prostate cancer: a phase I/II clinical trial. Eur Urol. 2000;38:208-217.
  77. Morse MA, Lyerly HK, Gilboa E, Thomas E, Nair SK. Optimization of the sequence of antigen loading and CD40-ligand-induced maturation of dendritic cells. Cancer Res. 1998;58:2965-2968.
  78. Mosca PJ, Hobeika AC, Clay TM, et al. A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment. Blood. 2000;96:3499-3504.
  79. Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 1999;59:56-58.
  80. Morse MA, Deng Y, Coleman D, Hull S, et al. A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin Cancer Res. 1999;5:1331-1338.
  81. Li Y, Bendandi M, Deng Y, et al. Tumor-specific recognition of human myeloma cells by idiotype-induced CD8+ T cells. Blood. 2000;96:2828-2833.
  82. Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell Vaccine. Cancer Res. 2001;61:6451-6458.
  83. Sadanga N, Nagashima H, Mashino K, et al. Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas. Clin Cancer Res. 2001;7:2277-2284.
  84. Fong L, Hou Y, Rivas A, et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA. 2001;98:8809-8814.
  85. Toungouz M, Libin M, Bulte F, et al. Transient expansion of peptide-specific lymphocytes producing IFN-gamma after vaccination with dendritic cells pulsed with MAGE peptides in patients with MAGE-A1/A3-positive tumors. J Leukoc Biol. 2001;69:937-943.
  86. Rains N, Cannan RF, Chen W, Stubbs RS. Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer. Hepatogastroenterology. 2001;48:347-351.
  87. Fong L, Brockstedt D, Benike C, Wu L, Engleman EG. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol. 2001;166:4254-4259.
  88. Yu JS, Wheeler CJ, Zeltzer PM, et al. Vaccination of malignant gliomas patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T cell infiltration. Cancer Res. 2001:61:842-847.
  89. Nishiyama T, Tachibana M, Horiguchi Y, et al. Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-2 peptide. Clin Cancer Res. 2001;7:23-31.
  90. Small EJ, Fratesi P, Reese DM, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000;18:3894-3903.
  91. Schuler-Thurner B, Dieckmann D, Keikavoussi P, et al. Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived dendritic cells. J Immunol. 2000;165:3492-3496.
  92. Panelli MC, Wunderlich J, Jeffries J, et al. Phase I study in patients with metastatic melanoma of immunization with dendritic cells in presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100. J Immunother. 2000;23:487-498.
  93. Titzer S, Christensen O, Manzke O, et al. Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects. Br J Haematol. 2000;108:805-816.
  94. Liso A, Stockerl-Goldstein KE, Auffermann-Gretzinger S, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood progenitor cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2000;6:621-627.

Continue to Post Test