Abstract
As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e. g., Melan-A/ MART-1, tyrosinase, gp 100). Some target antigens are specificallyexpressed in tumors of different types but not in normal tissues (e. g., MAGE-3), while other possible targets are antigens that are expressed at low level in normal tissues and are over-expressed in tumors of different types (e. g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (pS3) or tumor-specific post-translational modified proteins (underglycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, these antigens tend to be poorly inmmunogenic by themselves and vaccines containingthem generally require the inclusion of potent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Many adjuvants currently under evaluation for use in cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via toll-like receptors (TLRs) and promote effective uptake, processing and presentation of antigen to T-cells in draining lymph nodes.
Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for lipid A have allowed for a better understanding of how this immunostimulant functions with regard to induction of innate and adaptive immune responses.
Although severallipid A species, includingLPS and synthetic analogs, have been developed and tested asmonotherapeutics for the treatment of cancer,1–8 only 3-O-desacyl-4′-monophosphoryllipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL comprises the lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the l-phosphare have been removed by successiveacid and base hydrolysis.9 LPS and MPL induce similar cytokine profiles, but MPLis at least 1OO-fold lesstoxic.9,10 lOMPL has been administered to more than 300, 000 human subjects in studies of next-generation vaccines.11
In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various cancer vaccines containingMPL, either alone or combined with other immunostimulants, Such as cell wall skeleton (CWS) of Mycobacterium phlei in the adjuvant Detox™; Biomira, Inc.), the saponin QS-21 (in the adjuvants AS01B and AS02B; GSK Biologicals) or with QS-21 and CpG oligonucleotides (in the adjuvant AS15; GSK Biologicals) will be summarized. Combining MPL with other immunostimulants has been demonstrated to be advantageous in many cases and may be required to elicit the full complement of activities necessary to achieve an effective immune response and overcome the ability of tumors to evade attack by the immune system. In this chapter, information relating to vaccines targeting specific cancers will be presented in the first section, while information relating to vaccines targeting multiple tumor types by the induction of immune responses to shared TAAs is presented in the second section.
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References
Otto F, Schmid P, Mackensen A et al. Phase II trial of intravenous endotoxin in patients with colorectal and nonsmall cell lung cancer. Eur J Cancer 1996; 32:1712–1718.
Engelhardt R, Mackensen A, Galanos C. Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. Cancer Res 1991; 51:2524–2530.
Mackensen A, Galanos C, Engelhardt R. Modulating activity of interferon-gamma on endotoxin-induced cytokine production in cancer patients. Blood 1991; 78:3254–3258.
Mackensen A, Galanos C, Wehr U et al. Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients. Eur Cytokine Netw 1992; 3:571–579.
Goto S, Sakai S, Kera J et al. Intradermal administration of lipopolysaccharide in treatment of human cancer. Cancer Immunol Immunother 1996; 42(4):255–261.
Vosika G J, Barr C, Gilbertson D. Phase-1 study of intravenous modified lipid A. Cancer Immunol Immunother 1984; 18(2):107–112.
Kiani A, Tschiersch A, Gaboriau E et al. Downregulation of the proinHammatory cytokine response to endotoxin by pretreatment with the nontoxic lipid A analog SDZ MRL 953 in cancer patients. Blood 1997; 90(4): 1673–1683.
de Bono JS, Dalgleish AG, Carmichael J et al. Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. Clin Cancer Res 2000; 6(2):397–405.
Myers KR, Truchot AT, Ward J et al. A critical determinant of lipid A endotoxic activity. In: Nowotny A, Spitzer JJ, Ziegler EJ, editors. Cellular and Molecular Aspects of Endotoxin Reactions. Amsterdam: Elsevier Sciences Publishers B V, 1990:145–156.
Ulrich JT, Masihi KN, Lange W. Mechanisms of nonspecific resistance to microbial infections induced by trehalose dirnycolate (TDM) and monophosphoryllipid A (MPL). In: Masihi KN, Lange W, editors. Advances in the Biosciences. Great Britain: Pergamon Journals Ltd., 1988:167–178.
Evans JT, Cluff CW, Johnson DA et al. Enhancement of antigen-specificimmunity via the TLR4 ligands MPL adjuvant and Ribi 529. Expert Review Vaccines 2003; 2(2):219–229.
Woodlock TJ, Sahasrabudhe DM, Marquis DM et al. Active specific immunotherapy for metastatic colorectal carcinoma: Phase I study of an allogeneic cell vaccine plus low-dose interleukin-1 c, J Immunother 1999; 22(3):251–259.
Shetye SF, Frodin J-E, Christensson B. Immunohistochemical monitoring of metastatic colorectal carcinoma in patients treated with monoclonal antibodies (MAb 17-0lA). Cancer Immunol Immunother 1988; 27:154–162.
Neidhart J, Allen KO, Barlow DL et al. Immunization of colorectal cancer patients with recombinant baculovirus-derived KSA (Ep-CAM) formulated with monophosphoryllipid A in liposomal emulsion, with and without granulocyte-macrophage colony-stimulating factor. Vaccine 2004; 22(5–6):773–780.
Papsidero LD, Kuriyama M, Wang MC et al. Prostate antigen: a marker for human prostate epithelial cells. J Natl Cancer Inst 1981; 66(1):37–42.
Oesterling JE. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 1991; 145(5):907–923.
Harris DT, Matyas GR, Mastrangelo M J et al. Inducing immunity to prostate specific antigen (PSA) in prostate cancer patients. Proc ASCO 1999; 18:1693.
Meidenbauer N, Harris DT, Spitler LE et al. Generation of PSA-reactive effector cells after vaccination with a PSA-based vaccine in patients with prostate cancer. Prostate 2000; 43(2):88–100.
Mitchell MS, Kan-Mitchell J, Kempf RA et al. Active specific immunotherapy for melanoma: Phase I trial of allogeneic lysates and a novel adjuvant. Cancer Res 1988; 48(20):5883–5893.
Mitchell MS, Harel W, Kempf RA et al. Active-specific immunotherapy for melanoma. J Clin Oncol 1990; 8(5):856–869.
Vose BM. Quantitation of proliferative and cytotoxic precursor cells directed against human tumours: limiting dilution analysis in peripheral blood and at the tumour site. Int J Cancer 1982; 30(2):135–142.
Mitchell MS, Harel W, Groshen S. Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 1992; 10(7):1158–1164. Sosman JA, Sondak VK. Melacine: an allogeneic melanoma tumor cell lysate vaccine. Expert Rev Vaccines 2003; 2(3):353–368.
Elliott GT, McLeod RA, Perez J et al. Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol 1993; 9(3):264–272.
Mitchell MS, Von Eschen KB. Phase III trial of Melacine melanoma theraccine versus combination chemotherapy in the treatment of stage IV melanoma. Proceedings of the American Society of Clinical Oncology 1997; 16, 494a.
Sosman JA, Unger JM, Liu PY et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome. J Clin Oncol 2002; 20(8):2067–2075.
Sondak VK, Sosman JA. Results of clinical trials with an allogeneic melanoma tumor cell lysate vaccine: Melacine, Semin Cancer Biol 2003; 13:409–415.
Sosman JA, Sondak VK. Melacine: an allogeneic melanoma tumor cell lysate vaccine. Expert Rev Vaccines 2003; 2(3):353–368.
Mitchell MS, Jakowatz J, Harel W et al. Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 1994; 12(2):402–411.
Vaishampayan U, Abrams J, Darrah D et al. Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res 2002; 8(12):3696–3701.
Mitchell MS. Immunotherapy as part of combinations for the treatment of cancer. Int Immunopharmacol 2003; 3(8):1051–1059.
Mitchell MA, Abrams J, Kashani-Sabet M et al. Interim analysis of a phase III stratified randomized trial of Melacine + low-dose Intron-A versus high-dose Intron-A for resected stage III melanoma. Am Soc Clin Onco 2003; 22:709a.
Schultz N, Oratz R, Chen D et al. Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine 1995; 13(5):503–508.
Eton O, Kharkevitch DD, Gianan MA et al. Active immunotherapy with ultraviolet B-irradiated autologous whole melanoma cells plus DETOX in patients with metastatic melanoma. Clin Cancer Res 1998; 4(3):619–627.
Wong R, Lau R, Chang J et al. Immune responses to a class II helper peptide epitope in patients with stage III/IV resected melanoma. Clin Cancer Res 2004; 10(15):5004–5013.
Lienard D, Rimoldi D, Marchand M et al. Ex vivo detectable activation of Melan-A-specific T-cells correlating with inflammatory skin reactions in melanoma patients vaccinated with peptides in IFA. Cancer Immun 2004; 4:4.
Marchand M, Punt CJ, Aamdal S et al. Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report. Eur J Cancer 2003; 39(1):70–77.
Vantomme V, Dantinne C, Amrani N. Immunologic analysis of a phase I/Il study of vaccination with MAGE-3 protein combined with the AS02B adjuvant in patients with MAGE-3-positive tumors. J Immunother 2004; 27:124–135.
Atanackovic D, Altorki NK, Stockert E et al. Vaccine-induced CD4+ T-cell responses to MAGE-3 protein in lung cancer patients. J Immunol 2004; 172(5):3289–3296.
Brichard V. Development of cancer vaccines with the MAGE-3 protein. Cancer Immunity 2005; 5(1):16.
Brichard V. CVADD 2005; Portugal.
Zotter S, Hageman PC, Lossnitzer A et al. Tissue and tumor distribution of human polymorphic epithelial mucin. Cancer Rev 1988; 11–12:55–101.
Ho SB, Niehans GA, Lyftogt C et al. Heterogeneity of mucin gene expression in normal and neoplastic tissues. Cancer Res 1993; 53(3):641–651.
Burchell J, Gendler S, Taylor-Papadimitriou J et al. Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Res 1987; 47(20):5476–5482.
Kjeldsen T, Clausen H, Hirohashi S et al. Preparation and characterization of monoclonal antibodies directed to the tumor-associated O-linked sialosyl-2-6 alpha-N-acetylgalactosaminyl (sialosyl-Tn) epitope, Cancer Res 1988; 48(8):2214–2220.
Ramanathan RK, Lee KM, McKolanis J et al. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother 2005; 54(3):254–264.
Palmer M, Parker J, Modi S et al. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV nonsmall-cell lung cancer. Clin Lung Cancer 2001; 3(1):49–57.
North SA, Graham K, Bodnar D et al. A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy. J Urol 2006; 176(1):91–95.
Butts C, Murray N, Maksymiuk A et al. Randomized phase lIB trial of BLP25 liposome vaccine in stage IIIB and IV nonsmall-celllung cancer. J Clin Oncol 2005; 23(27):6674–6681.
Machiels JP, Reilly RT, Emens LA et al. Cyclophosphamide, doxorubicin and pacliraxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001; 61(9):3689–3697.
Bass KK, Mastrangelo M J. Immunoprotentiation with low-dose cyclophosphamide in the active specific immunotherapy of cancer. Cancer Immunol Immunother 1998; 47:1–12.
Longenecker BM, MacLean G. Prospects for mucin epitopes in cancer vaccines. Immunologist 1993; 1:89–93.
Itzkowitz SH, Bloom EJ, Kokal WA et al. Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients. Cancer 1990; 66(9):1960–1966.
Springer GF. T and Tn, general carcinoma autoantigens. Science 1984; 224(4654):1198–1206.
Kobayashi H, Terao T, Kawashima Y. Serum sialyl Tn as an independent predictor of poor prognosis in patients with epithelial ovarian cancer. J Clin Oncol 1992; 10(1):95–101.
Thor A, Ohuchi N, Szpak CA et al. Distribution of oncofetal antigen tumor-associated glycoprotein-72 defined by monoclonal antibody B72. 3. Cancer Res 1986; 46(6):3118–3124.
Nuti M, Teramoto YA, Mariani-Costantini R et al. A monoclonal antibody (B72. 3) defines patterns of distribution of a novel tumor-associated antigen in human mammary carcinoma cell populations. Int J Cancer 1982; 29(5):539–545.
Yoneawa S, Tachidawa T, Shin S. Sialosyl-Tn antigen: its distribution in normal human tissues and expression in adenocarcinomas. Am J Clin Pathol 1992; 98:167–174.
Longenecker BM, Reddish M, Miles D et al. Synthetic Tumor-Associated Sialyl-Tn Antigen as an Immunotherapeutic Cancer Vaccine. Vaccine Res 1993; 2(3):151–162.
O’Boyle K, Zamore R, Adluri S et al. Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn. Cancer Res 1992; 52(20):5663–5667.
Berendt M J, North R J. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor; J Exp Med 1980; 151(1):69–80.
MacLean GD, Reddish M, Koganty RR et al. Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. Cancer Immunol Immunother 1993; 36(4):215–222.
Miles DW, Towlson KE, Graham R et al. A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer. Br J Cancer 1996; 74(8):1292–1296.
MacLean GD, Miles DW, Rubens RD et al. Enhancing the effect of THERATOPE Stn-KLN cancer vaccine in patients with metastatic breast cancer by pretreatment with low dose intravenous cyclophosphamide. J Immunother 1996; 19(4):309–316.
Miles D, Ibrahim N, Roche H. An international randomized phase III clinical trial of STn-KLH (Theratope) therapeutic cancer vaccine in metastic breast cancer patients. Proceedings 27th Annual San Antonio Breast Cancer Symposium 2003;(36).
Ibrahim NK, Murray J, Parker J. Humoral immune-response to naturally occurring STn in metastatic breast cancer (MBC pts) treated with STn-KLH vaccine. Am Soc Clin Onco2004; 22:S174.
Majordomo J, Tres A, Miles D. Long-term follow-up of patients concomitantly treated with hormone therapy in a prospective controlled randomized multicenter clinical study comparing STn-KLH vaccine with KLH control in Stave IV breast cancer following front-line chemotherapy. Proc Am Soc Clin Oncol 2004; 22:1882S.
Holmberg LA, Oparin DV, Gooley T et al. Clinical outcome of breast and ovarian cancer patients treated with high-dose chemotherapy, autologous stem cell rescue and THERATOPE STn-KLH cancer vaccine. Bone Marrow Transplant 2000; 2S(12):1233–1241.
Holmberg LA, Sandmaier BM. Theratope(R) vaccine (STn-KLH). Expert Opin Biol Ther 2001; 1(S):881–891.
Holmberg LA, Oparin DV, Gooley T et al. The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope). Clin Breast Cancer 2003; 3 SuppI4:S144–S151.
Holmberg LA, Sandmaier BM. Vaccination with Theratope (STn-KLH) as treatment for breast cancer. Expert Rev Vaccines 2004; 3(6):655–663.
Khleif SN, Abrams SI, Hamilton JM et al. A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. J Immunother 1999; 22(2):155–165.
Johnson AG. Molecular adjuvants and immunomodulators: new approaches to immunization. Clin Microbiol Rev 1994; 7(3):277–289.
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Cluff, C.W. (2009). Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines: Clinical Results. In: Jeannin, JF. (eds) Lipid A in Cancer Therapy. Advances in Experimental Medicine and Biology, vol 667. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1603-7_10
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