Abstract
Recent preclinical evidence substantially supports the successful combination of chemotherapies and active immunotherapy for cancer treatment. These data sustain the effect of sequential combination schemes (vaccine plus chemotherapy or vice versa), which could be difficult to implement in clinical practice. Since chemotherapy is the standard treatment for most cancers, ethical issues forbid its delay and make difficult the evaluation of other treatments such as using an immunotherapeutic agent. Besides, vaccines must be applied as soon as possible to advanced cancer patients, in order to give them time to develop an effective immune response. Thus, a clinically attractive scenario is the concomitant application of treatments. However, little is known about the specific effect of different chemotherapeutic agents when combined with a cancer vaccine in such concomitant treatment. In this work, we analyze the influence of high-dose carboplatin or paclitaxel in the generation of a specific immune response when administered concomitantly with an OVA vaccine. Interestingly, neither carboplatin nor paclitaxel affects the humoral and CTL in vivo response generated by the vaccine. Moreover, an enhancement of the overall anti-tumor effect was observed in animals treated with OVA/CF vaccine combined with cytotoxic drugs. Moreover, the effect of the concomitant treatment was tested using a tumor-related antigen, the epidermal growth factor (EGF). Animals administered with EGF–P64k/Montanide and cytotoxic agents showed an antibody response similar to that from control animals. Therefore, our study suggests that carboplatin and paclitaxel can be concomitantly combined with active immunotherapies in the clinical practice of advanced cancer patients.
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References
Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274
Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 170:4905–4913
Polak L, Turk JL (1974) Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature 249:654–656
Zhang L, Dermawan K, Jin M, Liu R, Zheng H, Xu L, Zhang Y, Cai Y, Chu Y, Xiong S (2008) Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219–229
Kang TH, Lee JH, Song CK, Han HD, Shin BC, Pai SI, Hung CF, Trimble C, Lim JS, Kim TW et al (2007) Epigallocatechin-3-gallate enhances CD8+ T cell-mediated antitumor immunity induced by DNA vaccination. Cancer Res 67:802–811
Song CK, Han HD, Noh KH, Kang TH, Park YS, Kim JH, Park ES, Shin BC, Kim TW (2007) Chemotherapy enhances CD8(+) T cell-mediated antitumor immunity induced by vaccination with vaccinia virus. Mol Ther 15:1558–1563
Han HD, Song CK, Park YS, Noh KH, Kim JH, Hwang T, Kim TW, Shin BC (2008) A chitosan hydrogel-based cancer drug delivery system exhibits synergistic antitumor effects by combining with a vaccinia viral vaccine. Int J Pharm 350:27–34
Correale P, Del Vecchio MT, La Placa M, Montagnani F, Di Genova G, Savellini GG, Terrosi C, Mannucci S, Giorgi G, Francini G et al (2008) Chemotherapeutic drugs may be used to enhance the killing efficacy of human tumor antigen peptide-specific CTLs. J Immunother 31:132–147
Hayakawa M, Kawaguchi S, Ishii S, Murakami M, Uede T (1997) B7-1-transfected tumor vaccine counteracts chemotherapy-induced immunosuppression and prolongs the survival of rats bearing highly metastatic osteosarcoma cells. Int J Cancer 71:1091–1102
Zheng SJ, Zheng SP, Huang FY, Jiao CL, Wu RL (2007) Synergistic anti-tumor effect of recombinant chicken fibroblast growth factor receptor-1-mediated anti-angiogenesis and low-dose gemcitabine in a mouse colon adenocarcinoma model. World J Gastroenterol 13:2484–2489
Akbulut H, Tang Y, Akbulut KG, Maynard J, Zhang L, Deisseroth A (2006) Antitumor immune response induced by it injection of vector-activated dendritic cells and chemotherapy suppresses metastatic breast cancer. Mol Cancer Ther 5:1975–1985
Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689–3697
Ko HJ, Kim YJ, Kim YS, Chang WS, Ko SY, Chang SY, Sakaguchi S, Kang CY (2007) A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67:7477–7486
Kim CH, Woo SJ, Park JS, Kim HS, Park MY, Park SD, Hong YK, Kim TG (2007) Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma. Immunology 122:615–622
Park SD, Kim CH, Kim CK, Park JA, Sohn HJ, Hong YK, Kim TG (2007) Cross-priming by temozolomide enhances antitumor immunity of dendritic cell vaccination in murine brain tumor model. Vaccine 25:3485–3491
Yang L, Carbone DP (2004) Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 92:13–27
Gabrilovich DI, Chen HL, Girgis KR (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103
Loeffler CM, Smyth MJ, Longo DL (1992) Immunoregulation in cancer-bearing hosts: downregulation of gene expression and cytotoxic function in CD8 T cells. J Immunol 149:949–956
Qin Z, Noffz G, Mohauot M (1997) Interleukin-10 prevent dendritic cell accumulation and vaccination with granulocyte-macrophage colony-stimulating factor gene-modified tumor cells. J Immunol 159:770–776
Malmberg KJ (2004) Effective immunotherapy against cancer: a question of overcoming immune suppression and immune escape? Cancer Immunol Immunother 53:879–892
Timmerman JM, Czerwinski DK, Davis TA, Hsu FJ, Benike C, Hao ZM, Taidi B, Rajapaksa R, Caspar CB, Okada CY et al (2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99:1517–1526
Arteaga CL (2003) ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res 284:122–130
Garcia B, Neninger E, de la Torre A, Leonard I, Martinez R, Viada C, Gonzalez G, Mazorra Z, Lage A, Crombet T (2008) Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine. Clin Cancer Res 14:840–846
Gonzalez G, Crombet T, Catala M, Mirabal V, Hernandez J, Gonzalez Y, Marinello P, Guillen G, Lage A (1998) A novel cancer vaccine composed of human-recombinant epidermal growth factor linked to a carrier protein: report of a pilot clinical trial. Ann Oncol 9:431–435
Gonzalez G, Crombet T, Torres F, Catala M, Alfonso L, Osorio M, Neninger E, Garcia B, Mulet A, Perez R et al (2003) Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy. Ann Oncol 14:461–466
Montero E, Valdes M, Avellanet J, Lopez A, Perez R, Lage A (2009) Chemotherapy induced transient B-cell depletion boosts antibody-forming cells expansion driven by an epidermal growth factor-based cancer vaccine. Vaccine 27:2230–2239
Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, Becker M, Merk J (2008) Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res 14:6456–6468
Vicari AP, Luu R, Zhang N, Patel S, Makinen SR, Hanson DC, Weeratna RD, Krieg AM (2009) Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 58:615–628
Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553
Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114:280–290
Schnurr M, Chen Q, Shin A, Chen W, Toy T, Jenderek C, Green S, Miloradovic L, Drane D, Davis ID et al (2005) Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood 105:2465–2472
Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM (2008) Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112:610–618
Timmerman JM, Czerwinski DK, Davis TA, Hsu FJ, Benike C, Hao ZM, Taidi B, Rajapaksa R, Caspar CB, Okada CY et al (2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99:1517–1526
Krishna IV, Vanaja GR, Kumar NS, Suman G (2009) Cytotoxic studies of anti-neoplastic drugs on human lymphocytes—in vitro studies. Cancer Biomarkers 5:261–272
Dunde S, Geissler A, Olfe J, Starke A, Domanska G, Schuett C, Kiank-Nussbaum C (2011) Side effects of control treatment can conceal experimental data when studying stress responses to injection and psychological stress in mice. Lab Anim (NY) 40:119–128
Rinehart J, Keville L, Measel J, Spiekerman AM, Burke K (1995) Corticosteroid alteration of carboplatin-induced hematopoietic toxicity in a murine model. Blood 86:4493–4499
Wang H, Li M, Rinehart JJ, Zhang R (2004) Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine. Cancer Chemother Pharmacol 53:459–467
Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344
Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868
Lee M, Yea SS, Jeon YJ (2000) Paclitaxel causes mouse splenic lymphocytes to a state hyporesponsive to lipopolysaccharide stimulation. Int J Immunopharmacol 22:615–621
Yuan L, Wu L, Chen J, Wu Q, Hu S (2010) Paclitaxel acts as an adjuvant to promote both Th1 and Th2 immune responses induced by ovalbumin in mice. Vaccine 28:4402–4410
Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384
Markasz L, Skribek H, Uhlin M, Otvos R, Flaberg E, Eksborg S, Olah E, Stuber G, Szekely L (2008) Effect of frequently used chemotherapeutic drugs on cytotoxic activity of human cytotoxic T-lymphocytes. J Immunother 31:283–293
Samanta S, Alam SM, Basu S, Maji T, Roy DK, Jha T (2007) Chemoimmunotherapeutic approach to prolonged survival time in combination with immunization and glutamic acid derivatives with antitumor activity in tumor-bearing mice. Biol Pharm Bull 30:2334–2339
Eralp Y, Wang X, Wang JP, Maughan MF, Polo JM, Lachman LB (2004) Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model. Breast Cancer Res 6:R275–R283
Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont JA, Urba W, Blumenstein B, Sacks N, Keilholz U et al (2007) A clinical development paradigm for cancer vaccines and related biologics. J Immunother 30:1–15
Weng W, Czerwinski D, Levy R (2007) Humoral immune response and immunoglobulin G Fc receptor genotype are associated with better clinical outcome following idiotype vaccination in follicular lymphoma patients regardless of their response to induction chemotherapy. Blood 109:951–953
Cassidy PB, Moos PJ, Kelly RC, Fitzpatrick FA (2002) Cyclooxygenase-2 induction by paclitaxel, docetaxel, and taxane analogues in human monocytes and murine macrophages: structure-activity relationships and their implications. Clin Cancer Res 8:846–855
Collins TS, Lee LF, Ting JP (2000) Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism. Cancer Immunol Immunother 49:78–84
Crown J, O’Leary M (2000) The taxanes: an update. Lancet 355:1176–1178
Kirikae T, Ojima I, Fuero-Oderda C, Lin S, Kirikae F, Hashimoto M, Nakanoc M (2000) Structural significance of the acyl group at the C-10 position and the A ring of the taxane core of paclitaxel for inducing nitric oxide and tumor necrosis factor production by murine macrophages. FEBS Lett 478:221–226
Kim YM, Paik SG (2005) Induction of expression of inducible nitric oxide synthase by taxol in murine macrophage cells. Biochem Biophys Res Commun 326:410–416
El-Gazzar A, Perco P, Eckelhart E, Anees M, Sexl V, Mayer B, Liu Y, Mikulits W, Horvat R, Pangerl T et al (2010) Natural immunity enhances the activity of a DR5 agonistic antibody and carboplatin in the treatment of ovarian cancer. Mol Cancer Ther 9:1007–1018
Geller MA, Bui-Nguyen TM, Rogers LM, Ramakrishnan S (2010) Chemotherapy induces macrophage chemoattractant protein-1 production in ovarian cancer. Int J Gynecol Cancer 20:918–925
Gonzalez G, Lage A (2007) Cancer vaccines for hormone/growth factor immune deprivation: a feasible approach for cancer treatment. Curr Cancer Drug Targets 7:229–241
Campbell MJ, Esserman L, Levy R (1988) Immunotherapy of established murine B cell lymphoma. J Immunol 141:3227–3233
Rodriguez PC, Neninger E, García B, Popa X, Viada C, Luaces P, González G, Lage A, Montero E, Crombet T (2011) Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an epidermal growth factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients. J Immune Based Ther Vaccines 9:7
Neninger E, Verdecia BG, Crombet T, Viada C, Pereda S, Leonard I, Mazorra Z, Fleites G, González M, Wilkinson B et al (2009) Combining an EGF-based cancer vaccine with chemotherapy in advanced non-small cell lung cancer. J Immunother 32:92–99
Yanagimoto H, Mine T, Yamamoto K, Satoi S, Terakawa N, Takahashi K, Nakahara K, Honma S, Tanaka M, Mizoguchi J et al (2007) Immunological evaluation of personalized peptide vaccination with gemcitabine for pancreatic cancer. Cancer Sci 98:605–611
Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J et al (2006) A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 12:1260–1269
Sato Y, Fujiwara T, Mine T, Shomura H, Homma S, Maeda Y, Tokunaga N, Ikeda Y, Ishihara Y, Yamada A et al (2007) Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients. Cancer Sci 98:1113–1119
Kaufman HL, Lenz HJ, Marshall J, Singh D, Garett C, Cripps C, Moore M, von Mehren M, Dalfen R, Heim WJ et al (2008) Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin Cancer Res 14:4843–4849
Weihrauch MR, Ansen S, Jurkiewicz E, Geisen C, Xia Z, Anderson KS, Gracien E, Schmidt M, Wittig B, Diehl V et al (2005) Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5-fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer. Clin Cancer Res 11:5993–6001
Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E et al (2008) Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 14:1455–1463
Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC et al (2009) Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol 27:5911–5918
von Mehren M, Arlen P, Gulley J, Rogatko A, Cooper HS, Meropol NJ, Alpaugh RK, Davey M, McLaughlin S, Beard MT et al (2001) 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 7:1181–1191
Small E, Demkow T, Gerritson W et al (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel vs docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). GU ASCO
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Special thanks to Drs. Sebastien and Ruby Lemoine for carefully reviewing the manuscript. This study was supported by the Cuban Government.
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Diaz, Y., Tundidor, Y., Lopez, A. et al. Concomitant combination of active immunotherapy and carboplatin- or paclitaxel-based chemotherapy improves anti-tumor response. Cancer Immunol Immunother 62, 455–469 (2013). https://doi.org/10.1007/s00262-012-1345-y
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DOI: https://doi.org/10.1007/s00262-012-1345-y