Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nature Rev. Immunol. 6, 715–727 (2006).
Kelland, L. R. Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur. J. Cancer 40, 827–836 (2004).
Prendergast, G. C. & Jaffee, E. M. Cancer immunologists and cancer biologists: why we didn't talk then but need to now. Cancer Res. 67, 3500–3504 (2007).
Marzo, A. L. et al. Tumor antigens are constitutively presented in the draining lymph nodes. J. Immunol. 162, 5838–5845 (1999).
Weiner, H. L. & Cohen, J. A. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult. Scler. 8, 142–154 (2002).
Weinblatt, M. E. et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822 (1985).
Seggewiss, R. et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105, 2473–2479 (2005).
Mumprecht, S., Matter, M., Pavelic, V. & Ochsenbein, A. F. Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections. Blood 108, 3406–3413 (2006).
The first observation of the deleterious role of imatinib mesylate on memory T-cell responses in mice.
Mattiuzzi, G. N. et al. Development of Varicella–Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Clin. Cancer Res. 9, 976–980 (2003).
Galon, J. et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 16, 61–71 (2002).
Rozkova, D., Horvath, R., Bartunkova, J. & Spisek, R. Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors. Clin. Immunol. 120, 260–271 (2006).
Chiossone, L. et al. Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. Blood 109, 3767–3775 (2007).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54–61 (2007).
The first demonstration of the role of cell-surface calreticulin in the uptake of dying tumour cells by DCs and, therefore, its involvement in antitumour immune responses.
Grunhagen, D. J. et al. One hundred consecutive isolated limb perfusions with TNF-α and melphalan in melanoma patients with multiple in-transit metastases. Ann. Surg. 240, 939–947; discussion 947–948 (2004).
Thom, A. K. et al. Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon γ, and melphalan. J. Clin. Oncol. 13, 264–273 (1995).
Lin, W. W. & Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007).
Morgan, D. J., Kreuwel, H. T. & Sherman, L. A. Antigen concentration and precursor frequency determine the rate of CD8+ T cell tolerance to peripherally expressed antigens. J. Immunol. 163, 723–727 (1999).
Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).
The important link between the intrinsic and the extrinsic tumour-suppressor mechanisms is highlighted by showing that the DNA-damage response induces expression of NKG2D ligands in an ATM- or ATR-dependent manner.
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
This paper shows the pivotal role of p53 in established and ongoing tumorigenesis. Restoration of p53 function in established tumours leads to tumour regression by promoting tumour-cell senescence and an inflammatory cascade, leading to the recruitment of neutrophils, macrophages and NK cells.
Hareyama, M. et al. Effect of radiation on the expression of carcinoembryonic antigen on the membranes of human gastric adenocarcinoma cells — immunological study using monoclonal antibodies. Nippon Igaku Hoshasen Gakkai Zasshi 48, 1572–1574 (1988).
Gaugler, M. H. et al. Late and persistent up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression by ionizing radiation in human endothelial cells in vitro. Int. J. Radiat. Biol. 72, 201–209 (1997).
Garnett, C. T. et al. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res. 64, 7985–7994 (2004).
Lugade, A. A. et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 174, 7516–7523 (2005).
Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).
This paper describes the immunological side effects of irradiation in vivo, showing that distant tumours can regress as a result of local irradiation and the synergistic antitumour effects between adoptive cell therapy and irradiation. Also, a comprehensive study of antigen processing and the presentation machinery following irradiation of tumour cells is provided.
Milas, L. et al. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res. 64, 5074–5077 (2004).
Muranski, P. et al. Increased intensity lymphodepletion and adoptive immunotherapy — how far can we go? Nature Clin. Pract. Oncol. 3, 668–681 (2006).
Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
A seminal clinical demonstration that lymphodepletion followed by adoptive T-cell therapy can have a positive impact on advanced melanomas.
North, R. J. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J. Exp. Med. 155, 1063–1074 (1982).
This study shows that cyclophosphamide can inhibit tumour-induced suppressor T cells, thereby working in synergy with adoptive cell transfer.
Dudley, M. E. et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23, 2346–2357 (2005).
Paulos, C. M. et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117, 2197–2204 (2007).
Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).
Badovinac, V. P., Messingham, K. A., Jabbari, A., Haring, J. S. & Harty, J. T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nature Med. 11, 748–756 (2005).
Wrzesinski, C. et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J. Clin. Invest. 117, 492–501 (2007).
An important observation indicating the clinical benefit expected when combining vaccination and adoptive cell transfer after lymphodepletion.
Turk, J. L. & Parker, D. Effect of cyclophosphamide on immunological control mechanisms. Immunol. Rev. 65, 99–113 (1982).
Lutsiak, M. E. et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105, 2862–2868 (2005).
Schiavoni, G. et al. Cyclophosphamide induces type I interferon and augments the number of CD44hi T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 95, 2024–2030 (2000).
The first demonstration that low doses of cyclophosphamide can promote type I IFN secretion.
Glaser, M. Regulation of specific cell-mediated cytotoxic response against SV40-induced tumor associated antigens by depletion of suppressor T cells with cyclophosphamide in mice. J. Exp. Med. 149, 774–779 (1979).
Sutmuller, R. P. 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).
Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).
MacLean, G. D., Miles, D. W., Rubens, R. D., Reddish, M. A. & Longenecker, B. M. Enhancing the effect of THERATOPE STn–KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J. Immunother. Emphasis Tumor. Immunol. 19, 309–316 (1996).
Berd, D., Maguire, H. C. Jr & Mastrangelo, M. J. Induction of cell-mediated immunity to autologous melanoma cells and regression of metastases after treatment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res. 46, 2572–2577 (1986).
Berd, D. & Mastrangelo, M. J. Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2H4+ suppressor-inducer T-cells. Cancer Res. 48, 1671–1675 (1988).
Ghiringhelli, F. et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J. Exp. Med. 202, 1075–1085 (2005).
The first demonstration of the inhibitory effect of TReg cells on NK-cell responses in mice and humans in vitro and in vivo.
Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).
A clinical protocol testing the dose of oral cyclophosphamide needed to control end-stage tumours associated with restoration of T-cell and NK-cell functions in patients.
Orsini, F., Pavelic, Z. & Mihich, E. Increased primary cell-mediated immunity in culture subsequent to adriamycin or daunorubicin treatment of spleen donor mice. Cancer Res. 37, 1719–1726 (1977).
A pioneering study highlighting the indirect role of anthracyclines in boosting cellular immunity.
Arinaga, S., Akiyoshi, T. & Tsuji, H. Augmentation of the generation of cell-mediated cytotoxicity after a single dose of adriamycin in cancer patients. Cancer Res. 46, 4213–4216 (1986).
Nigam, A. et al. Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. Int. J. Oncol. 12, 161–170 (1998).
Zagozdzon, R. et al. Effective chemo-immunotherapy of L1210 leukemia in vivo using interleukin-12 combined with doxorubicin but not with cyclophosphamide, paclitaxel or cisplatin. Int. J. Cancer 77, 720–727 (1998).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Byrd-Leifer, C. A., Block, E. F., Takeda, K., Akira, S. & Ding, A. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur. J. Immunol. 31, 2448–2457 (2001).
Machiels, J. P. et al. 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 (2001).
Interesting and elegant work providing evidence for the synergistic antitumour effects of genetically modified tumour vaccines and chemotherapy, both overcoming tumour-induced tolerance.
Yu, B. et al. Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin. Cancer Res. 9, 285–294 (2003).
Chu, Y. et al. Efficacy of GM-CSF-producing tumor vaccine after docetaxel chemotherapy in mice bearing established Lewis lung carcinoma. J. Immunother. 29, 367–380 (2006).
Carson, W. E. 3rd, Shapiro, C. L., Crespin, T. R., Thornton, L. M. & Andersen, B. L. Cellular immunity in breast cancer patients completing taxane treatment. Clin. Cancer Res. 10, 3401–3409 (2004).
Nowak, A. K., Robinson, B. W. & Lake, R. A. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res. 62, 2353–2358 (2002).
Qin, Z. et al. B cells inhibit induction of T cell-dependent tumor immunity. Nature Med. 4, 627–630 (1998).
Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).
Nowak, A. K. et al. 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 (2003).
Nowak, A. K., Robinson, B. W. & Lake, R. A. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 63, 4490–4496 (2003).
The first study to delineate the idea that chemotherapy-induced cell death can be immunogenic rather than tolerogenic in tumour-bearing mice.
Plate, J. M., Plate, A. E., Shott, S., Bograd, S. & Harris, J. E. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol. Immunother. 54, 915–925 (2005).
Levitt, M. L. et al. Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms. Lung Cancer 43, 335–344 (2004).
Correale, P. et al. Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J. Clin. Oncol. 23, 8950–8958 (2005).
Galetto, A. et al. Drug- and cell-mediated antitumor cytotoxicities modulate cross-presentation of tumor antigens by myeloid dendritic cells. Anticancer Drugs 14, 833–843 (2003).
Tanaka, F. et al. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int. J. Cancer 101, 265–269 (2002).
Correale, P. et al. 5-fluorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine. J. Natl Cancer Inst. 97, 1437–1445 (2005).
Lubbert, M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr. Top. Microbiol. Immunol. 249, 135–164 (2000).
Serrano, A. et al. Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int. J. Cancer 94, 243–251 (2001).
Kozar, K. et al. Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2′-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice. Clin. Cancer Res. 9, 3124–3133 (2003).
Baguley, B. C. Antivascular therapy of cancer: DMXAA. Lancet Oncol. 4, 141–148 (2003).
Jassar, A. S. et al. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 65, 11752–11761 (2005).
Roberts, Z. J. et al. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J. Exp. Med. 204, 1559–1569 (2007).
References 69,70,71 highlight the unexpected immunological side effects of the flavonoids.
Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004).
Fernandez, N. C. et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nature Med. 5, 405–411 (1999).
Taieb, J. et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nature Med. 12, 214–219 (2006).
References 72 and 74 highlight the role of imatinib mesylate in enhancing innate immune responses, leading to the regression of NK-cell-dependent tumours.
Lake, R. A. & Robinson, B. W. Immunotherapy and chemotherapy — a practical partnership. Nature Rev. Cancer 5, 397–405 (2005).
Somersan, S. et al. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J. Immunol. 167, 4844–4852 (2001).
Srivastava, P. K. Immunotherapy for human cancer using heat shock protein-peptide complexes. Curr. Oncol. Rep. 7, 104–108 (2005).
Binder, R. J. & Srivastava, P. K. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nature Immunol. 6, 593–599 (2005).
Li, Z. et al. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia. Clin. Cancer Res. 11, 4460–4468 (2005).
Spisek, R. et al. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 109, 4839–4845 (2007).
Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of γ-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).
Obeid, M. et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220, 22–34 (2007)
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007).
The first demonstration of a role for TLR4 and HMGB1 in the antitumour effects that are mediated by chemotherapy and radiotherapy.
Apetoh L et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220, 47–59 (2007).
Shiratsuchi, A., Watanabe, I., Takeuchi, O., Akira, S. & Nakanishi, Y. Inhibitory effect of Toll-like receptor 4 on fusion between phagosomes and endosomes/lysosomes in macrophages. J. Immunol. 172, 2039–2047 (2004).
Antonia, S. J. et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin. Cancer Res. 12, 878–887 (2006).
Gribben, J. G. et al. Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy. Clin. Cancer Res. 11, 4430–4436 (2005).
Arlen, P. M. et al. 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 (2006).
Noguchi, M. et al. Immunological evaluation of individualized peptide vaccination with a low dose of estramustine for HLA-A24+ HRPC patients. Prostate 63, 1–12 (2005).
Sun, T. et al. FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer. J. Exp. Med. 202, 967–974 (2005).
Lech-Maranda, E. et al. Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood 103, 3529–3534 (2004).
Bushley, A. W. et al. Polymorphisms of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and IL-18 and the risk of ovarian cancer. Gynecol. Oncol. 95, 672–679 (2004).
Nimmerjahn, F. & Ravetch, J. V. Antibodies, Fc receptors and cancer. Curr. Opin. Immunol. 19, 239–245 (2007).
Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12 (Suppl. 2), 1463–1467 (2005).
Zitvogel, L. et al. Immune response against dying tumor cells. Adv. Immunol. 84, 131–179 (2004).
Claude, L. et al. Lymphopenia: a new independent prognostic factor for survival in patients treated with whole brain radiotherapy for brain metastases from breast carcinoma. Radiother. Oncol. 76, 334–339 (2005).
Schuerwegh, A. J., van Offel, J. F., Bridts, C. H., Stevens, W. J. & De Clerck, L. S. Influence of longterm therapy with methotrexate and low dose corticosteroids on type 1 and type 2 cytokine production in CD4+ and CD8+ T lymphocytes of patients with rheumatoid arthritis. J. Rheumatol. 28, 1793–1799 (2001).
Panici, P. B. et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J. Natl Cancer Inst. 97, 560–566 (2005).
Chan, O. T. & Yang, L. X. The immunological effects of taxanes. Cancer Immunol. Immunother. 49, 181–185 (2000).
Chakraborty, M. et al. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 64, 4328–4337 (2004).
Cho, B. K., Rao, V. P., Ge, Q., Eisen, H. N. & Chen, J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J. Exp. Med. 192, 549–556 (2000).
Ge, Q., Hu, H., Eisen, H. N. & Chen, J. Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. Proc. Natl Acad. Sci. USA 99, 2989–2994 (2002).
Ghiringhelli, F. et al. 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 (2004).
Mullins, D. W., Burger, C. J. & Elgert, K. D. Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide. J. Immunol. 162, 6811–6818 (1999).
Yuan, L. et al. Restoration of macrophage tumoricidal activity by bleomycin correlates with the decreased production of transforming growth factor β in rats bearing KDH-8 hepatoma cells. Cancer Immunol. Immunother. 45, 71–76 (1997).
Hornung, R. L., Young, H. A., Urba, W. J. & Wiltrout, R. H. Immunomodulation of natural killer cell activity by flavone acetic acid: occurrence via induction of interferon α/β. J. Natl Cancer Inst. 80, 1226–1231 (1988).
Keilholz, U. et al. Dacarbazine, cisplatin, and interferon-α2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J. Clin. Oncol. 23, 6747–6755 (2005).
Bajetta, E. et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-α2b in metastatic melanoma. Ann. Oncol. 17, 571–577 (2006).
Massacesi, C., Burattini, L., Marcucci, F. & Bonsignori, M. Short communication: the efficacy of fixed dose rate infusion of gemcitabine combined with IFN-α2a in patients with advanced refractory renal cell carcinoma. J. Interferon Cytokine Res. 25, 165–168 (2005).
Atzpodien, J. et al. Interleukin-2- and interferon α2a-based immunochemotherapy in advanced renal cell carcinoma: a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J. Clin. Oncol. 22, 1188–1194 (2004).
Parra, H. S. et al. Combined regimen of cisplatin, doxorubicin, and α-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP). Cancer 92, 650–656 (2001).
Ishida, A. et al. Intrapleural cisplatin and OK432 therapy for malignant pleural effusion caused by non-small cell lung cancer. Respirology 11, 90–97 (2006).
Kasamon, Y. L. et al. Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia. Clin. Cancer Res. 11, 8413–8417 (2005).
Gomez, G. G., Hutchison, R. B. & Kruse, C. A. Chemo-immunotherapy and chemo-adoptive immunotherapy of cancer. Cancer Treat. Rev. 27, 375–402 (2001).
Ehrlich, P. Über den jetztigen Stand der Karzinomforschung. Ned.Tijdschr. Geneeskd. 5, 273–290, 1909 (in German).
Burnet, M. Cancer; a biological approach. I. The processes of control. BMJ 1, 779–786 (1957).
van den Broek, M. E. et al. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 184, 1781–1790 (1996).
Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).