ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Combination strategies for enhancing the efficacy of immunotherapy in cancer patients
Federica Moschella,
Enrico Proietti,
Imerio Capone,
Filippo Belardelli,
Federica Moschella
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorEnrico Proietti
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorImerio Capone
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorFilippo Belardelli
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorFederica Moschella,
Enrico Proietti,
Imerio Capone,
Filippo Belardelli,
Federica Moschella
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorEnrico Proietti
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorImerio Capone
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorFilippo Belardelli
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
Search for more papers by this authorAddress for correspondence: Filippo Belardelli, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. [email protected]
Abstract
A major challenge in cancer immunotherapy is the identification of effective strategies for enhancing its clinical efficacy. One approach is based on adjuvants capable of breaking tolerance against tumor-associated antigens. Interferon-α(IFN-α), an antiviral cytokine with a long record of clinical use, has recently been shown to act as an effective adjuvant in cancer patients. Notably, a special interest is currently focused on the use of dendritic cells (DC) generated in the presence of IFN-α (IFN-DC) for the preparation of anticancer vaccines. An additional approach for enhancing the response to immunotherapy relies on its combination with chemotherapy. In fact, an ensemble of results from both studies in animal models and pilot clinical trials suggest that certain chemotherapeutic agents can act, under defined conditions, as strong adjuvants for enhancing the efficacy of immunotherapy. These results open new opportunities for designing mechanism-based combination therapies involving both chemotherapy and new-generation cancer vaccines, including IFN-DC-based vaccines.
References
- 1 Disis, M.L., H. Bernhard & E.M. Jaffee. 2009. Use of tumour-responsive T cells as cancer treatment. Lancet. 373: 673–683.
- 2 Rosenberg, S.A., J.C. Yang & N.P. Restifo. 2004. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10: 909–915.
- 3 Galon, J. et al . 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960–1964.
- 4 Zou, W. 2006. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6: 295–307.
- 5 Nagaraj, S. & D.I. Gabrilovich. 2008. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 68: 2561–2563.
- 6 Wei, W.Z. et al . 2005. Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25 +regulatory T cell-depleted mice. Cancer Res. 65: 8471–8478.
- 7 Phan, G.Q. et al . 2003. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA 100: 8372–8377.
- 8 Le Bon, A. & D.F. Tough. 2002. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14: 432–436.
- 9 Belardelli, F. & I. Gresser. 1996. The neglected role of type I interferon in the T-cell response: implications for its clinical use. Immunol. Today 17: 369–372.
- 10 Ferrantini, M., I. Capone & F. Belardelli. 2007. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie 89: 884–893.
- 11 Ferrantini, M. & F. Belardelli. 2000. Gene therapy of cancer with interferon: lessons from tumor models and perspectives for clinical applications. Semin. Cancer Biol. 10: 145–157.
- 12 Belardelli, F. et al . 1998. The induction of in vivo proliferation of long-lived CD44hi CD8+ T cells after the injection of tumor cells expressing IFN-alpha1 into syngeneic mice. Cancer Res. 58: 5795–5802.
- 13 Sikora, A.G. et al . 2009. IFN-alpha enhances peptide vaccine-induced CD8+ T cell numbers, effector function, and antitumor activity. J. Immunol. 182: 7398–7407.
- 14 Santini, S.M. et al . 2000. Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice. J. Exp. Med. 191: 1777–1788.
- 15 Santini, S.M. et al . 2009. IFN-alpha in the generation of dendritic cells for cancer immunotherapy. Handb. Exp. Pharmacol. 295–317.
- 16 Parlato, S. et al . 2001. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood 98: 3022–3029.
- 17 Moschella, F. et al . 2003. Gene expression profiling and functional activity of human dendritic cells induced with IFN-alpha-2b: implications for cancer immunotherapy. Clin. Cancer Res. 9: 2022–2031.
- 18 Lapenta, C. et al . 2003. Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. J. Exp. Med. 198: 361–367.
- 19 Lapenta, C. et al . 2006. IFN-alpha-conditioned dendritic cells are highly efficient in inducing cross-priming CD8(+) T cells against exogenous viral antigens. Eur. J. Immunol. 36: 2046–2060.
- 20 Le Bon, A. et al . 2001. Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14: 461–470.
- 21 Belardelli, F. et al . 2002. Interferon-alpha in tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13: 119–134.
- 22 Rizza, P. et al . 2008. Evaluation of the effects of human leukocyte IFN-alpha on the immune response to the HBV vaccine in healthy unvaccinated individuals. Vaccine 26: 1038–1049.
- 23 Miquilena-Colina, M.E. et al . 2009. Recombinant interferon-alpha2b improves immune response to hepatitis B vaccination in haemodialysis patients: results of a randomised clinical trial. Vaccine 27: 5654–5660.
- 24 Di Pucchio, T. et al . 2006. Immunization of stage IV melanoma patients with Melan-A/MART-1 and gp100 peptides plus IFN-alpha results in the activation of specific CD8(+) T cells and monocyte/dendritic cell precursors. Cancer Res. 66: 4943–4951.
- 25 Gogas, H. et al . 2006. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N. Engl. J. Med. 354: 709–718.
- 26 Kirkwood, J.M. et al . 2009. Immunogenicity and antitumor effects of vaccination with peptide vaccine+/-granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin. Cancer Res. 15: 1443–1451.
- 27 Gogas, H. & J.M. Kirkwood. 2009. Predictors of response to interferon therapy. Curr. Opin. Oncol. 21: 138–143.
- 28 Maguire, H.C., Jr. & V.L. Ettore. 1967. Enhancement of dinitrochlorobenzene (DNCB) contact sensitization by cyclophosphamide in the guinea pig. J. Invest. Dermatol. 48: 39–43.
- 29 Rosenberg, S.A., P. Spiess & R. Lafreniere. 1986. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233: 1318–1321.
- 30 Awwad, M. & R.J. North. 1988. Cyclophosphamide (Cy)-facilitated adoptive immunotherapy of a Cy-resistant tumour. Evidence that Cy permits the expression of adoptive T-cell mediated immunity by removing suppressor T cells rather than by reducing tumour burden. Immunology 65: 87–92.
- 31 Garaci, E. et al . 1990. Combination treatment using thymosin alpha 1 and interferon after cyclophosphamide is able to cure Lewis lung carcinoma in mice. Cancer Immunol. Immunother. 32: 154–160.
- 32 Garaci, E. et al . 1993. Antitumor effect of thymosin alpha 1/interleukin-2 or thymosin alpha 1/interferon alpha, beta following cyclophosphamide in mice injected with highly metastatic Friend erythroleukemia cells. J. Immunother. Emphasis. Tumor Immunol. 13: 7–17.
- 33 Pica, F. et al . 1998. High doses of thymosin alpha 1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma. Anticancer Res. 18: 3571–3578.
- 34 Nowak, A.K., R.A. Lake & B.W. Robinson. 2006. Combined chemoimmunotherapy of solid tumours: improving vaccines? Adv. Drug Deliv. Rev. 58: 975–990.
- 35 Dummer, W. et al . 2002. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J. Clin. Invest. 110: 185–192.
- 36 Proietti, E. et al . 1998. Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice. J. Clin. Invest. 101: 429–441.
- 37 Vierboom, M.P. et al . 2000. Cyclophosphamide enhances anti-tumor effect of wild-type p53-specific CTL. Int. J. Cancer 87: 253–260.
- 38 Machiels, J.P. et al . 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.
- 39 Dudley, M.E. et al . 2002. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298: 850–854.
- 40 Schiavoni, G. et al . 2000. Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 95: 2024–2030.
- 41 Hermans, I.F. et al . 2003. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res. 63: 8408–8413.
- 42 Matar, P. et al . 2002. Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol. Immunother. 50: 588–596.
- 43 Ghiringhelli, F. et al . 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.
- 44 Lutsiak, M.E. et al . 2005. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105: 2862–2868.
- 45 Bracci, L. et al . 2007. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin. Cancer Res. 13: 644–653.
- 46 Gattinoni, L. et al . 2005. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202: 907–912.
- 47 Salem, M.L. et al . 2007. Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J. Immunother. 30: 40–53.
- 48 Radojcic, V. et al . 2009. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol. Immunother.
- 49 Van Der Most, R.G. et al . 2008. Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all. Cell Death Differ. 15: 13–20.
- 50 Green, D.R. et al . 2009. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9: 353–363.
- 51 Casares, N. et al . 2005. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202: 1691–1701.
- 52 Berd, D., H.C. Maguire, Jr. & M.J. Mastrangelo. 1986. 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.
- 53
Bystryn, J.C.
et al
. 1988. Immunogenicity of a polyvalent melanoma antigen vaccine in humans.
Cancer
61: 1065–1070.
10.1002/1097-0142(19880315)61:6<1065::AID-CNCR2820610602>3.0.CO;2-L CASPubMedWeb of Science®Google Scholar
- 54 Berd, D. et al . 1990. Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J. Clin. Oncol. 8: 1858–1867.
- 55 Livingston, P.O. et al . 1994. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J. Clin. Oncol. 12: 1036–1044.
- 56 Vaishampayan, U. et al . 2002. Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin. Cancer Res. 8: 3696–3701.
- 57 Hoon, D.S. et al . 1990. Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res. 50: 5358–5364.
- 58 Ghiringhelli, F. et al . 2007. 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.
- 59 Dudley, M.E. et al . 2005. 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.
- 60 Dudley, M.E. et al . 2008. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26: 5233–5239.
- 61 North, S.A. et al . 2006. A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy. J. Urol. 176: 91–95.
- 62 MacLean, G.D. et al . 1996. 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.
- 63 Gonzalez, G. et al . 2003. Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy. Ann. Oncol. 14: 461–466.
- 64 Neninger, E. et al . 2009. Combining an EGF-based cancer vaccine with chemotherapy in advanced nonsmall cell lung cancer. J. Immunother. 32: 92–99.
- 65 Holtl, L. et al . 2005. Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol. Immunother. 54: 663–670.
- 66 Nistico, P. et al . 2009. Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients. Int. J. Cancer. 124: 130–139.
- 67 Tong, Y., W. Song & R.G. Crystal. 2001. Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Res. 61: 7530–7535.
