A B-cell lymphoma vaccine using a depot formulation of interleukin-2 induces potent antitumor immunity despite increased numbers of intratumoral regulatory T cells
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Therapeutic vaccination holds great potential as complementary treatment for non-Hodgkin’s lymphoma. Here, we report that a therapeutic whole cell vaccine formulated with IL-2 adsorbed onto aluminum hydroxide as cytokine-depot formulation elicits potent antitumor immunity and induces delayed tumor growth, control of tumor dissemination and longer survival in mice challenged with A20-lymphoma. Therapeutic vaccination induced higher numbers of tumor’s infiltrating lymphocytes (CD4+ and CD8+ T cells and NK cells), and the production of IFN-γ and IL-4 by intratumoral CD4+ T cells. Further, strong tumor antigen-specific cellular responses were detected at systemic level. Both the A20-derived antigenic material and the IL-2 depot formulation were required for induction of an effective immune response that impacted on cancer progression. All mice receiving any form of IL-2, either as part of the vaccine or alone as control, showed higher numbers of CD4+CD25+/highFoxp3+ regulatory T cells (Treg) in the tumor, which might have a role in tumor progression in these animals. Nevertheless, for those animals that received the cytokine as part of the vaccine formulation, the overall effect was improved immune response and less disseminated disease, suggesting that therapeutic vaccination overcomes the potential detrimental effect of intratumoral Treg cells. Overall, the results presented here show that a simple vaccine formulation, that can be easily prepared under GMP conditions, is a promising strategy to be used in B-cell lymphoma and may have enough merit to be tested in clinical trials.
KeywordsLymphoma Vaccine Interleukin-2 Aluminum hydroxide Regulatory T cells
This work was partially supported by a grant from the Comisión Sectorial de Investigación Científica (CSIC). Universidad de la República. Uruguay. S. Grille was funded by a scholarship of ProInBio, Uruguay and CSIC. The authors thank Prof. Dr. Miguel Torres and Tech. Mr. Marcelo Curbelo of the Departament of Radiotherapy, Hospital de Clínicas for technical assistance. S.G. designed and performed the experiments, and analyzed data. D.L. and J.A.C. designed the experiments and analyzed data. A.B. performed the experiments, collected and analyzed data. E.C and F.W.F. contributed with vital reagents (IL-2-AL), and contributed to experimental design. M.N. analyzed the data and S.G., D.L., and J.A.C. wrote the manuscript.
- 1.Marcus R, Hagenbeek A (2007) The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Eur J Haematol Suppl (67):5–14Google Scholar
- 2.Neelapu SS, Kwak LW (2007) Vaccine therapy for B-cell lymphomas: next-generation strategies. In: Gewirtz AM, Winter JN, Zuckerman K (eds) American Society of Hematology education program book. Atlanta, GA, pp 243–249Google Scholar
- 7.Timmerman JM, Czerwinski DK, Davis TA, Hsu FJ, Benike C, Hao ZM, Taidi B, Rajapaksa R, Caspar CB, Okada CY, Van BA, Liles TM, Engleman EG, Levy R (2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99(5):1517–1526CrossRefPubMedGoogle Scholar
- 15.Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105–2116PubMedGoogle Scholar
- 18.Gluck WL, Hurst D, Yuen A, Levine AM, Dayton MA, Gockerman JP, Lucas J, Denis-Mize K, Tong B, Navis D, Difrancesco A, Milan S, Wilson SE, Wolin M (2004) Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-Hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin Cancer Res 10(7):2253–2264CrossRefPubMedGoogle Scholar
- 19.Eisenbeis CF, Grainger A, Fischer B, Baiocchi RA, Carrodeguas L, Roychowdhury S, Chen L, Banks AL, Davis T, Young D, Kelbick N, Stephens J, Byrd JC, Grever MR, Caligiuri MA, Porcu P (2004) Combination immunotherapy of B-cell non-Hodgkin’s lymphoma with rituximab and interleukin-2: a preclinical and phase I study. Clin Cancer Res 10(18 Pt 1):6101–6110CrossRefPubMedGoogle Scholar
- 22.Falkenberg Frank W, Krup Oliver C (1999) Compositions and methods for treatment of tumors and metastatic diseases. 261816. 18-6-2002. 3-2-1999. Ref Type: PatentGoogle Scholar
- 34.Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S (2008) Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica 93(2):193–200CrossRefPubMedGoogle Scholar
- 39.Cesana GC, DeRaffele G, Cohen S, Moroziewicz D, Mitcham J, Stoutenburg J, Cheung K, Hesdorffer C, Kim-Schulze S, Kaufman HL (2006) Characterization of CD4+ CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 24(7):1169–1177CrossRefPubMedGoogle Scholar
- 40.Kato Y, Yoshimura K, Shin T, Verheul H, Hammers H, Sanni TB, Salumbides BC, Van EK, Schulick R, Pili R (2007) Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma. Clin Cancer Res 13(15 Pt 1):4538–4546CrossRefPubMedGoogle Scholar