Safety and Immunogenicity of Recombinant WT1 Antigen-Specific Cancer Immunotherapeutic Combined With Infusion of Treg Depleted T Cells for Adult WT1 Acute Myeloid Leukemia

Summary

The purpose of this study is to evaluate the safety and the efficacy of combined treatment strategy of WT1ASCI, infusion of ex vivo regulatory T cells depleted T lymphocytes and in vivo regulatory T cells depletion as post-consolidation therapy in patients with WT1-positive Acute Myeloid Leukemia. The study will also evaluate the clinical activity and immune response of this approach in bad risk patients in CR1 and all patients in CR2 or CR3, non eligible for an allogeneic Hematopoietic Stem Cell Transplantation

Timeline

Start

2011-12

Primary completion

2013-12

Completion

2014-12

Publications

• Background Alatrash G, Molldrem JJ. Vaccines as consolidation therapy for myeloid leukemia. Expert Rev Hematol. 2011 Feb;4(1):37-50. doi: 10.1586/ehm.10.80.
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• Background Cao X. Regulatory T cells and immune tolerance to tumors. Immunol Res. 2010 Mar;46(1-3):79-93. doi: 10.1007/s12026-009-8124-7.
• Background Zhao J, Cao Y, Lei Z, Yang Z, Zhang B, Huang B. Selective depletion of CD4+CD25+Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels. Cancer Res. 2010 Jun 15;70(12):4850-8. doi: 10.1158/0008-5472.CAN-10-0283. Epub 2010 May 25.
• Background Cao Y, Zhao J, Yang Z, Cai Z, Zhang B, Zhou Y, Shen GX, Chen X, Li S, Huang B. CD4+FOXP3+ regulatory T cell depletion by low-dose cyclophosphamide prevents recurrence in patients with large condylomata acuminata after laser therapy. Clin Immunol. 2010 Jul;136(1):21-9. doi: 10.1016/j.clim.2010.02.020. Epub 2010 Mar 24.
• Background Casalegno-Garduno R, Schmitt A, Wang X, Xu X, Schmitt M. Wilms' tumor 1 as a novel target for immunotherapy of leukemia. Transplant Proc. 2010 Oct;42(8):3309-11. doi: 10.1016/j.transproceed.2010.07.034.
• Background Copier J, Dalgleish AG, Britten CM, Finke LH, Gaudernack G, Gnjatic S, Kallen K, Kiessling R, Schuessler-Lenz M, Singh H, Talmadge J, Zwierzina H, Hakansson L. Improving the efficacy of cancer immunotherapy. Eur J Cancer. 2009 May;45(8):1424-31. doi: 10.1016/j.ejca.2008.12.017. Epub 2009 Jan 21.
• Background Nizar S, Copier J, Meyer B, Bodman-Smith M, Galustian C, Kumar D, Dalgleish A. T-regulatory cell modulation: the future of cancer immunotherapy? Br J Cancer. 2009 Jun 2;100(11):1697-703. doi: 10.1038/sj.bjc.6605040. Epub 2009 Apr 21.
• Background Dao T, Scheinberg DA. Peptide vaccines for myeloid leukaemias. Best Pract Res Clin Haematol. 2008 Sep;21(3):391-404. doi: 10.1016/j.beha.2008.05.001.
• Background Tsuboi A, Oka Y, Kyo T, Katayama Y, Elisseeva OA, Kawakami M, Nishida S, Morimoto S, Murao A, Nakajima H, Hosen N, Oji Y, Sugiyama H. Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease. Leukemia. 2012 Jun;26(6):1410-3. doi: 10.1038/leu.2011.343. Epub 2011 Dec 13. No abstract available.
• Background Tamura H, Dan K, Yokose N, Iwakiri R, Ohta M, Sakamaki H, Tohyama K, Kondo A, Hyodo H, Nakamura K, Yamashita T, Elisseeva OA, Oka Y, Oji Y, Sugiyama H, Ogata K. Prognostic significance of WT1 mRNA and anti-WT1 antibody levels in peripheral blood in patients with myelodysplastic syndromes. Leuk Res. 2010 Aug;34(8):986-90. doi: 10.1016/j.leukres.2009.11.029. Epub 2010 Jan 19.
• Background Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. doi: 10.1111/j.1348-0421.2008.00080.x.
• Background Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH, Soma T, Tamaki H, Kawakami M, Oji Y, Hosen N, Kubota T, Nakagawa M, Yamagami T, Hiraoka A, Tsukaguchi M, Udaka K, Ogawa H, Kishimoto T, Nomura T, Sugiyama H. Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood. 2002 May 1;99(9):3272-9. doi: 10.1182/blood.v99.9.3272.
• Background Elkord E, Alcantar-Orozco EM, Dovedi SJ, Tran DQ, Hawkins RE, Gilham DE. T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther. 2010 Nov;10(11):1573-86. doi: 10.1517/14712598.2010.529126.
• Background Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Tanaka-Harada Y, Hosen N, Nishida S, Shirakata T, Nakajima H, Tatsumi N, Hashimoto N, Taguchi T, Ueda S, Nonomura N, Takeda Y, Ito T, Myoui A, Izumoto S, Maruno M, Yoshimine T, Noguchi S, Okuyama A, Kawase I, Oji Y, Sugiyama H. A clear correlation between WT1-specific Th response and clinical response in WT1 CTL epitope vaccination. Anticancer Res. 2010 Jun;30(6):2247-54.
• Background Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. 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. 2007 May;56(5):641-8. doi: 10.1007/s00262-006-0225-8. Epub 2006 Sep 8.
• Background Golovina TN, Vonderheide RH. Regulatory T cells: overcoming suppression of T-cell immunity. Cancer J. 2010 Jul-Aug;16(4):342-7. doi: 10.1097/PPO.0b013e3181eb336d.
• Background Ochsenreither S, Fusi A, Busse A, Bauer S, Scheibenbogen C, Stather D, Thiel E, Keilholz U, Letsch A. "Wilms Tumor Protein 1" (WT1) peptide vaccination-induced complete remission in a patient with acute myeloid leukemia is accompanied by the emergence of a predominant T-cell clone both in blood and bone marrow. J Immunother. 2011 Jan;34(1):85-91. doi: 10.1097/CJI.0b013e3181f3cc5c.
• Background Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW, Hofmann WK, Uharek L, Thiel E, Scheibenbogen C. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood. 2009 Jun 25;113(26):6541-8. doi: 10.1182/blood-2009-02-202598. Epub 2009 Apr 23.
• Background Maslak PG, Dao T, Krug LM, Chanel S, Korontsvit T, Zakhaleva V, Zhang R, Wolchok JD, Yuan J, Pinilla-Ibarz J, Berman E, Weiss M, Jurcic J, Frattini MG, Scheinberg DA. Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood. 2010 Jul 15;116(2):171-9. doi: 10.1182/blood-2009-10-250993. Epub 2010 Apr 16.
• Background Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57-117. doi: 10.1016/S0065-230X(10)07003-X.
• Background Nakahara T, Uchi H, Lesokhin AM, Avogadri F, Rizzuto GA, Hirschhorn-Cymerman D, Panageas KS, Merghoub T, Wolchok JD, Houghton AN. Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. Blood. 2010 Jun 3;115(22):4384-92. doi: 10.1182/blood-2009-11-251231. Epub 2010 Feb 12.
• Background Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010 Aug 15;127(4):759-67. doi: 10.1002/ijc.25429.
• Background Millar MR, MacKay P, Levene M, Langdale V, Martin C. Enterobacteriaceae and neonatal necrotising enterocolitis. Arch Dis Child. 1992 Jan;67(1 Spec No):53-6. doi: 10.1136/adc.67.1_spec_no.53.
• Background Oka Y, Sugiyama H. WT1 peptide vaccine, one of the most promising cancer vaccines: its present status and the future prospects. Immunotherapy. 2010 Sep;2(5):591-4. doi: 10.2217/imt.10.58. No abstract available.
• Background Radojcic V, Bezak KB, Skarica M, Pletneva MA, Yoshimura K, Schulick RD, Luznik L. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother. 2010 Jan;59(1):137-48. doi: 10.1007/s00262-009-0734-3. Epub 2009 Jul 10.
• Background Rezvani K. Peptide vaccine therapy for leukemia. Int J Hematol. 2011 Mar;93(3):274-280. doi: 10.1007/s12185-011-0781-3. Epub 2011 Mar 8.
• Background Sakaguchi S. Regulatory T cells: history and perspective. Methods Mol Biol. 2011;707:3-17. doi: 10.1007/978-1-61737-979-6_1.
• Background Schabowsky RH, Madireddi S, Sharma R, Yolcu ES, Shirwan H. Targeting CD4+CD25+FoxP3+ regulatory T-cells for the augmentation of cancer immunotherapy. Curr Opin Investig Drugs. 2007 Dec;8(12):1002-8.
• Background Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011 Mar 25;331(6024):1565-70. doi: 10.1126/science.1203486.
• Background Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011 Jul;33(4):369-83. doi: 10.1007/s00281-011-0245-0. Epub 2011 May 25.
• Background Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13824-9. doi: 10.1073/pnas.1008051107. Epub 2010 Jul 14.
• Background Wang X, Zheng J, Liu J, Yao J, He Y, Li X, Yu J, Yang J, Liu Z, Huang S. Increased population of CD4(+)CD25(high), regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. Eur J Haematol. 2005 Dec;75(6):468-76. doi: 10.1111/j.1600-0609.2005.00537.x.
• Background Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010 Jan;33(1):1-7. doi: 10.1097/CJI.0b013e3181b88ffc.

Drugs

Indications