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01-02-2011 | Original Article

Primed tumor-reactive multifunctional CD62L⁺ human CD8⁺ T cells for immunotherapy

Authors: Matthias Wölfl, Katharina Merker, Henner Morbach, Stefaan W. Van Gool, Matthias Eyrich, Philip D. Greenberg, Paul G. Schlegel

Published in: Cancer Immunology, Immunotherapy | Issue 2/2011

Abstract

T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naïve CD8⁺ T cells, a single stimulation with peptide-pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L⁺, CCR7⁺, CD28⁺). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy.

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Disis ML, Bernhard H, Jaffee EM (2009) Use of tumour-responsive T cells as cancer treatment. Lancet 373(9664):673–683. doi:10.1016/S0140-6736(09)60404-9 CrossRefPubMed

Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6(5):383–393. doi:10.1038/nri1842 CrossRefPubMed

Ho WY, Yee C, Greenberg PD (2002) Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends. J Clin Invest 110(10):1415–1417. doi:10.1172/JCI17214 PubMed

Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M, Kenyon K, Davis MM, Riddell SR, Greenberg PD (2000) Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 192(11):1637–1644CrossRefPubMed

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99(25):16168–16173. doi:10.1073/pnas.242600099 CrossRefPubMed

Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239. doi:10.1200/JCO.2008.16.5449 CrossRefPubMed

Mackensen A, Meidenbauer N, Vogl S, Laumer M, Berger J, Andreesen R (2006) Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol 24(31):5060–5069. doi:10.1200/JCO.2006.07.1100 CrossRefPubMed

Schultze JL, Grabbe S, von Bergwelt-Baildon MS (2004) Dcs and CD40-activated B cells: current and future avenues to cellular cancer immunotherapy. Trends Immunol 25(12):659–664. doi:10.1016/j.it.2004.09.016 CrossRefPubMed

Oelke M, Maus MV, Didiano D, June CH, Mackensen A, Schneck JP (2003) Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nat Med 9(5):619–624. doi:10.1038/nm869 CrossRefPubMed

10.

Ho WY, Nguyen HN, Wolfl M, Kuball J, Greenberg PD (2006) In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naive repertoire. J Immunol Methods 310(1–2):40–52. doi:10.1016/j.jim.2005.11.023 CrossRefPubMed

11.

Alves NL, Arosa FA, van Lier RA (2007) Common gamma chain cytokines: dissidence in the details. Immunol Lett 108(2):113–120. doi:10.1016/j.imlet.2006.11.006 CrossRefPubMed

12.

Li Y, Bleakley M, Yee C (2005) IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J Immunol 175(4):2261–2269 (pii:175/4/2261)PubMed

13.

Wolfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakley M, Greenberg PD (2007) Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 110(1):201–210. doi:10.1182/blood-2006-11-056168 CrossRefPubMed

14.

Rapoport AP, Stadtmauer EA, Aqui N, Vogl D, Chew A, Fang HB, Janofsky S, Yager K, Veloso E, Zheng Z, Milliron T, Westphal S, Cotte J, Huynh H, Cannon A, Yanovich S, Akpek G, Tan M, Virts K, Ruehle K, Harris C, Philip S, Vonderheide RH, Levine BL, June CH (2009) Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of costimulated autologous T cells. Clin Cancer Res 15(13):4499–4507. doi:10.1158/1078-0432.CCR-09-0418 CrossRefPubMed

15.

Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, Veloso E, Zheng Z, Westphal S, Mair R, Chi N, Ratterree B, Pochran MF, Natt S, Hinkle J, Sickles C, Sohal A, Ruehle K, Lynch C, Zhang L, Porter DL, Luger S, Guo C, Fang HB, Blackwelder W, Hankey K, Mann D, Edelman R, Frasch C, Levine BL, Cross A, June CH (2005) Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 11(11):1230–1237. doi:10.1038/nm1310 CrossRefPubMed

16.

De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE, Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14(10):3098–3104. doi:10.1158/1078-0432.CCR-07-4875 CrossRefPubMed

17.

Wolfl M, Rutebemberwa A, Mosbruger T, Mao Q, Li HM, Netski D, Ray SC, Pardoll D, Sidney J, Sette A, Allen T, Kuntzen T, Kavanagh DG, Kuball J, Greenberg PD, Cox AL (2008) Hepatitis c virus immune escape via exploitation of a hole in the T cell repertoire. J Immunol 181(9):6435–6446 (pii:181/9/6435)PubMed

18.

Pannetier C, Cochet M, Darche S, Casrouge A, Zoller M, Kourilsky P (1993) The sizes of the CDr3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci USA 90(9):4319–4323CrossRefPubMed

19.

Romero P, Valmori D, Pittet MJ, Zippelius A, Rimoldi D, Levy F, Dutoit V, Ayyoub M, Rubio-Godoy V, Michielin O, Guillaume P, Batard P, Luescher IF, Lejeune F, Lienard D, Rufer N, Dietrich PY, Speiser DE, Cerottini JC (2002) Antigenicity and immunogenicity of Melan-A/Mart-1 derived peptides as targets for tumor reactive CTL in human melanoma. Immunol Rev 188:81–96 (pii:imr18808)CrossRefPubMed

20.

Zhang JG, Eguchi J, Kruse CA, Gomez GG, Fakhrai H, Schroter S, Ma W, Hoa N, Minev B, Delgado C, Wepsic HT, Okada H, Jadus MR (2007) Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res 13(2 Pt 1):566–575. doi:10.1158/1078-0432.CCR-06-1576

21.

Busam KJ, Iversen K, Coplan KA, Old LJ, Stockert E, Chen YT, McGregor D, Jungbluth A (1998) Immunoreactivity for A103, an antibody to Melan-A (Mart-1), in adrenocortical and other steroid tumors. Am J Surg Pathol 22(1):57–63CrossRefPubMed

22.

Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15(17):5323–5337. doi:10.1158/1078-0432.CCR-09-0737 CrossRefPubMed

23.

Zippelius A, Pittet MJ, Batard P, Rufer N, de Smedt M, Guillaume P, Ellefsen K, Valmori D, Lienard D, Plum J, MacDonald HR, Speiser DE, Cerottini JC, Romero P (2002) Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J Exp Med 195(4):485–494CrossRefPubMed

24.

Van Der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van Den Eynde BJ, Brasseur F, Boon T (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188:51–64 (pii:imr18806)CrossRef

25.

Ginaldi L, De Martinis M, D’Ostilio A, Marini L, Loreto MF, Martorelli V, Quaglino D (1999) The immune system in the elderly: II. Specific cellular immunity. Immunol Res 20(2):109–115CrossRefPubMed

26.

Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P (2000) Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 164(9):4507–4512 (pii:ji_v164n9p4507)PubMed

27.

Alves NL, Arosa FA, van Lier RA (2005) IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells. J Immunol 175(2):755–762 (pii:175/2/755)PubMed

28.

Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA (1991) Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173(3):721–730CrossRefPubMed

29.

Topp MS, Riddell SR, Akatsuka Y, Jensen MC, Blattman JN, Greenberg PD (2003) Restoration of CD28 expression in CD28− CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. J Exp Med 198(6):947–955. doi:10.1084/jem.20021288jem CrossRefPubMed

30.

Blank C, Gajewski TF, Mackensen A (2005) Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54(4):307–314. doi:10.1007/s00262-004-0593-x CrossRefPubMed

31.

Brunner T, Wasem C, Torgler R, Cima I, Jakob S, Corazza N (2003) Fas (CD95/apo-1) ligand regulation in T cell homeostasis, cell-mediated cytotoxicity and immune pathology. Semin Immunol 15(3):167–176CrossRefPubMed

32.

Kobayashi N, Takata H, Yokota S, Takiguchi M (2004) Down-regulation of CXCR4 expression on human CD8+ T cells during peripheral differentiation. Eur J Immunol 34(12):3370–3378. doi:10.1002/eji.200425587 CrossRefPubMed

33.

Appay V, Douek DC, Price DA (2008) CD8+ T cell efficacy in vaccination and disease. Nat Med 14(6):623–628. doi:10.1038/nm.f.1774 CrossRefPubMed

34.

Speiser DE, Baumgaertner P, Voelter V, Devevre E, Barbey C, Rufer N, Romero P (2008) Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc Natl Acad Sci USA 105(10):3849–3854. doi:10.1073/pnas.0800080105 CrossRefPubMed

35.

Loftus DJ, Castelli C, Clay TM, Squarcina P, Marincola FM, Nishimura MI, Parmiani G, Appella E, Rivoltini L (1996) Identification of epitope mimics recognized by CTL reactive to the melanoma/melanocyte-derived peptide MART-1(27–35). J Exp Med 184(2):647–657CrossRefPubMed

36.

Dutoit V, Rubio-Godoy V, Pittet MJ, Zippelius A, Dietrich PY, Legal FA, Guillaume P, Romero P, Cerottini JC, Houghten RA, Pinilla C, Valmori D (2002) Degeneracy of antigen recognition as the molecular basis for the high frequency of naive A2/Melan-A peptide multimer(+) CD8(+) T cells in humans. J Exp Med 196(2):207–216CrossRefPubMed

37.

Voelter V, Rufer N, Reynard S, Greub G, Brookes R, Guillaume P, Grosjean F, Fagerberg T, Michelin O, Rowland-Jones S, Pinilla C, Leyvraz S, Romero P, Appay V (2008) Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor. Int Immunol 20(8):1087–1096. doi:10.1093/intimm/dxn066 CrossRefPubMed

38.

Christensen O, Lupu A, Schmidt S, Condomines M, Belle S, Maier A, Hose D, Neuber B, Moos M, Kleist C, Terness P, Ho AD, Goldschmidt H, Klein B, Hundemer M (2009) Melan-A/Mart1 analog peptide triggers anti-myeloma T-cells through crossreactivity with HM1.24. J Immunother 32(6):613–621. doi:10.1097/CJI.0b013e3181a95198 CrossRefPubMed

39.

Godet Y, Moreau-Aubry A, Guilloux Y, Vignard V, Khammari A, Dreno B, Jotereau F, Labarriere N (2008) Meloe-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. J Exp Med 205(11):2673–2682. doi:10.1084/jem.20081356 CrossRefPubMed

40.

Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK (2007) Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27(2):203–213. doi:10.1016/j.immuni.2007.07.007 CrossRefPubMed

41.

Mitchell DA, Fecci PE, Sampson JH (2008) Immunotherapy of malignant brain tumors. Immunol Rev 222:70–100. doi:10.1111/j.1600-065X.2008.00603.x CrossRefPubMed

42.

Saikali S, Avril T, Collet B, Hamlat A, Bansard JY, Drenou B, Guegan Y, Quillien V (2007) Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRviii, IL-13ralpha2, gp100 and TRP-2 for immunotherapy. J Neurooncol 81(2):139–148. doi:10.1007/s11060-006-9220-3 CrossRefPubMed

43.

Schuster K, Gadiot J, Andreesen R, Mackensen A, Gajewski TF, Blank C (2009) Homeostatic proliferation of naive CD8+ T cells depends on CD62L/L-selectin-mediated homing to peripheral LN. Eur J Immunol 39(11):2981–2990. doi:10.1002/eji.200939330 CrossRefPubMed

44.

Ghosh A, Koestner W, Hapke M, Schlaphoff V, Langer F, Baumann R, Koenecke C, Cornberg M, Welte K, Blazar BR, Sauer MG (2009) Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras. Blood 113(18):4440–4448. doi:10.1182/blood-2008-09-181677 CrossRefPubMed

45.

Tawab A, Fan Y, Read EJ, Kurlander RJ (2009) Effect of ex vivo culture duration on phenotype and cytokine production by mature dendritic cells derived from peripheral blood monocytes. Transfusion 49(3):536–547. doi:10.1111/j.1537-2995.2008.02020.x CrossRefPubMed

46.

Montes M, Rufer N, Appay V, Reynard S, Pittet MJ, Speiser DE, Guillaume P, Cerottini JC, Romero P, Leyvraz S (2005) Optimum in vitro expansion of human antigen-specific CD8 T cells for adoptive transfer therapy. Clin Exp Immunol 142(2):292–302. doi:10.1111/j.1365-2249.2005.02914.x CrossRefPubMed

47.

Li Y, Yee C (2008) IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111(1):229–235. doi:10.1182/blood-2007-05-089375 CrossRefPubMed

48.

Lin Y, Gallardo HF, Ku GY, Li H, Manukian G, Rasalan TS, Xu Y, Terzulli SL, Old LJ, Allison JP, Houghton AN, Wolchok JD, Yuan J (2009) Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses. Cytotherapy 11(7):912–922. doi:10.3109/14653240903136987 CrossRefPubMed

49.

Ten Brinke A, van Schijndel G, Visser R, de Gruijl TD, Zwaginga JJ, van Ham SM (2010) Monophosphoryl lipid a plus IFNgamma maturation of dendritic cells induces antigen-specific CD8(+) cytotoxic T cells with high cytolytic potential. Cancer Immunol Immunother 59(8):1185–1195. doi:10.1007/s00262-010-0843-z CrossRefPubMed

50.

Ten Brinke A, Karsten ML, Dieker MC, Zwaginga JJ, van Ham SM (2007) The clinical grade maturation cocktail monophosphoryl lipid a plus IFNgamma generates monocyte-derived dendritic cells with the capacity to migrate and induce Th1 polarization. Vaccine 25(41):7145–7152. doi:10.1016/j.vaccine.2007.07.031 CrossRefPubMed

Title: Primed tumor-reactive multifunctional CD62L+ human CD8+ T cells for immunotherapy
Authors: Matthias Wölfl
Katharina Merker
Henner Morbach
Stefaan W. Van Gool
Matthias Eyrich
Philip D. Greenberg
Paul G. Schlegel
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-010-0928-8

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