A goal of cancer immunologists is to harness cellular immune responses to achieve anti-cancer responses. One of the strongest activating stimuli for the immune system is the encounter with cells expressing allogeneic HLA molecules. While alloreactive responses can negatively impact of the outcome of hematopoietic stem cell transplant because of graft-versus-host disease (GVHD), these same responses can have anti-leukemic effects. Donor lymphocyte infusions have been used in an attempt to harness alloreactive responses to achieve anti-leukemic responses. Because this protocol is usually carried out in the absence of recipient anti-donor responses, this protocol often induces GVHD as well as anti-leukemic responses. A recent study indicated the infusion of large number of haploidentical donor cells (1–2 × 10 8 CD3 + cells/kg) into patients with refractory hematological malignancies (100 cGy total body irradiation) resulted in 14 (7 major) responses/26 patients. A rapidly developing cytokine storm was observed, while no persisting donor cells could be detected at two weeks after infusion eliminating the possibility of GVHD. Characterization of the effector mechanisms responsible for the anti-leukemic responses in this protocol, should guide new approaches for achieving enhanced anti-leukemic responses using this protocol.
Blazar, B.R.; Murphy, W.J.; Abedi, M. Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol. 2012, 12, 443–458, doi:10.1038/nri3212.
[3]
Weiden, P.L.; Flournoy, N.; Thomas, E.D.; Prentice, R.; Fefer, A.; Buckner, C.D.; Storb, R. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 1979, 300, 1068–1073, doi:10.1056/NEJM197905103001902.
[4]
Kolb, H.J. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008, 112, 4371–4383, doi:10.1182/blood-2008-03-077974.
[5]
Bar, M.; Sandmaier, B.M.; Inamoto, Y.; Bruno, B.; Hari, P.; Chauncey, T.; Martin, P.J.; Storb, R.; Maloney, D.G.; Storer, B.; et al. Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: Prognostic relevance of the initial CD3+ T cell dose. Biol. Blood Marrow Transplant. 2013, 19, 949–957, doi:10.1016/j.bbmt.2013.03.001.
[6]
Dey, B.R.; McAfee, S.; Colby, C.; Cieply, K.; Caron, M.; Saidman, S.; Preffer, F.; Shaffer, J.; Tarbell, N.; Sackstein, R.; et al. Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation. Br. J. Haematol. 2005, 128, 351–359, doi:10.1111/j.1365-2141.2004.05328.x.
[7]
Rubio, M.T.; Kim, Y.M.; Sachs, T.; Mapara, M.; Zhao, G.; Sykes, M. Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusion in mixed chimeras prepared with nonmyeloablative conditioning: Critical role for recipient-derived IFN-gamma. Blood 2003, 102, 2300–2307, doi:10.1182/blood-2002-12-3949.
[8]
Rubio, M.T.; Saito, T.I.; Kattleman, K.; Zhao, G.; Buchli, J.; Sykes, M. Mechanisms of the antitumor responses and host-versus-graft reactions induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: A critical role for recipient CD4+ T cells and recipient leukocyte infusion-derived IFN-gamma-producing CD8+ T cells. J. Immunol. 2005, 175, 665–676.
[9]
Saito, T.I.; Li, H.W.; Sykes, M. Invariant NKT cells are required for antitumor responses induced by host-versus-graft responses. J. Immunol. 2010, 185, 2099–2105, doi:10.4049/jimmunol.0901985.
[10]
Saito, T.I.; Rubio, M.T.; Sykes, M. Clinical relevance of recipient leukocyte infusion as antitumor therapy following nonmyeloablative allogeneic hematopoietic cell transplantation. Exp. Hematol. 2006, 34, 1271–1277.
[11]
Symons, H.J.; Levy, M.Y.; Wang, J.; Zhou, X.; Zhou, G.; Cohen, S.E.; Luznik, L.; Levitsky, H.I.; Fuchs, E.J. The allogeneic effect revisited: Exogenous help for endogenous, tumor-specific T cells. Biol. Blood Marrow Transplant. 2008, 14, 499–509, doi:10.1016/j.bbmt.2008.02.013.
Guo, M.; Hu, K.X.; Yu, C.L.; Sun, Q.Y.; Qiao, J.H.; Wang, D.H.; Liu, G.X.; Sun, W.J.; Wei, L.; Sun, X.D.; et al. Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients. Blood 2011, 117, 936–941, doi:10.1182/blood-2010-06-288506.
[14]
Guo, M.; Hu, K.X.; Liu, G.X.; Yu, C.L.; Qiao, J.H.; Sun, Q.Y.; Qiao, J.X.; Dong, Z.; Sun, W.J.; Sun, X.D.; et al. HLA-mismatched stem-cell microtransplantation as postremission therapy for acute myeloid leukemia: Long-term follow-up. J. Clin. Oncol. 2012, 30, 4084–4090, doi:10.1200/JCO.2012.42.0281.
[15]
Byrd, J.C.; Mrozek, K.; Dodge, R.K.; Carroll, A.J.; Edwards, C.G.; Arthur, D.C.; Pettenati, M.J.; Patil, S.R.; Rao, K.W.; Watson, M.S.; et al. retreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002, 100, 4325–4336, doi:10.1182/blood-2002-03-0772.
[16]
Fast, L.D. Recipient CD8+ cells are responsible for the rapid elimination of allogeneic donor lymphoid cells. J. Immunol. 1996, 157, 4805–4810.
[17]
Fast, L.D. Recipient elimination of allogeneic lymphoid cells: Donor CD4(+) cells are effective alloantigen-presenting cells. Blood 2000, 96, 1144–1149.
[18]
D’Orsogna, L.J.; van den Heuvel, H.; van der Meer-Prins, E.M.; Roelen, D.L.; Doxiadis, II; Claas, F.H. Stimulation of human EBV- and CMV-specific cytolytic effector function using allogeneic HLA molecules. J. Immunol. 2012, 189, 4825–4831, doi:10.4049/jimmunol.1200096.
Morris, G.P.; Allen, P.M. Cutting edge: Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease. J. Immunol. 2009, 182, 6639–6643, doi:10.4049/jimmunol.0900638.
[21]
Morris, G.P.; Uy, G.L.; Donermeyer, D.; Dipersio, J.F.; Allen, P.M. Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease. Sci. Transl. Med. 2013, 5, 188ra174.
[22]
Lask, A.; Goichberg, P.; Cohen, A.; Goren-Arbel, R.; Milstein, O.; Aviner, S.; Feine, I.; Ophir, E.; Reich-Zeliger, S.; Hagin, D.; et al. TCR-independent killing of B cell malignancies by anti-third-party CTLs: The critical role of MHC-CD8 engagement. J. Immunol. 2011, 187, 2006–2014, doi:10.4049/jimmunol.1100095.
[23]
Lask, A.; Ophir, E.; Or-Geva, N.; Cohen-Fredarow, A.; Afik, R.; Eidelstein, Y.; Reich-Zeliger, S.; Nathansohn, B.; Edinger, M.; Negrin, R.S.; et al. A new approach for eradication of residual lymphoma cells by host nonreactive anti-third-party central memory CD8 T cells. Blood 2013, 121, 3033–3040, doi:10.1182/blood-2012-06-432443.
[24]
Tietze, J.K.; Wilkins, D.E.; Sckisel, G.D.; Bouchlaka, M.N.; Alderson, K.L.; Weiss, J.M.; Ames, E.; Bruhn, K.W.; Craft, N.; Wiltrout, R.H.; et al. Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy. Blood 2012, 119, 3073–3083, doi:10.1182/blood-2011-07-369736.
[25]
Franciszkiewicz, K.; Le Floc’h, A.; Boutet, M.; Vergnon, I.; Schmitt, A.; Mami-Chouaib, F. CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res. 2013, 73, 617–628, doi:10.1158/0008-5472.CAN-12-2569.
[26]
Ruggeri, L.; Capanni, M.; Urbani, E.; Perruccio, K.; Shlomchik, W.D.; Tosti, A.; Posati, S.; Rogaia, D.; Frassoni, F.; Aversa, F.; et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002, 295, 2097–2100, doi:10.1126/science.1068440.
[27]
Cooley, S.; Weisdorf, D.J.; Guethlein, L.A.; Klein, J.P.; Wang, T.; Le, C.T.; Marsh, S.G.; Geraghty, D.; Spellman, S.; Haagenson, M.D.; et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010, 116, 2411–2419, doi:10.1182/blood-2010-05-283051.
[28]
Sivori, S.; Carlomagno, S.; Falco, M.; Romeo, E.; Moretta, L.; Moretta, A. Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: Implications in haploidentical HSCT. Blood 2011, 117, 4284–4292.
[29]
Waggoner, S.N.; Cornberg, M.; Selin, L.K.; Welsh, R.M. Natural killer cells act as rheostats modulating antiviral T cells. Nature 2012, 481, 394–398.
[30]
Cook, K.D.; Whitmire, J.K. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J. Immunol. 2013, 190, 641–649, doi:10.4049/jimmunol.1202448.
[31]
Rabinovich, B.A.; Li, J.; Shannon, J.; Hurren, R.; Chalupny, J.; Cosman, D.; Miller, R.G. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J. Immunol. 2003, 170, 3572–3576.
[32]
Olson, J.A.; Leveson-Gower, D.B.; Gill, S.; Baker, J.; Beilhack, A.; Negrin, R.S. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 2010, 115, 4293–4301, doi:10.1182/blood-2009-05-222190.
[33]
Cobbold, M.; De La Pena, H.; Norris, A.; Polefrone, J.M.; Qian, J.; English, A.M.; Cummings, K.L.; Penny, S.; Turner, J.E.; Cottine, J.; et al. MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. Sci. Transl. Med. 2013, 5, 203ra125, doi:10.1126/scitranslmed.3006061.
[34]
Katz, D.H.; Davie, J.M.; Paul, W.E.; Benacerraf, B. Carrier function in anti-hapten antibody responses. IV. Experimental conditions for the induction of hapten-specific tolerance or for the stimulation of anti-hapten anamnestic responses by “nonimmunogenic” hapten-polypeptide conjugates. J. Exp. Med. 1971, 134, 201–223, doi:10.1084/jem.134.1.201.
[35]
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264, doi:10.1038/nrc3239.
[36]
Dolen, Y.; Esendagli, G. Myeloid leukemia cells with a B7-2(+) subpopulation provoke Th-cell responses and become immuno-suppressive through the modulation of B7 ligands. Eur. J. Immunol. 2013, 43, 747–757, doi:10.1002/eji.201242814.
[37]
Corm, S.; Berthon, C.; Imbenotte, M.; Biggio, V.; Lhermitte, M.; Dupont, C.; Briche, I.; Quesnel, B. Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients’ sera by HPLC and is inducible by IFN-gamma. Leuk. Res. 2009, 33, 490–494, doi:10.1016/j.leukres.2008.06.014.
[38]
Curti, A.; Aluigi, M.; Pandolfi, S.; Ferri, E.; Isidori, A.; Salvestrini, V.; Durelli, I.; Horenstein, A.L.; Fiore, F.; Massaia, M.; et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia 2007, 21, 353–355, doi:10.1038/sj.leu.2404485.
[39]
Fritsch, K.; Finke, J.; Grullich, C. Suppression of granzyme B activity and caspase-3 activation in leukaemia cells constitutively expressing the protease inhibitor 9. Ann. Hematol. 2013, 92, 1603–1609, doi:10.1007/s00277-013-1846-6.
[40]
Zhang, L.; Chen, X.; Liu, X.; Kline, D.E.; Teague, R.M.; Gajewski, T.F.; Kline, J. CD40 ligation reverses T cell tolerance in acute myeloid leukemia. J. Clin. Invest. 2013, 123, 1999–2010, doi:10.1172/JCI63980.
[41]
Matsushita, H.; Vesely, M.D.; Koboldt, D.C.; Rickert, C.G.; Uppaluri, R.; Magrini, V.J.; Arthur, C.D.; White, J.M.; Chen, Y.S.; Shea, L.K.; et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012, 482, 400–404, doi:10.1038/nature10755.
[42]
Vago, L.; Perna, S.K.; Zanussi, M.; Mazzi, B.; Barlassina, C.; Stanghellini, M.T.; Perrelli, N.F.; Cosentino, C.; Torri, F.; Angius, A.; et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N. Engl. J. Med. 2009, 361, 478–488, doi:10.1056/NEJMoa0811036.
[43]
Almand, B.; Clark, J.I.; Nikitina, E.; van Beynen, J.; English, N.R.; Knight, S.C.; Carbone, D.P.; Gabrilovich, D.I. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 2001, 166, 678–689.
[44]
Shenghui, Z.; Yixiang, H.; Jianbo, W.; Kang, Y.; Laixi, B.; Yan, Z.; Xi, X. Elevated frequencies of CD4(+) CD25(+) CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int. J. Cancer. 2011, 129, 1373–1381, doi:10.1002/ijc.25791.
[45]
Szczepanski, M.J.; Szajnik, M.; Czystowska, M.; Mandapathil, M.; Strauss, L.; Welsh, A.; Foon, K.A.; Whiteside, T.L.; Boyiadzis, M. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin. Cancer Res. 2009, 15, 3325–3332, doi:10.1158/1078-0432.CCR-08-3010.
[46]
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, 75, 468–476, doi:10.1111/j.1600-0609.2005.00537.x.
[47]
Grupp, S.A.; Kalos, M.; Barrett, D.; Aplenc, R.; Porter, D.L.; Rheingold, S.R.; Teachey, D.T.; Chew, A.; Hauck, B.; Wright, J.F.; et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 2013, 368, 1509–1518, doi:10.1056/NEJMoa1215134.
[48]
Teachey, D.T.; Rheingold, S.R.; Maude, S.L.; Zugmaier, G.; Barrett, D.M.; Seif, A.E.; Nichols, K.E.; Suppa, E.K.; Kalos, M.; Berg, R.A.; et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013, 121, 5154–5157, doi:10.1182/blood-2013-02-485623.
[49]
Sliwkowski, M.X.; Mellman, I. Antibody therapeutics in cancer. Science 2013, 341, 1192–1198, doi:10.1126/science.1241145.
[50]
Houot, R.; Kohrt, H.; Levy, R. Boosting antibody-dependant cellular cytotoxicity against tumor cells with a CD137 stimulatory antibody. Oncoimmunology 2012, 1, 957–958, doi:10.4161/onci.19974.
[51]
Kohrt, H.E.; Houot, R.; Weiskopf, K.; Goldstein, M.J.; Scheeren, F.; Czerwinski, D.; Colevas, A.D.; Weng, W.K.; Clarke, M.F.; Carlson, R.W.; et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 2012, 122, 1066–1075, doi:10.1172/JCI61226.
[52]
Marabelle, A.; Kohrt, H.; Sagiv-Barfi, I.; Ajami, B.; Axtell, R.C.; Zhou, G.; Rajapaksa, R.; Green, M.R.; Torchia, J.; Brody, J.; et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 2013, 123, 2447–2463, doi:10.1172/JCI64859.
[53]
Rutten, C.E.; van Luxemburg-Heijs, S.A.; Halkes, C.J.; van Bergen, C.A.; Marijt, E.W.; Oudshoorn, M.; Griffioen, M.; Falkenburg, J.H. Patient HLA-DP-specific CD4+ T cells from HLA-DPB1-mismatched donor lymphocyte infusion can induce graft-versus-leukemia reactivity in the presence or absence of graft-versus-host disease. Biol. Blood Marrow Transplant. 2013, 19, 40–48, doi:10.1016/j.bbmt.2012.07.020.
[54]
Stevanovic, S.; van Bergen, C.A.; van Luxemburg-Heijs, S.A.; van der Zouwen, B.; Jordanova, E.S.; Kruisselbrink, A.B.; van de Meent, M.; Harskamp, J.C.; Claas, F.H.; Marijt, E.W.; et al. HLA class II upregulation during viral infection leads to HLA-DP-directed graft-versus-host disease after CD4+ donor lymphocyte infusion. Blood 2013, 122, 1963–1973, doi:10.1182/blood-2012-12-470872.
[55]
Jones-Mason, M.E.; Zhao, X.; Kappes, D.; Lasorella, A.; Iavarone, A.; Zhuang, Y. E protein transcription factors are required for the development of CD4(+) lineage T cells. Immunity 2012, 36, 348–361, doi:10.1016/j.immuni.2012.02.010.
[56]
Rui, J.; Liu, H.; Zhu, X.; Cui, Y.; Liu, X. Epigenetic silencing of CD8 genes by ThPOK-mediated deacetylation during CD4 T cell differentiation. J. Immunol. 2012, 189, 1380–1390, doi:10.4049/jimmunol.1201077.
[57]
Mucida, D.; Husain, M.M.; Muroi, S.; van Wijk, F.; Shinnakasu, R.; Naoe, Y.; Reis, B.S.; Huang, Y.; Lambolez, F.; Docherty, M.; et al. Transcriptional reprogramming of mature CD4(+) helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat. Immunol. 2013, 14, 281–289, doi:10.1038/ni.2523.
[58]
Hua, L.; Yao, S.; Pham, D.; Jiang, L.; Wright, J.; Sawant, D.; Dent, A.L.; Braciale, T.J.; Kaplan, M.H.; Sun, J. Cytokine-Dependent Induction of CD4+ T cells with Cytotoxic Potential during Influenza Virus Infection. J. Virol. 2013, 87, 11884–11893, doi:10.1128/JVI.01461-13.
