An immune edited tumour versus a tumour edited immune system: prospects for immune therapy of acute myeloid leukaemia

  • Lucas Chan
  • Nicola R. Hardwick
  • Barbara-ann Guinn
  • Dave Darling
  • Joop Gäken
  • Joanna Galea-Lauri
  • Aloysius Y. Ho
  • Ghulam J. Mufti
  • Farzin Farzaneh
Symposium Paper

Abstract

Cell based therapies for acute myeloid leukaemia (AML) have made significant progress in the last decade benefiting the prognosis and survival of patients with this aggressive form of leukaemia. Due to advances in haematopoietic stem cell transplantation (HSCT) and particularly the advent of reduced intensity conditioning (RIC), the scope of transplantation has now extended to those patients previously ineligible due to age and health restrictions and has been associated with a decrease in transplant related mortality. The apparent graft versus leukaemia (GvL) effect observed following HSCT demonstrates the potential of the immune system to target and eradicate AML cells. Building on previously published pre-clinical studies by ourselves and others, we are now initiating a Phase I clinical study in which lentiviral vectors are used to genetically modify AML cells to express B7.1 (CD80) and IL-2. By combining allogeneic HSCT with immunisation, using the autologous AML cells expressing B7.1 and IL-2, we hope to stimulate immune eradication of residual AML cells in poor prognosis patients that have achieved donor chimerism. In this report we describe the background to cell therapy based approaches for AML, and discuss difficulties associated with the deployment of a chronically stimulated, hence exhausted/depleted immune system to eradicate tumour cells that have already escaped immune surveillance.

Keywords

Acute myeloid leukaemia Whole cell vaccine B7.1 IL-2 Immunotherapy Lentivirus 

Abbreviations

HSCT

Haematopoietic stem cell transplant

AML

Acute myeloid leukaemia

GvL

Graft versus leukaemia

DLI

Donor leukocyte infusion

VUD

Volunteer unrelated donor

GvHD

Graft versus host disease

MDS

Myelodysplastic syndrome

RIC

Reduced intensity conditioning

APC

Antigen presenting cell

mHA

Minor histocompatibility antigens

LD-DC

Leukaemia derived-dendritic cell

CTL

Cytotoxic T lymphocytes

References

  1. 1.
    Laimer M, Lanschuetzer CM, Hintner H (2004) Interaction between the immune system and tumor cells: cutaneous disorders as a consequence of autoimmunity and immunosuppression. Ann N Y Acad Sci 1028:375–379PubMedCrossRefGoogle Scholar
  2. 2.
    Dunn GP, Ikeda H, Bruce AT, Koebel C, Uppaluri R, Bui J, Chan R, Diamond M, White JM, Sheehan KC, Schreiber RD (2005) Interferon-gamma and cancer immunoediting. Immunol Res 32:231–246PubMedCrossRefGoogle Scholar
  3. 3.
    Schreiber RD (2005) Cancer vaccines 2004 opening address: the molecular and cellular basis of cancer immunosurveillance and immunoediting. Cancer Immun 5(Suppl 1):1PubMedGoogle Scholar
  4. 4.
    Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334PubMedCrossRefGoogle Scholar
  5. 5.
    Carreno BM, Carter LL, Collins M (2005) Therapeutic opportunities in the B7/CD28 family of ligands and receptors. Curr Opin Pharmacol 5:424–430PubMedCrossRefGoogle Scholar
  6. 6.
    Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krahn G, Heilmann V, Gschwend J, Bergmann L, Dohner H, Schmitt M (2002) Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol 30:1029–1035PubMedCrossRefGoogle Scholar
  7. 7.
    Greiner J, Ringhoffer M, Taniguchi M, Hauser T, Schmitt A, Dohner H, Schmitt M (2003) Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. Int J Cancer 106:224–231PubMedCrossRefGoogle Scholar
  8. 8.
    Guinn BA, Bland EA, Lodi U, Liggins AP, Tobal K, Petters S, Wells JW, Banham AH, Mufti GJ (2005) Humoral detection of leukaemia-associated antigens in presentation acute myeloid leukaemia. Biochem Biophys Res Commun 335:1293–1304PubMedCrossRefGoogle Scholar
  9. 9.
    Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, Hoelzer D (1997) High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90:1217–1225PubMedGoogle Scholar
  10. 10.
    Gaiger A, Reese V, Disis ML, Cheever MA (2000) Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 96:1480–1489PubMedGoogle Scholar
  11. 11.
    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 (2002) Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 99:3272–3279PubMedCrossRefGoogle Scholar
  12. 12.
    Wu F, Oka Y, Tsuboi A, Elisseeva OA, Ogata K, Nakajima H, Fujiki F, Masuda T, Murakami M, Yoshihara S, Ikegame K, Hosen N, Kawakami M, Nakagawa M, Kubota T, Soma T, Yamagami T, Tsukaguchi M, Ogawa H, Oji Y, Hamaoka T, Kawase I, Sugiyama H (2005) Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies. Leukemia 19:268–274PubMedCrossRefGoogle Scholar
  13. 13.
    Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S, Nagorsen D, Keilholz U (2002) CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 100:2132–2137PubMedCrossRefGoogle Scholar
  14. 14.
    Andersen MH, Svane IM, Kvistborg P, Nielsen OJ, Balslev E, Reker S, Becker JC, Straten PT (2005) Immunogenicity of Bcl-2 in patients with cancer. Blood 105:728–734PubMedCrossRefGoogle Scholar
  15. 15.
    Whiteway A, Corbett T, Anderson R, Macdonald I, Prentice HG (2003) Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission. Br J Haematol 120:442–451PubMedCrossRefGoogle Scholar
  16. 16.
    Boyer MW, Waller EK, Bray RA, Unangst T, Johnson TS, Phillips C, Jurickova I, Winton EF, Yeager AM (2000) Cytokine upregulation of the antigen presenting function of acute myeloid leukemia cells. Leukemia 14:412–418PubMedCrossRefGoogle Scholar
  17. 17.
    Charbonnier A, Gaugler B, Sainty D, Lafage-Pochitaloff M, Olive D (1999) Human acute myeloblastic leukemia cells differentiate in vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias. Eur J Immunol 29:2567–2578PubMedCrossRefGoogle Scholar
  18. 18.
    Harrison BD, Adams JA, Briggs M, Brereton ML, Yin JA (2001) Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia. Blood 97:2764–2771PubMedCrossRefGoogle Scholar
  19. 19.
    Roddie PH, Horton Y, Turner ML (2002) Primary acute myeloid leukaemia blasts resistant to cytokine-induced differentiation to dendritic-like leukaemia cells can be forced to differentiate by the addition of bryostatin-1. Leukemia 16:84–93PubMedCrossRefGoogle Scholar
  20. 20.
    Cignetti A, Vallario A, Roato I, Circosta P, Allione B, Casorzo L, Ghia P, Caligaris-Cappio F (2004) Leukemia-derived immature dendritic cells differentiate into functionally competent mature dendritic cells that efficiently stimulate T cell responses. J Immunol 173:2855–2865PubMedGoogle Scholar
  21. 21.
    Kufner S, Fleischer RP, Kroell T, Schmid C, Zitzelsberger H, Salih H, Valle FD, Treder W, Schmetzer HM (2005) Serum-free generation and quantification of functionally active leukemia-derived DC is possible from malignant blasts in acute myeloid leukemia and myelodysplastic syndromes. Cancer Immunol Immunother. DOI 10.1007/s00262–004–0657-yGoogle Scholar
  22. 22.
    Hirst WJ, Buggins A, Darling D, Gaken J, Farzaneh F, Mufti GJ (1997) Enhanced immune costimulatory activity of primary acute myeloid leukaemia blasts after retrovirus-mediated gene transfer of B7.1. Gene Ther 4:691–699PubMedCrossRefGoogle Scholar
  23. 23.
    Stripecke R, Cardoso AA, Pepper KA, Skelton DC, Yu XJ, Mascarenhas L, Weinberg KI, Nadler LM, Kohn DB (2000) Lentiviral vectors for efficient delivery of CD80 and granulocyte-macrophage-colony-stimulating factor in human acute lymphoblastic leukemia and acute myeloid leukemia cells to induce antileukemic immune responses. Blood 96:1317–1326PubMedGoogle Scholar
  24. 24.
    Koya RC, Kasahara N, Pullarkat V, Levine AM, Stripecke R (2002) Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses. Leukemia 16:1645–1654PubMedCrossRefGoogle Scholar
  25. 25.
    Bain C, Merrouche Y, Puisieux I, Duc A, Colombo MP, Favrot M (1996) B7.1 gene transduction of human renal-cell-carcinoma cell lines restores the proliferative response and cytotoxic function of allogeneic T cells. Int J Cancer 67:769–776PubMedCrossRefGoogle Scholar
  26. 26.
    Fenton RG, Turcovski-Corrales SM, Taub DD (1998) Induction of melanoma antigen-specific cytotoxic T lymphocytes in vitro by stimulation with B7-expressing human melanoma cell lines. J Immunother 21:95–108PubMedCrossRefGoogle Scholar
  27. 27.
    Kim SJ, Sadelain M, Lee JS, Seong RH, Yun YS, Jang YJ, Chung HY (1999) Adoptive-transfer therapy of tumors with the tumor-specific primary cytotoxic T cells induced in vitro with the B7.1-transduced MCA205 cell line. Cancer Immunol Immunother 47:257–264PubMedCrossRefGoogle Scholar
  28. 28.
    Miyazono Y, Kamogawa Y, Ryo K, Furukawa T, Mitsuhashi M, Yamauchi K, Kameoka T, Hayashi N (1999) Effect of B7.1-transfected human colon cancer cells on the induction of autologous tumour-specific cytotoxic T cells. J Gastroenterol Hepatol 14:997–1003PubMedCrossRefGoogle Scholar
  29. 29.
    Schendel DJ, Frankenberger B, Jantzer P, Cayeux S, Nobetaner E, Willimsky G, Maget B, Pohla H, Blankenstein T (2000) Expression of B7.1 (CD80) in a renal cell carcinoma line allows expansion of tumor-associated cytotoxic T lymphocytes in the presence of an alloresponse. Gene Ther 7:2007–2014PubMedCrossRefGoogle Scholar
  30. 30.
    Wang YC, Zhu L, McHugh R, Graham SD Jr, Hillyer CD, Dillehay D, Sell KW, Selvaraj P (1996) Induction of autologous tumor-specific cytotoxic T-lymphocyte activity against a human renal carcinoma cell line by B7–1 (CD8O) costimulation. J Immunother Emphasis Tumor Immunol 19:1–8PubMedGoogle Scholar
  31. 31.
    Yang S, Darrow TL, Seigler HF (1997) Generation of primary tumor-specific cytotoxic T lymphocytes from autologous and human lymphocyte antigen class I-matched allogeneic peripheral blood lymphocytes by B7 gene-modified melanoma cells. Cancer Res 57:1561–1568PubMedGoogle Scholar
  32. 32.
    Wendelbo O, Nesthus I, Sjo M, Paulsen K, Ernst P, Bruserud O (2004) Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia. Cancer Immunol Immunother 53:740–747PubMedCrossRefGoogle Scholar
  33. 33.
    Buggins AG, Lea N, Gaken J, Darling D, Farzaneh F, Mufti GJ, Hirst WJ (1999) Effect of costimulation and the microenvironment on antigen presentation by leukemic cells. Blood 94:3479–3490PubMedGoogle Scholar
  34. 34.
    Buggins AG, Milojkovic D, Arno MJ, Lea NC, Mufti GJ, Thomas NS, Hirst WJ (2001) Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways. J Immunol 167:6021–6030PubMedGoogle Scholar
  35. 35.
    Beverly B, Kang SM, Lenardo MJ, Schwartz RH (1992) Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol 4:661–671PubMedCrossRefGoogle Scholar
  36. 36.
    Gaken J, Darling D, Hollingsworth S, Hirst W, Peakman M, Kuiper M, Humphries S, Towner P, Mufti GJ, Farzaneh F (1994) Synergy between B7.1 and IL-2 gene modification in the induction of tumour rejection. Cancer Gene Therapy 1:212Google Scholar
  37. 37.
    Salvadori S, Gansbacher B, Wernick I, Tirelli S, Zier K (1995) B7–1 amplifies the response to interleukin-2-secreting tumor vaccines in vivo, but fails to induce a response by naive cells in vitro. Hum Gene Ther 6:1299–1306PubMedCrossRefGoogle Scholar
  38. 38.
    Gaken JA, Hollingsworth SJ, Hirst WJ, Buggins AG, Galea-Lauri J, Peakman M, Kuiper M, Patel P, Towner P, Patel PM, Collins MK, Mufti GJ, Farzaneh F, Darling DC (1997) Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors. Hum Gene Ther 8:477–488PubMedCrossRefGoogle Scholar
  39. 39.
    Bubenik J, Rosser P, Bubenikova D, Simova J, Indrova M, Sloncova E (1997) Tumour vaccines expressing IL-2, CD80, and IL-2 plus CD80 gene. Intl J Oncol 11:1213–1219Google Scholar
  40. 40.
    Emtage PC, Wan Y, Bramson JL, Graham FL, Gauldie J (1998) A double recombinant adenovirus expressing the costimulatory molecule B7-1 (murine) and human IL-2 induces complete tumor regression in a murine breast adenocarcinoma model. J Immunol 160:2531–2538PubMedGoogle Scholar
  41. 41.
    Cayeux S, Richter G, Becker C, Beck C, Aicher A, Pezzutto A, Dorken B, Blankenstein T (1997) Lack of correlation between rejection of tumor cells co-expressing interleukin-2 and B7.1 and vaccine efficiency. Eur J Immunol 27:1657–1662PubMedCrossRefGoogle Scholar
  42. 42.
    Galea-Lauri J, Darling D, Gan SU, Krivochtchapov L, Kuiper M, Gaken J, Souberbielle B, Farzaneh F (1999) Expression of a variant of CD28 on a subpopulation of human NK cells: implications for B7-mediated stimulation of NK cells. J Immunol 163:62–70PubMedGoogle Scholar
  43. 43.
    Gao JX, Liu X, Wen J, Caligiuri MA, Stroynowski I, Zheng P, Liu Y (2003) Two-signal requirement for activation and effector function of natural killer cell response to allogeneic tumor cells. Blood 102:4456–4463PubMedCrossRefGoogle Scholar
  44. 44.
    Barnard AL, Farzaneh F, Gaken J, Darling D (2000) Local versus systemic interleukin-2: tumor formation by wild-type and B7-1-positive murine melanoma cells. Cancer Gene Ther 7:207–214PubMedCrossRefGoogle Scholar
  45. 45.
    Ge NL, Ye SL, Zheng N, Sun RX, Liu YK, Tang ZY (2003) Prevention of hepatocellular carcinoma in mice by IL-2 and B7-1 genes co-transfected liver cancer cell vaccines. World J Gastroenterol 9:2182–2185PubMedGoogle Scholar
  46. 46.
    Larchian WA, Horiguchi Y, Nair SK, Fair WR, Heston WD, Gilboa E (2000) Effectiveness of combined interleukin 2 and B7.1 vaccination strategy is dependent on the sequence and order: a liposome-mediated gene therapy treatment for bladder cancer. Clin Cancer Res 6:2913–2920PubMedGoogle Scholar
  47. 47.
    Kochling J, Konig-Merediz SA, Stripecke R, Buchwald D, Korte A, Von Einsiedel HG, Sack F, Henze G, Seeger K, Wittig B, Schmidt M (2003) Protection of mice against Philadelphia chromosome-positive acute lymphoblastic leukemia by cell-based vaccination using nonviral, minimalistic expression vectors and immunomodulatory oligonucleotides. Clin Cancer Res 9:3142–3149PubMedGoogle Scholar
  48. 48.
    Gaken J, Jiang J, Daniel K, van Berkel E, Hughes C, Kuiper M, Darling D, Tavassoli M, Galea-Lauri J, Ford K, Kemeny M, Russell S, Farzaneh F (2000) Fusagene vectors: a novel strategy for the expression of multiple genes from a single cistron. Gene Ther 7:1979–1985PubMedCrossRefGoogle Scholar
  49. 49.
    Chan L, Nesbeth D, Mackey T, Galea-Lauri J, Gaken J, Martin F, Collins M, Mufti G, Farzaneh F, Darling D (2005) Conjugation of lentivirus to paramagnetic particles via nonviral proteins allows efficient concentration and infection of primary acute myeloid leukemia cells. J Virol 79:13190–13194PubMedCrossRefGoogle Scholar
  50. 50.
    Bello-Fernandez C, Stasakova J, Renner A, Carballido-Perrig N, Koening M, Waclavicek M, Madjic O, Oehler L, Haas O, Carballido JM, Buschle M, Knapp W (2003) Retrovirus-mediated IL-7 expression in leukemic dendritic cells generated from primary acute myelogenous leukemias enhances their functional properties. Blood 101:2184–2190PubMedCrossRefGoogle Scholar
  51. 51.
    Roddie PH, Paterson T, Turner ML (2000) Gene transfer to primary acute myeloid leukaemia blasts and myeloid leukaemia cell lines. Cytokines Cell Mol Ther 6:127–134PubMedGoogle Scholar
  52. 52.
    Wattel E, Vanrumbeke M, Abina MA, Cambier N, Preudhomme C, Haddada H, Fenaux P (1996) Differential efficacy of adenoviral mediated gene transfer into cells from hematological cell lines and fresh hematological malignancies. Leukemia 10:171–174PubMedGoogle Scholar
  53. 53.
    Gonzalez R, Vereecque R, Wickham TJ, Vanrumbeke M, Kovesdi I, Bauters F, Fenaux P, Quesnel B (1999) Increased gene transfer in acute myeloid leukemic cells by an adenovirus vector containing a modified fiber protein. Gene Ther 6:314–320PubMedCrossRefGoogle Scholar
  54. 54.
    Heinzinger NK, Bukinsky MI, Haggerty SA, Ragland AM, Kewalramani V, Lee MA, Gendelman HE, Ratner L, Stevenson M, Emerman M (1994) The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci USA 91:7311–7315PubMedCrossRefGoogle Scholar
  55. 55.
    Yao XJ, Subbramanian RA, Rougeau N, Boisvert F, Bergeron D, Cohen EA (1995) Mutagenic analysis of human immunodeficiency virus type 1 Vpr: role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation. J Virol 69:7032–7044PubMedGoogle Scholar
  56. 56.
    Bambacioni F, Casati C, Serafini M, Manganini M, Golay J, Introna M (2001) Lentiviral vectors show dramatically increased efficiency of transduction of human leukemic cell lines. Haematologica 86:1095–1096PubMedGoogle Scholar
  57. 57.
    Biagi E, Bambacioni F, Gaipa G, Casati C, Golay J, Biondi A, Introna M (2001) Efficient lentiviral transduction of primary human acute myelogenous and lymphoblastic leukemia cells. Haematologica 86:13–16PubMedGoogle Scholar
  58. 58.
    Stripecke R, Koya RC, Ta HQ, Kasahara N, Levine AM (2003) The use of lentiviral vectors in gene therapy of leukemia: combinatorial gene delivery of immunomodulators into leukemia cells by state-of-the-art vectors. Blood Cells Mol Dis 31:28–37PubMedCrossRefGoogle Scholar
  59. 59.
    Chan L, Hardwick N, Darling D, Galea-Lauri J, Gaken J, Devereux S, Kemeny M, Mufti G, Farzaneh F (2005) IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. Mol Ther 11:120–131PubMedCrossRefGoogle Scholar
  60. 60.
    Hughes C, Galea-Lauri J, Farzaneh F, Darling D (2001) Streptavidin paramagnetic particles provide a choice of three affinity-based capture and magnetic concentration strategies for retroviral vectors. Mol Ther 3:623–630PubMedCrossRefGoogle Scholar
  61. 61.
    Nesbeth D, Williams S, Chan L, Brain T, Slater N, Farzaneh F, Darling D (2005) Metabolic biotinylation of lentiviral pseudotypes for scaleable paramagnetic microparticle dependent manipulation. Mol TherGoogle Scholar
  62. 62.
    Ho AY, Pagliuca A, Kenyon M, Parker JE, Mijovic A, Devereux S, Mufti GJ (2004) Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 104:1616–1623PubMedCrossRefGoogle Scholar
  63. 63.
    Molldrem JJ, Lee PP, Kant S, Wieder E, Jiang W, Lu S, Wang C, Davis MM (2003) Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells. J Clin Invest 111:639–647PubMedGoogle Scholar
  64. 64.
    Klenerman P, Cerundolo V, Dunbar PR (2002) Tracking T cells with tetramers: new tales from new tools. Nat Rev Immunol 2:263–272PubMedCrossRefGoogle Scholar
  65. 65.
    Nelson BH (2004) IL-2, regulatory T cells, and tolerance. J Immunol 172:3983–3988PubMedGoogle Scholar
  66. 66.
    Ahmadzadeh M, Rosenberg SA (2005) IL-2 administration increases CD4+CD25hiFoxp3+ regulatory T cells in cancer patients. BloodGoogle Scholar
  67. 67.
    Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Lucas Chan
    • 1
  • Nicola R. Hardwick
    • 1
  • Barbara-ann Guinn
    • 1
  • Dave Darling
    • 1
  • Joop Gäken
    • 1
  • Joanna Galea-Lauri
    • 1
  • Aloysius Y. Ho
    • 1
  • Ghulam J. Mufti
    • 1
  • Farzin Farzaneh
    • 1
  1. 1.King’s College London, Department of Haematological Molecular MedicineThe Rayne InstituteLondonUK

Personalised recommendations