Summary:
A CD8 murine monoclonal antibody-coated high-density microparticle (HDM) has been developed, which allows for the rapid depletion of CD8+ T cells from apheresis products by gravity sedimentation. We conducted a study to determine the efficacy and safety of CD8 depletion of donor lymphocyte infusions (DLI) to treat relapse after stem cell transplantation using the Eligix CD8-HDM Cell Separation System. Patients were targeted to receive 3 × 107 CD4+ T cells/kg. Nine patients were enrolled, three with CML, three myeloma, two CLL, and one NHL. A median of 1 × 1010 mononuclear cells were obtained by apheresis and processed. The median depletion of CD8+ cells was 99.3% (97.8−>99.5%). CD8 depletion was highly specific, with a median recovery of CD4+ cells of 75%. A median of 2.9 × 107 CD4+ cells/kg was infused. No infusional toxicity was noted. All CML patients achieved a complete molecular remission. A CLL patient demonstrated a complete response. One patient developed GVHD (grade II acute GVHD and subsequently chronic GVHD). The CD8-HDM Cell Separation System appears to be highly selective and effective in depleting CD8+ T cells from DLI apheresis products, and CD8-depleted DLI is capable of mediating a graft-versus-leukemia effect while minimizing GVHD.
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References
Weiden PL, Sullivan K, Flournoy N et al. Antileukemic effect of chronic graft-versus-host disease. Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304: 1529–1533.
Weiden PL, Flournoy N, Sanders JE et al. Anti-leukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13: 248–251.
Odom LF, August CS, Githens JH et al. Remission of relapsed leukaemia during a graft-versus-host reaction. A ‘graft-versus-leukaemia reaction’ in man? Lancet 1978; 2: 537–540.
Higano CS, Brixey M, Bryant EM et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation. A case report of a probable graft-versus-leukemia effect. Transfusion 1990; 50: 175–177.
Collins RH, Rogers ZR, Bennett M et al. Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation. Apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 1992; 10: 391–395.
Abraham R, Szer J, Bardy P, Grigg A . Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants. Bone Marrow Transplant 1997; 20: 773–777.
Sanders JE, Buckner CD, Clift RA et al. Second marrow transplants in patients with leukemia who relapse after allogeneic marrow transplantation. Bone Marrow Transplant 1988; 3: 11–19.
Radich JP, Sanders JE, Buckner CD et al. Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens. J Clin Oncol 1993; 11: 304–313.
Mrsic M, Horowitz MM, Atkinson K et al. Second HLA-identical sibling transplants for leukemia recurrence. Bone Marrow Transplant 1992; 9: 269–275.
Kolb H, Mittermuller J, Clemm C et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.
Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.
van Rhee F, Cullis JO, Feng L et al. Donor leukocyte transfusions (DLT) for relapse of chronic myleoid leukemia after allogeneic bone marrow transplant. Blood 1993; 82 (Suppl. 1): 416a.
Bar BMAM, Schattenberg A, Mensink EJBM et al. Donor leukocyte infusions for chronic myeloid leukemia after allogeneic bone marrow transplanation. J Clin Oncol 1993; 11: 513–519.
Porter DL, Roth MS, McGarigle C et al. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myelogenous leukemia. N Engl J Med 1994; 330: 100–106.
Drobyski WR, Keever CA, Roth MS et al. Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose. Blood 1993; 82: 2310–2318.
Antin JH . Graft-versus-leukemia: no longer an epiphenomenon (editorial). Blood 1993; 82: 2273–2277.
van Rhee F, Lin F, Cullis JO et al. Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for givien donor leukocyte transfusions before the onset of hematologic relapse. Blood 1994; 83: 3377–3383.
Collins R, Shpilberg O, Drobyski W et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.
Champlin R, Ho W, Gajewski J et al. Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood 1990; 76: 418–423.
Soiffer RJ, Gonin R, Murray C et al. Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation. Blood 1993; 82: 2216–2223.
Giralt S, Hester J, Huh Y et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995; 86: 4337–4343.
Alyea EP, Soiffer RJ, Canning C et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91: 3671–3680.
Centers for Disease Control. Revised guidelines for performing CD4+ T cell determinations in persons infected with human immunodeficiency virus (HIV). MMWR 1997; 42: 1–29.
Bonini C, Verzeletti S, Servida P et al. Transfer of the HSV-TK gene into donor peripheral blood lymphocytes for in vivo immunomodulation of donor antitumor immunity after ALLO-BMT (Meeting abstract). Blood 1994; 84: 110a.
Mackinnon S, Papadapoulos EB, Carabasi MH et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 1995; 86: 1261–1268.
Dazzi F, Szydlo RM, Craddock C et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 2000; 95: 67–71.
Shimoni A, Gajewski JA, Donato M et al. Long-term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant 2001; 7: 568–575.
Soiffer RJ, Alyea EP, Hochberg E et al. Randomized trial of CD8+ T cell-depletion in the prevention of graft-versus-host disease associated with donor lymphocyte infusion. Biol Blood Marrow Transplant 2002; 8: 625–632.
Claret EJ, Alyea EP, Orsini E et al. Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion. J Clin Invest 1997; 100: 855–866.
Orsini E, Alyea EP, Schlossman R et al. Changes in T cell receptor repertoire associated with graft-versus-tumor effect and graft-versus-host disease in patients with relapsed multiple myeloma after donor lymphocyte infusion. Bone Marrow Transplant 2000; 25: 623–632.
Zorn E, Wang KS, Hochberg EP et al. Infusion of CD4+ donor lymphocytes induces the expansion of CD8+ donor T cells with cytolytic activity directed against recipient hematopoietic cells. Clin Cancer Res 2002; 8: 2052–2060.
Wu CJ, Yang XF, McLaughlin S et al. Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. J Clin Invest 2000; 106: 705–714.
Bellucci R, Wu CJ, Chiaretti S et al. Complete response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood 2004; 103: 656–663.
Wu CJ, Chillemi A, Alyea EP et al. Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 2000; 95: 352–359.
Yang XF, Wu CJ, Chen L et al. CML28 is a broadly immunogenic antigen, which is overexpressed in tumor cells. Cancer Res 2002; 62: 5517–5522.
Yang XF, Wu CJ, McLaughlin S et al. CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. Proc Natl Acad Sci USA 2001; 98: 7492–7497.
Acknowledgements
This work was supported by NIH grant AI29530 and Biotransplant Inc. and in part by the Ted and Eileen Pasquarello Leukaemia Research Fund. Dr Soiffer is a Clinical Research Scholar of the Leukemia and Lymphoma Society.
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Alyea, E., Canning, C., Neuberg, D. et al. CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant 34, 123–128 (2004). https://doi.org/10.1038/sj.bmt.1704536
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DOI: https://doi.org/10.1038/sj.bmt.1704536
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