Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Patent
1996-09-16
1998-12-01
Saunders, David
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
424 937, 424 855, 424 857, 424 852, 424 854, 4241441, A61K 3821, A61K 4505, A61K 39395, A01N 6300
Patent
active
058434356
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to methods of eradicating residual tumor cells following surgical intervention, chemotherapy and/or radiotherapy. The methods involve administration of allogeneic lymphocytes following autologous stem cell transplantation. More particularly, this invention relates to use of HLA-compatible or HLA-mismatched allogeneic lymphocytes to induce a graft-versus-malignant cell response following autologous stem cell transplantation.
BACKGROUND OF THE INVENTION
Patients with malignant hematological disorders resistant to conventional doses of chemotherapy and/or radiation may be treated by autologous or allogeneic bone marrow transplantation. Bone marrow transplantation (BMT) makes it possible to administer to patients with resistant disease high, "supralethal," combinations of chemotherapy and radiation, ignoring the irreversible toxicity of such therapeutic combinations on the normal bone marrow compartment. Nevertheless, such "debulking" of a patient's tumor(s) can leave a fraction of residual malignant cells that may lead to disease relapse. Several lines of evidence suggest that a significant proportion of the beneficial effect of allogeneic BMT (i.e., BMT from an individual not genetically identical to the host patient) stems from cell-mediated interactions of immune cells of donor origin against residual tumor cells in the host that have escaped the chemoradiotherapy debulking regimen.
Following allogeneic BMT, the incidence of relapse is significantly lower in leukemia patients with clinical manifestations of acute or chronic graft versus host disease (GVHD), as compared with patients with no GVHD, indicating that immune-mediated allogeneic interactions or immunocompetent cells of donor origin against the host are also accompanied by graft vs. leukemia (GVL) effects. Weiden et al., N. Engl. J. Med. 300: 1068 (1979); Weiden et al., N. Engl. J. Med. 304: 1529-33 (1981); Weiden et al., Transplantation 13: 248-51 (1981); Barrett et al., Blood 74: 862 (1989); Sullivan et al., Blood 73:1720 (1989); Horowitz et al., Blood 75: 555 (1990); Slavin et al., Bone Marrow Transplant. 6: 155-61 (1990).
Higher relapse rates seem to occur in patients undergoing allogeneic BMT with T-lymphocyte depletion for prevention of GVHD compared to recipients of non-T cell depleted marrow allografts, regardless of the severity of GVHD. Horowitz et al., Blood 75:555 (1990); Slavin et al., Bone Marrow Transplant. 6:155-61 (1990); Goldman et al., Ann. Inter. Med. 108: 806-14 (1988); Ringden and Horowitz, Transplant. Proc. 21: 2989-92 (1989); Goldman et al., Ann. Int. Med. 108: 806 (1988). Likewise, relapse rates in patients with acute leukemia or chronic myeloid leukemia reconstituted by bone marrow grafts obtained from an identical twin (syngeneic grafts) are significantly higher than in those reconstituted by bone marrow cells obtained from an HLA-identical but non-syngeneic sibling. Ringden and Horowitz, Transplant. Proc. 21: 2989-92 (1989). Similarly, relapse rates following transplantation of the patient's own (autologous) marrow, even following adequate purging in vitro for elimination of residual leukemia cells, are significantly higher than following allogeneic BMT. Armitage, Curr. Opinion in Hematol. 1993: 240-45 (1993). Thus, the less-than optimal results with autologous BMT (ABMT) are similar to the results seen with syngeneic marrow transplantation. All of the above data suggests that in practical terms GVHD or GVHD-potential correlates with a lower incidence of relapse.
Allogeneic donor cells may also play a role against lymphoma, as shown in experimental animals, Slavin et al., Cancer Immunol. Immunother. 11: 155-58 (1981), and humans. Phillips et al., J. Clin. Oncol. 4: 480-88 (1986); Ernst et al., Proc. of the 4th International Conference on Lymphoma, Lugano 1990, Abstract #P35; Chopra et al., J. Clin. Oncol. 10: 1690-95 (1992). As shown in experimental animals, graft-versus-tumor effects (GVT), similar to graft versus-leukemia effects (GVL), may occur following BMT, indepen
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Baxter International Inc.
Buonaiuto Mark J.
Ellinger Mark S.
Hadasit Medical Research Services and Development Ltd.
Saunders David
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