Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
1997-11-14
2003-04-08
Scheiner, Laurie (Department: 1648)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C424S093710, C435S007240, C435S325000, C435S372300, C435S372200, C435S375000
Reexamination Certificate
active
06544787
ABSTRACT:
BACKGROUND OF THE INVENTION
High dose or lethal conditioning regimens using chemotherapy and/or radiation therapy followed by rescue with allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (ASCT) have been the treatments of choice for patients with a variety of hematologic malignancies and chemosensitive solid tumors resistant to conventional doses of chemotherapy. A common source of stem cells for such procedures has been the bone marrow. Recently, peripheral blood stem cells (PBSC) have also been used. As such, the terms “allogeneic bone marrow transplantation” (allo-BMT) and “autologous bone marrow transplantation” (ABMT) are widely used in the literature to refer to particular types of allo-SCT and ASCT, respectively, whether the rescue is with bone marrow or PBSC.
Current procedures typically employ allo-SCT or ASCT after myeloablative/lymphoablative (M/L) conditioning. As the name implies, M/L conditioning involves elimination, through cell killing, blocking, and/or down-regulation, of substantially all the hematopoietic stem cells and lymphocytes of the patient. Patients treated by allo-SCT or ASCT can develop major complications due to the M/L conditioning. In addition, patients receiving allo-SCT are susceptible to graft versus host disease (GVHD), as well as to graft rejection. Moreover, relapse is still a frequent problem in these patients.
Several attempts to improve disease-free survival by increasing the intensity of the M/L conditioning have failed due to unacceptable toxicity. Furthermore, increasing the intensity of the M/L conditioning does not appear to improve the outcome by decreasing the rate of relapse. A wide variety of protocols of varying intensities have been used among greater than 30,000 transplants worldwide reported to the International Bone Marrow Transplant Registry. Despite these numerous attempts to vary the intensity of the conditioning regimens, there have not been any documented significant differences in the over-all patient outcomes.
The use of M/L conditioning followed by rescue with allo-SCT is often accompanied by graft-versus-tumor (GVT), for example, graft-versus-leukemia (GVL), responses. Over the years, immune interactions between allogeneic donor-derived immunocompetent T lymphocytes acting against host-type tumor cells have been shown to be of major therapeutic importance. For example, significantly better anti-tumor effects have been induced by allo-SCT as compared with ASCT or transplants from an identical twin.
Relapse following allo-SCT or ASCT in patients has sometimes been reversed by adoptive allogeneic cell therapy (allo-CT) using donor lymphocyte infusions (DLI). Complete eradication of tumor cells by DLI, despite resistance of the tumor cells to maximally tolerated doses of M/L conditioning, suggests that alloreactive T lymphocytes may represent a crucial weapon against tumor cells. Allogeneic stem cell transplantation leading to engraftment of allogeneic stem cells in the host may function merely to induce a state of host-versus-graft tolerance, allowing concomitantly or subsequently administered allogeneic donor-derived T lymphocytes to survive and to recognize and eradicate host-derived tumor cells.
In fact, the main therapeutic component of allo-SCT may be ascribed to T lymphocyte mediated GVT or GVL effects rather than to physical elimination of tumor cells by the M/L conditioning prior to transplantation. GVL or GVT effects mediated by T lymphocytes generally occur in the context of allo-SCT, allogeneic peripheral blood stem cell transplantation (allo-PBSCT; i.e., one form of allo-SCT) or allo-CT. However, as discussed above, these procedures can lead to complications related to the M/L conditioning, GVHD, and/or graft rejection.
SUMMARY OF THE INVENTION
This invention provides for new methods of treating a human patient with a pathogenic cell disease. It has been discovered that conditioning regimens can be designed that allow the patient to retain relatively high levels of either stem cells or functional lymphocytes. Thus, in one method, the conditioning regimen is designed to eliminate the patient's T lymphocytes but to allow retention of a functional population of the patient's hematopoietic stem cells. In a second method, the conditioning regimen is designed to ablate the patient's stem cells but to allow retention of a functional population of the patient's lymphocytes. In both methods, after the patient has been treated with the conditioning regimen, a donor-derived allogeneic stem cell preparation is administered to the patient.
Patients treated according to the methods of the invention develop donor-specific unresponsiveness and also develop relatively fewer complications than with the standard M/L regimens. The method also provides a platform for performing allo-CT for inducing GVL, GVT or graft versus autoimmunity (GVA) effects, and allows for development of patient-specific allogeneic stem cell preparations.
In a first aspect, the invention features a method of treating a human patient having a pathogenic cell disease. The method includes treating the patient with a conditioning regimen that retains a functional population of the patient's hematopoietic stem cells. The method also involves administering a preparation that includes allogeneic stem cells from a donor to the patient under conditions effective for inducing host anti-donor unresponsiveness. The regimen can be a m/L conditioning regimen or a -/L conditioning regimen. Preferably, the allogeneic stem cells are peripheral blood stem cells, cord blood stem cells or bone marrow stem cells.
The method may also include a step of providing allogeneic cell therapy to the patient. The allogeneic cell therapy is provided following induction of host anti-donor unresponsiveness and in the absence of significant GVHD. The allogeneic cell therapy can include administration of donor T lymphocytes in graded increments while controlling for GVHD without immunosuppression. The T lymphocytes may be lifespan-limited. The T lymphocytes may be CD8+ cells or CD4+ cells. In one embodiment, allogeneic cell therapy may include administration of donor T lymphocytes activated in vitro, prior to administration, to the patient. In another embodiment, allogeneic cell therapy may include in vivo administration of T cell activator to the patient.
The conditioning regimen can include administration of one or more agents such as purine analogs, alkylating agents or anti-leukocyte globulins. In one embodiment, the purine analog is fludarabine and the anti-leukocyte globulin is anti-T lymphocyte globulin.
In another embodiment, the regimen includes administration of fludarabine, anti-T lymphocyte globulin and an alkylating agent. The alkylating agent may be, for example, busulfan or cyclophosphamide.
Pathogenic cell diseases treatable with the methods include malignant diseases such as chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, myelodysplastic syndrome or multiple myeloma. The malignant disease may also be a solid tumor as in metastatic breast cancer.
In another embodiment, the pathogenic cell disease can be a non-malignant diseases such as &bgr;-thalassemia major, Blackfan Diamond Anemia, Gaucher's anemia, Fanconi's anemia or AIDS. The non-malignant disease may also be an autoimmune disease.
In a second aspect, the invention features treating a patient having a pathogenic cell disease with a conditioning regimen that retains a functional population of the patient's T lymphocytes. This second method also includes administering a preparation that includes allogeneic stem cells from a donor to the patient under conditions effective for inducing host anti-donor unresponsiveness. The regimen can be a M/- or a M/l conditioning regimen.
The method may also include a step of providing a regimen of allogeneic cell therapy to the patient following induction of the host anti-donor responsiveness and in the absence of significant
G. E. Ehrlich Ltd.
Hadash Medical Research Services and Development Ltd.
Parkin Jeffrey S.
Scheiner Laurie
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