Non-myeloablative tolerogenic treatment

Details Non-myeloablative tolerogenic treatment Non-myeloablative tolerogenic treatment

2000-02-16

2002-09-10

Schwartzman, Robert A. (Department: 1632)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

C424S093210, C514S002600, C514S04400A, C435S325000

Reexamination Certificate

active

06447767

ABSTRACT:

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
BACKGROUND OF THE INVENTION
Transplantation of organs, hematopoietic cells and somatic cells has been a crucial therapeutic regimen for patients suffering from a variety of maladies. Although the techniques necessary for transplants are quite straight-forward, the great stumbling block for successful transplantation has been the immune system. A fundamental problem has been the great vigor with which the host immune system reacts against introduction of antigens found in donor tissues or cells.
Transplantation of allogeneic donor (i.e., the same species but not genetically identical to the host patient) or xenogeneic donor (i.e., a species other than that of the host) grafts has posed particularly great difficulties. The continued functioning of any donor graft depends upon continued functioning of the donor cells that make up that graft. The cells of donor grafts, however, can elicit an immune reaction on the part of the host that, if unchecked, may lead to destruction of the graft.
One method of alleviating the reaction by the host against a graft has been administration of immunosuppressive treatment to the host. Unfortunately, despite the availability of new and very effective immunosuppressive drugs, recurrent episodes of acute and chronic graft rejection remain common, frequently causing loss of graft function. Moreover, the long-term success of transplantation is often limited by complications resulting from drug-related toxicity and from long-term immunosuppression (e.g. infections and secondary malignancies). In addition, transplantation of bone marrow cells (BMC) or small intestine, which are rich in immunocompetent lymphocytes, frequently is associated with a potential life-threatening complication due to graft versus host disease (GVHD).
It has been shown that a full hematopoietic chimera, i.e., a patient whose own BMC have been 100% replaced by permanently engrafted BMC from another individual (donor), can permanently accept donor-derived allografts with no need for maintenance immunosuppressive therapy. However, induction of full hematopoietic chimerism has been difficult to accomplish. First, substantially complete destruction of the host's immunohematopoietic compartment (“lethal” conditioning) is usually required for engraftment of matched and especially mismatched BMC. With lethal conditioning of the host, GVHD consistently causes morbidity or mortality. In such cases, T cell depletion of the graft hematopoietic material represents the only approach for effective prevention of GVHD. T cell depletion in turn is associated with an increased incidence of graft rejection. To overcome the problem of graft rejection, recipients of T cell depleted marrow allografts may require particularly strong conditioning or, alternatively, very high numbers of T cell depleted BMC. Subjecting patients to aggressive rejection-prevention protocols, such as total body irradiation (TBI) alone or TBI in combination with a short course of immunosuppressive drugs is unlikely to be accepted by clinicians treating patients in need of organ allografts.
It has been proposed that true bilateral tolerance associated with mixed donor/recipient hematopoietic chimerism, i.e., the condition in which a patient possesses both recipient (host) and donor hematopoietic stem cells, rather than with full chimerism, would be preferable in clinical organ transplantation. Several experimental protocols have been designed to induce transplantation tolerance leading to mixed chimerism. Conditioning has required the use of high dose TBI followed by infusion with a mixture of T cell depleted donor and recipient BMC (Sachs et al.,
Ann. Thorac. Surg
., 56:1221 (1993); Ildstad et al.,
Nature
, 307:168 (1984)) or inoculation with donor BMC after lower dose TBI and infusion of a mixture of antibodies against CD4
+
T cells, CD8
+
T cells and NK cells leading to general pancytopenia. Tomita et al.,
J. Immunol
., 153:1087 (1994); Tomita et al.,
Transplantation
, 61:469 (1996). An alternative approach has been developed recently involving irradiation with a sublethal dose of TBI and inoculation with a very high number of T cell depleted donor-derived hematopoietic cells. Reisner et al., Immunol. Today, 16:437 (1995); Bachar-Lustig et al.,
Nature Medicine
, 12:1268 (1986). Tolerogenic treatments using cyclophosphamide (hereinafter also referred to as “Cytoxan” or “Cy”) in combination with TBI have also been described.
Total lymphoid irradiation (TLI) has been employed successfully as the sole preparatory regimen prior to infusion with donor BMC, to induce mixed hematopoietic chimerism and bilateral transplantation tolerance. Slavin S.,
Immunol. Today
, 3:88 (1987); Slavin et al.,
Isr. J. Med. Sci
., 22:264 (1986). TLI is non-myeloablative and routinely given safely on an outpatient basis to transplant recipients and patients with Hodgkin's disease. Unfortunately, consistent induction of chimerism using TLI has required very high cumulative doses of radiation (3,400-4,400 cGy) that again would not be desirable for transplant recipients. TLI has significant advantages over TBI, especially in the clinical setting. TLI, which involves selective irradiation of the lymphoid compartment without exposing the whole body to ionizing irradiation, is well tolerated. In addition, TLI preserves intact a significant portion of the host's immunohematopoietic system, with resultant retained memory to recall antigens including infective agents. However, long courses of TLI can be time consuming and may be associated with short and long-term side effects that may not be suitable for routine clinical application.
SUMMARY OF THE INVENTION
The invention provides a new method for treating a host mammal to induce transplantation tolerance to cell, tissue and organ allografts and xenografts. Such transplants can provide replacement therapy for enzyme or metabolic disorders and adoptive immunotherapy for cancer and life-threatening infections in humans. The method also can be used to provide new animal models for tolerance induction toward allogeneic and xenogeneic cells. The invention also provides a new method of non-syngeneic cell therapy in which the cell population used for therapy is substantially depleted of responsiveness to host antigens prior to administration to the host.
In general, the invention features a method of treating a host mammal, including (a) administering donor antigens from a non-syngeneic donor to the host mammal; (b) administering a non-myeloablative dose of lymphocytotoxic agent (e.g., cyclophosphamide) or tolerizing agent to the host mammal to selectively eliminate the host mammal's lymphocytes responding to the donor antigens; and (c) administering a preparation of hematopoietic stem cells from the non-syngeneic donor to the host mammal.
Prior to step (a), the host mammal can be administered an immunosuppressive agent in a non-myeloablative regimen sufficient to decrease the host mammal's functional T lymphocyte population. The immunosuppressive agent can include one or more of an immunosuppressive drug, an alkylating agent, ionizing radiation, or anti-leukocyte or anti-leukocyte function antibodies. It is particularly advantageous to use a short course of TLI (sTLI) as the immunosuppressive agent, for example 1-12, frequently 1-6, doses of 200 cGy/dose.
The donor antigens administered to the host mammal can include non-cellular antigens, cells, tissues and/or organs. For example, the donor antigens can include hematopoietic stem cells or other viable cells. If the donor antigens include viable cells such as hematopoietic stem cells, then the immunosuppressive regimen referenced above should decrease the T lymphocyte population of the host to a level permitting at least transient survival of the donor's cells. For example the T lymphocyte population of the host can be decreased by 90%, 95% or 99%.
The host mammal can be an animal or a human, for example a human cancer patie

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