Tumor radiosensitization using gene therapy

Details Tumor radiosensitization using gene therapy Tumor radiosensitization using gene therapy

2000-03-24

2003-04-22

Nguyen, Dave T. (Department: 1636)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

C424S184100, C424S277100, C424S093210, C514S04400A, C435S375000, C435S320100, C435S455000

Reexamination Certificate

active

06551588

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to cancer therapy and, more particularly, to compositions and methods for sensitizing a cancer in a subject to radiation therapy.
2. Background Information
Improved methods and novel agents for treating cancer have resulted in increased survival time and survival rate for patients with various types of cancer. For example, improved surgical and radiotherapeutic procedures result in more effective removal of localized tumors. Surgical methods, however, can be limited due, for example, to the location of a tumor or to dissemination of metastatic tumor cells. Radiotherapy also can be limited by these factors, which limits the dose that can be administered. Tumors that are relatively radioresistant will not be cured at such a dose.
Immunotherapeutic methods also are being examined as a means to treat a cancer by stimulating the patient's immune response against the cancer. In particular, the role of cytokines, which are cellular factors that can modulate an immune response, is an important factor to consider when planning an immunotherapeutic procedure. For example, expression of a cytokine such as interleukin-2 (IL-2) can increase the proliferation of T cells, which are involved in the cellular immune response against a cancer.
It is well known, however, that cytokine administration frequently is associated with toxic effects that limit the therapeutic value of these agents. For example, severe hypotension and edema limit the dose and efficacy of intravenous and intralymphatic IL-2 administration. In addition, flu-like symptoms or fatigue often are associated with the administration of various cytokines. The toxicity of systemically administered lymphokines is not surprising as these agents mediate local cellular interactions and normally are secreted only in very small quantities.
To circumvent the toxicity of systemic cytokine administration, an alternative approach involving cytokine gene transfer into tumor cells has produced anti-tumor immune responses in several animal tumor models. In these studies, the expression of cytokines following cytokine gene transfer into tumor cells resulted in a reduction in tumorigenicity of the cytokine-secreting tumor cells when implanted into syngeneic hosts. Reduction in tumorigenicity has been reported in studies using, for example, IL-2, interferon-&ggr; or interleukin-4. In addition, the treated animals often developed systemic anti-tumor immunity and were protected against subsequent tumor cell challenges with unmodified tumor cells.
Although a single treatment modality such as radiation therapy, chemotherapy, surgery or immunotherapy can result in improvement of a patient, superior results can be achieved when such modalities are used in combination. In particular, treatment with a combination of radiotherapy, which can be directed to a localized area containing a tumor, and chemotherapy or immunotherapy, which provide a systemic mode of treatment, can be useful where dissemination of the disease has occurred or is likely to occur. Unfortunately, the therapeutic usefulness of radiation therapy can be limited where the tumor cells are relatively radioresistant, since the does is limited by the tolerance of normal tissue in the radiation field. Thus, there exists a need to sensitize cancer tumors to the effects of radiotherapy so that it can more effectively reduce the severity of a tumor in a patient. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The invention provides a method of radiosensitizing a tumor in a subject by contacting the tumor with a cytokine such as interleukin-3 or granulocyte-macrophage colony stimulating factor or granulocyte colony stimulating factor. For example, the invention provides a method of radiosensitizing a tumor in a subject by contacting the tumor with interleukin-3. As an additional advantage, a method of the invention provides an enhanced systemic immune response in the subject against the cancer.
The invention also provides a method of radiosensitizing a tumor in a subject by administering, at a site other than the tumor, an immunizing composition containing a cytokine and a tumor antigen. For example, the invention provides a method of radiosensitizing a tumor in a subject by administering, at a site other than the tumor, tumor cells that have been genetically modified to express a cytokine.
The invention further provides a method of reducing the severity of a cancer in a subject by immunizing the subject, at a site other than the site of the tumor, with tumor cells genetically modified to express a cytokine express and secrete a cytokine, then administering a radiotherapeutic dose of radiation.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of radiosensitizing a tumor in a subject by contacting the tumor with a cytokine such as interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte colony stimulating factor (G-CSF). As used herein, the term “contacting,” when used in reference to a cytokine and a tumor, means that the cytokine is present in the location of the tumor, particularly in the location of a localized tumor. As disclosed herein, a tumor can be contacted with a cytokine, for example, by injecting a solution containing the cytokine into the region of the tumor, by administering a nucleic acid molecule encoding a cytokine into the region of the tumor, wherein the nucleic acid molecule is taken up by cells in the tumor such that the cytokine is expressed, or by administering a cell that has been genetically modified to express (and secrete) the cytokine into the region of a tumor.
Since an additional advantage of a method of the invention is that a systemic immune response against the cancer occurs in the subject, a composition containing a cytokine or a nucleic acid molecule encoding a cytokine is referred to herein generally as an “immunizing composition.” In addition, the term “immunizing” is used generally to refer to the administration of such an immunizing composition to a subject.
The invention also provides a method of radiosensitizing a tumor in a subject by administering, at a site other than the tumor, an immunizing composition comprising a cell genetically modified to express a cytokine. For example, the invention provides a method of radiosensitizing a tumor in a subject by administering to the subject an immunizing composition comprising tumor cells genetically modified to express a cytokine. Such an immunizing composition can be administered at the site of the tumor, in which case the cytokine is IL-3 or GM-CSF or G-CSF, or can be administered at a site other than the tumor site, in which case the cytokine can be an interleukin, an interferon, a tumor necrosis factor or a colony stimulating factor, and preferably is IL-3 or GM-CSF or G-CSF.
In one embodiment of the invention, an immunizing composition, which contains a cytokine such as IL-3 or GM-CSF or G-CSF, is administered at the site of a tumor in a subject. As a result, the microenvironment of the tumor is altered such that a systemic immune response against the tumor in the tumor occurs in the subject and the tumor is radiosensitized.
In another embodiment of the invention, an immunizing composition, which contains a cytokine and a tumor antigen, is administered at a site other than the tumor site in the subject. As a result of the administration of the immunizing composition at a site other than a tumor site, a systemic immune response is stimulated in the subject and the tumor can become radiosensitized.
An immunizing composition, which contains a cytokine or a nucleic acid molecule encoding a cytokine, can be administered to a subject having a cancer. As a result, an immune response is stimulated in the subject against the cancer, wherein the systemic immune response or alterations induced by the immune response in the tumor microenvironment can radiosensitize the subject's cancer. Subseq

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