Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1999-06-16
2001-10-09
Priebe, Scott D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093200, C424S155100, C424S093100, C435S320100, C435S325000, C514S04400A, C514S064000, C250S269600
Reexamination Certificate
active
06299873
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to a new method for the improvement of radiation therapy of malignant tumors.
BACKGROUND OF THE INVENTION
Typically, a patient with a malignant tumor undergoes preliminary therapy to greatly reduce the body burden of the malignant cells. This is conventionally accomplished by surgery. Depending on the clinical circumstances and on the type of malignancy, radiation therapy (“radiotherapy”) may be implemented after surgery or, less commonly, before surgery or even without surgery. Radiotherapy is conventionally accomplished using high-energy ionizing photons, typically gamma radiation with energies measured in the millions of electron volts. It has been noted there is an inadequacy of post-operative radiotherapy of the most common malignant brain tumors in humans, mainly glioblastoma multiforme. Conventional photon therapy generally mandates delivery of as much radiation to the tumor as can be physically delivered, subject to the limitation that vital organs and tissues in and around the tumor that are in the path of one or several of the convergent photon beams receive doses that are below their thresholds for causing clinical dysfunction or for causing acute or delayed radiation-induced necrosis. Unfortunately, this standard of dosimetry for conventional radiation therapy does not take into account thresholds for damage to the function or integrity of cells and tissues of the immune system that may be in the path of the gamma beams. (R. Barth,
Journal of Neuro
-
Oncology
, 1997.) Radiation therapy alone is often effective in slowing the growth of malignant tumors, but is usually incapable of preventing devastating recurrence for much longer than one year of deeply infiltrating growth of some types of malignancies, such as the most common primary malignant brain tumor, glioblastoma multiforme. Therapies for these recurrent tumors are generally palliative for only a few months before death occurs. If one attempts to use standard radiation therapy to kill individual clonogenic tumor cells several centimeters beyond the macroscopic periphery of the tumor, whether at its first occurrence or at its recurrence, such a large dose of radiation would be needed that normal brain structure and/or function would be compromised to some unacceptable degree. For example, long term (i.e., two years or more) survivors of glioblastoma multiforme frequently have profound neurological deficiencies attributed in part to the aggressive doses of radiation used to attain such long survivals. Nevertheless, it is known in the arts of therapeutics that even well tolerated doses of standard radiation therapy do help to reduce the burden of brain tumor cells remaining after primary surgical extirpation (i.e., debulking) of the malignancy.
The present art of radiation therapy of cancer uses standards for technique and dose that are unrelated to consideration of the function of the patient's immune system except in two circumstances: 1. where the therapy employs whole-body radiation; and 2. where partial or whole-body radiation follows or precedes chemotherapy. There is no method of radiation therapy used at present that requires that the patient's immune system be specifically modified and stimulated before or after radiotherapy, and that the radiotherapy be timed or given in dose levels that conform to the requirements of that stimulation.
Also, it is known that certain adjunct therapies, implemented after primary therapies, are useful in delaying and/or mitigating the regrowth of the cancer. Adjunct therapies known to be effective are chemotherapy, including antimitotic therapy and anti-angiogenesis therapy, additional radiation and further surgical removal or partial removal of the cancer.
To date, adjunct cancer therapies based on gene therapy or immunotherapy are often characterized by insufficiency of clinical relevance and/or of realism in preclinical experimentation. A variety of therapies dependent on the genetic modification of cells have been proposed. Some of them are being tested in clinical trials. To date, none has shown to be sufficiently efficacious to warrant widespread adoption for common malignancies of the brain. Although in vitro tumor cell death can often be demonstrated, transfection of an appropriate number of specific target tumor cells in patients is usually unattainable. There is no delivery system perfected that allows delivery of the gene used in therapy into all the tumor cells. Further, animal experiments are often designed to show proof of principle rather than control of large, imminently lethal, clinically analogous tumor models. For example, the experimental tumor can be far too small relative to the experimental animal organ under study to infer clinical relevance because of the lack of correlation in scale with the size of human tumors (at the time of clinical treatment) relative to the size of the human organ and/or organism. Additionally, in some instances, experimental immunotherapy or gene therapy is implemented at an inappropriate time, e.g., before the animal has time to manifest clinical symptoms; or after tumor cells, modified in vitro, are transplanted to the test animals. The elimination of such tumors may be of scientific importance without necessarily having practical clinical relevance. We define a clinically relevant brain tumor “imminently lethal”, for example, to be one that is so advanced such that the residual life span of the untreated concomitant controls will be no more than one third of total time between tumor inoculation and death from local tumor overgrowth in the brain. For example, the untreated 9L gliosarcoma causes death about three weeks after initiation. Clinically relevant experimental therapy is not begun until fourteen days after tumor inoculation. Anti-angiogenesis therapies, based mainly on the pioneering work of Dr. Judah Folkman and his colleagues, are at too early a stage of clinical investigation to be evaluated in the context of this invention. However, any of these innovative therapies that proves successful clinically is likely to augment rather than degrade the effectiveness of the improvement in radiation therapy taught in this invention.
SUMMARY OF THE INVENTION
The present invention combines the advantageous characteristics of these adjunct therapies while reducing or obviating such deficiencies as are indicated above. It involves a method of combining two disparate techniques, radiation therapy and immunotherapy or gene-modified immunotherapy (also called immunoprophylaxis when the treated malignancy is microscopic), with or without other adjunct therapies, to effect a clinically useful synergy that would not exist if the two above-named modalities were implemented independently or if only one of these two modalities were implemented. Critical to this synergy is the implementation of extensive in vitro culture and, if appropriate, genetic transformation of the tumor cells during the interval between the first neurosurgical debulking and the implementation of radiation therapy.
Advantages resulting from the combination therapy of the present invention are augmented by significant (unconventional) reduction in the length of time required for the primary radiation therapy. While conventional primary radiotherapy is implemented in small fractions daily over a period of several weeks (often six weeks), peripheral tumor nest cells are growing. In its preferred embodiment, this invention prescribes use of a radiation therapy method that is performed in a relatively short period. Massive tumor necrosis that typically ensues after such rapid irradiation is believed to cause leukocyte diapedesis from local blood vessels due to a steep gradient of leukotaxic substances diffusing from the necrobiotic tumor mass. The large influx of leukocytes into the tumor area within a short time period will enhance tumor cell surveillance and therefore enhances the prospects of immunotherapy as compared with the slow influx of leukocytes associated with prolonged, less inten
Coderre Jeffrey A.
Slatkin Daniel N.
Smilowitz Henry M.
Alix Yale & Ristas, LLP
Beckerleg Anne Marie S.
Priebe Scott D.
University of Connecticut
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