Combination viral-based and gene-based therapy of tumors

Details Combination viral-based and gene-based therapy of tumors Combination viral-based and gene-based therapy of tumors

1999-04-30

2003-08-05

Shukla, Ram R. (Department: 1632)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

C424S093100, C435S320100, C435S325000, C514S04400A

Reexamination Certificate

active

06602499

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a viral mutant capable of selectively killing tumor cells. More particularly, the present invention relates to a viral mutant capable of selectively killing tumor cells by a combination of viral mediated oncolysis and anti-cancer (“suicide”) gene therapy.
2. Related Art
A. Conventional Cancer Therapies
Neoplasia is a process that occurs in cancer, by which the normal controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in progressive growth. This impairment of control mechanisms allows a tumor to enlarge and occupy spaces in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites it will likely result in death of the individual.
In 1999, in the United States alone, approximately 563,100 people, or about 1,500 people per day, are expected to die of cancer. (Landis, et al., “Cancer Statistics, 1999
, ” CA Canc. J. Clin
. 49:8-31 (1999)). Moreover, cancer is a leading cause of death among children aged 1 to 14 years, second only to accidents. Id. Thus, clearly there is a need for the development of new cancer therapies.
1. Common Limitations of Conventional Therapies
The desired goal of cancer therapy is to kill cancer cells preferentially, without having a deleterious effect on normal cells. Several methods have been used in an attempt to reach this goal, including surgery, radiation therapy, and chemotherapy.
Surgery was the first cancer treatment available, and still plays a major role in diagnosis, staging, and treatment of cancer, and may be the primary treatment for early cancers (see Slapak, C. A., and Kufe, D. W., “Principles of Cancer Therapy,” in
Harrison 's Principles of Internal Medicine
, Fauci, A. S. et al., eds., 14th Ed., McGraw-Hill Cos., Inc., New York, 1998, at 524). However, although surgery may be an effective way to cure tumors confined to a particular site, these tumors may not be curable by resection due to micrometastatic disease outside the tumor field. Id. Any cancer showing a level of metastasis effectively cannot be cured through surgery alone. Id.
Radiation therapy is another local (nonsystemic) form of treatment used for the control of localized cancers. Id. at 525. Many normal cells have a higher capacity for intercellular repair than neoplastic cells, rendering them less sensitive to radiation damage. Radiation therapy relies on this difference between neoplastic and normal cells in susceptibility to damage by radiation, and the ability of normal organs to continue to function well if they are only segmentally damaged. Id. Thus, the success of radiation therapy depends upon the sensitivity of tissue surrounding the tumor to radiation therapy. Id. Radiation therapy is associated with side effects that depend in part upon the site of administration, and include fatigue, local skin reactions, nausea and vomiting. Id. at 526. In addition, radiation therapy is mutagenic, carcinogenic and teratogenic, and may place the patient at risk of developing secondary tumors. Id.
Other types of local therapy have been explored, including local hyperthermia (Salcman et al.,
J Neuro
-
Oncol
. 1:225-236 (1983)), photodynamic therapy (Cheng et al,
Surg. Neurol
. 25:423-435 (1986)), and interstitial radiation (Gutin et al.,
J. Neurosurgery
67:864-873 (1987)). Unfortunately, thus far these therapies have been met with only moderate success.
Local treatments, such as radiation therapy and surgery, offer a way of reducing the tumor mass in regions of the body that are accessible through surgical techniques or high doses of radiation therapy. However, more effective local therapies with fewer side effects are needed. Moreover, these treatments are not applicable to the destruction of widely disseminated or circulating tumor cells eventually found in most cancer patients. To combat the spread of tumor cells, systemic therapies are used.
One such systemic treatment is chemotherapy. Chemotherapy is the main treatment for disseminated, malignant cancers. (Slapak, C. A., and Kufe, D. W., “Principles of Cancer Therapy,” in
Harrison 's Principles of Internal Medicine
, Fauci, A. S. et al., eds., 14th Ed., McGraw-Hill Cos., Inc., New York, 1998, 527). However, chemotherapeutic agents are limited in their effectiveness for treating many cancer types, including many common solid tumors. See id This failure is in part due to the intrinsic or acquired drug resistance of many tumor cells. See id. at 533. Another drawback to the use of chemotherapeutic agents is their severe side effects. See id. at 532. These include bone marrow suppression, nausea, vomiting, hair loss, and ulcerations in the mouth. Id. Clearly, new approaches are needed to enhance the efficiency with which a chemotherapeutic agent can kill malignant tumor cells, while at the same time avoiding systemic toxicity.
2. Challenges Presented by Central Nervous System Tumors Another problem presented in cancer treatment is that certain types of cancer, e.g., gliomas, which are the most common primary tumor arising in the human brain, defy the current modalities of treatment. Despite surgery, chemotherapy, and radiation therapy, glioblastoma multiforme, the most common of the gliomas, is almost universally fatal (Schoenberg, in
Oncology of the Nervous System
, M. D. Walker, ed., Boston, Mass., Martinus Nijhoff (1983); Levin et al., Chapter 46 in
Cancer: Principles and Practice of Oncology
, vol. 2, 3rd ed., De Vita et al., eds., Lippincott Press, Philadelphia (1989), pages 1557-1611).
Gliomas represent nearly 40% of all primary brain tumors, with glioblastoma multiforme constituting the most malignant form (Schoenberg, “The Epidemiology of Nervous System Tumors,” in
Oncology of the Nervous System
, Walker, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1983)). The five year survival rate for persons with this high grade type of astrocytoma is less than 5 percent, given the current treatment modalities (surgery, radiation therapy and/or chemotherapy) (Mahaley et al.,
Neurosurgery
71: 826-836 (1989); Schoenberg, in
Oncology of the Nervous System
, Walker, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1983); Kim et al.,
J. Neurosurg
. 74:27-37 (1991), Daumas-Duport et al.,
Cancer
2:2152-2165 (1988)). After treatment with radiation therapy, glioblastomas usually recur locally. Hochberg et al.,
Neurology
30: 907 (1980). Neurologic dysfunction and death in an individual with glioblastoma are due to the local growth of the tumor. Systemic metastases are rare. Id. For this reason, regional cancer therapy methods, rather than systemic methods, may be especially suitable for the treatment of glioblastomas.
Moreover, glioblastomas are resistant to many chemotherapeutic agents, perhaps due to the proliferative characteristics of this tumor type. Many chemotherapeutic agents are cell-cycle-active, i.e., cytotoxic primarily to actively cycling cells (Slapak, C. A., and Kufe, D. W., “Principles of Cancer Therapy,” in
Harrison's Principles of Internal Medicine
, Fauci, A. S. et al., eds., 14th Ed., McGraw-Hill Cos., Inc., New York, 1998, 527). Generally, chemotherapy is most effective for cancers-with a small tumor burden where the growth fraction of the tumor is maximal. Id. The growth fraction for glioblastoma tumors is only 30%, with the remaining 70% of cells being in G
0
, a resting phase (cells in G
0
may die or may re-enter the active cell cycle; Yoshii et al.,
J. Neurosurg
. 65:659-663 (1986)). While the 30% of glioblastoma cells that are actively dividing contribute to the lethal progression of this tumor, the 70% that are quiescent are responsible for the resistance of these tumors to a number of chemotherapeutic agents that target actively proliferating cells.
Unfortunately, regional treatments, such as surgery and radiation therapy have also found limited success in the treatment of glioblastomas. (Burger et al.,
J. Neurosurg
. 58:159-169 (1983); Wowra et al.,
Acta Neurochir
. (Wien) 99:104-1

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