Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1997-11-20
2003-03-25
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S093200, C435S325000, C435S372000, C435S455000
Reexamination Certificate
active
06537523
ABSTRACT:
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
This invention was made at least in part with funds from the Federal government, and the government therefore may have certain rights in the invention.
FIELD OF THE INVENTION
The field of the invention relates to cancer therapy; human immunodeficiency virus; a recombinant macrophage; methods of diagnosis of macrophage involvement in cancer development; kits for use in diagnosis; and methods of treatment for cancer involving macrophage-induced tissue growth.
BACKGROUND OF THE INVENTION
Of the approximately 36,000 new cases of lymphoma diagnosed in the United States in 1992, between 8 and 27-o are estimated to have occurred in HIV-infected individuals (Gail, M. H. et al.,
J Natl Can Int
(1991) 83:695-701). Thus, HIV-related lymphoma represents a major clinical problem for physicians involved in the care of HIV-infected individuals.
The biology of AIDS lymphoma is controversial and appears complex. Early in the AIDS epidemic high grade non-Hodgkin's lymphoma (NHL) began to appear in individuals at risk for the development of AIDS (Ziegler, J. et al.,
N Eng J Med
(1984) 311:565-570). However, in the past several years, the incidence of NHL in HIV-infected individuals has increased (Harnly, M. E. et al.,
Am J. Epi
(1988) 128(2):261-267; Levine, A. et al.,
Ann Intern Med
(1984) 100:7-13). It is clear that as the AIDS epidemic expands, non-Hodgkin's lymphoma will become a continually more important health problem in HIV-infected individuals. As treatment for the underlying HIV disease becomes more successful and as patients survive for longer periods of time in-the absence of opportunistic infections, more cases of lymphoma will probably appear in this patient population.
The non-Hodgkin's lymphomas that develop in HIV-1 infected individuals fall into two main subcategories: the large cell lymphomas and the small non-cleaved cell Burkitt's lymphomas (Ziegler, J. et al., 1984, supra; Knowles, D.M. et al., Blood (1989) 73:792-799; Bermudez, M. et al.;
Am J Med
(1989) 86:71-76; Gill, P. et al.,
J Clin Oncol
(1987) 5:1322-1328; Kaplan, L. D. et al,
JAMA
(1989) 261:719-724; Knowles, D. M. et al.,
Ann Intern Med
(1988) 108:744-753; Lowenthal, D. A. et al.,
Cancer
(1988) 61:2325-2337). Both major classes of lymphoma are high grade 5neoplasms and are predominantly of B-cell origin (Ziegler, J. et al., 1984, supra.; Subar, M. et al., Blood (1988) 72:667-671.); however, T-cell lymphomas may also be increasing in frequency (Presant, C. A. et al.,
Cancer
(1987) 60:1459-1461; Nasr, S. et al.,
Cancer
(1988) 61:947-951; Herndier, B. et al., VII Intl Conference of Acquired Immunodeficiency Syndrome (AIDS), Florence, Italy, Jun.16-21, 1991). In HIV disease lymphomas tend to be diffusely aggressive, with approximately 90% originating from B-cells and 5-10% derived from T-cells. Approximately one-half of the large cell lymphomas are herein termed “mixed immunophenotype” lymphomas as they contain a mixture of B-cells, T-cells, and macrophages. AIDS-associated non-Hodgkin's lymphomas are commonly characterized by their very high rates of extranodal (85-97%) (Kaplan, L. D. et al.,
JAMA
(1989) 261:719-724; Burkes, R. L. et al.,
Arch Intern Med
(1986) 146:913-915; Balasubramanyam, A. et al.,
Chest
(1986) 90:243-246; Guarner, J. et al.,
Arch Pathol Lab Med
(1987) 111:254-256; Kaplan, L. et al.,
Ann Intern Med (
1989) 110:162; Friedman, S. L.,
Gastroenterol Clin North Am
(1988) 17:465-486) and central nervous system involvement (35k) (Baumgartner, J. et al.,
J Neurosurc
(1990) 73:206-211; Formenti, S.C. et al.,
Cancer
(1989) 63:1101-1107; Ciricillo, S. et al.,
J Neurosurq
(1990) 73:720-724), as well as their poor response to current chemotherapy protocols (Kaplan, L. D. et al., (1989) supra; Bermudez, M. et al.,
Am J Med
(1989) 86:71-76; Gill, P. et al.,
J Clin Oncol
(1987) 5:1322-1328; Urba, W. et al.,
Journal of the National Cancer Institute
(1990) 10:29-37; Kaplan, L. D. et al., JCO (1991) 9(6):929-940).
Lymphomas, in general, are a heterogeneous group of malignancies. Their biologic behavior ranges from indolent, requiring no therapy, to aggressive malignancies with few long-term survivors. The behavior of lymphoma is influenced by the immune status of the host. The risk of B-cell lymphoma is dramatically increased in individuals with defects of cell-mediated immunity. The best characterized of these groups is immunosuppressed allograft recipients, whose risk of developing lymphoma is between 50 and 60 times that of the general population. These individuals develop a spectrum of lymphoproliferative diseases ranging from typical monoclonal immunoblastic lymphoma to an aggressive form of polyclonal lymphoproliferative disease (Frizzera, G. et al.,
Cancer Res
(1981) 41:4262-4279; Hanto, D. W. et al.,
Cancer Res
(1981) 41:4253-4261; Hanto, D. W. et al.,
Ann Surg
(1983) 198:356-369) often associated with Epstein Barr Virus (Hanto, D. W. et al., (1981) supra; Penn, I.,
Transplant Proc
(1983) 15 (suppl 1):S2790-S2797; Shearer, W. T. et al.,
N Engl J Med
(1985) 312:1151-1159) infection. Clinically, lymphoma in these individuals presents aggressively at extranodal sites indicating a common feature between HIV-associated lymphomas and the molecular and clinical characteristics of the allograft-associated lymphomas.
The primary means of HIV lymphoma diagnosis remains microscopic examination of hematoxylin and eosin-stained sections from formalin-fixed tissue. Over time, pathologists have used clinical presentations, autopsy follow-up, and trial and error to develop histologic methods a of diagnosing and categorizing cancer. Missing a histologic diagnosis of cancer or ‘over-calling’ a cancer and subjecting a patient to cancer therapy are sufficient incentives for providing accurate diagnosis. Traditional histologic methods can be enhanced by phenotypic and, particularly, genotypic analyses of lymphomas where the discerned molecular changes of the affected tissue point to an alternative form of treatment.
SUMMARY OF THE INVENTION
The invention. relates to a method of diagnosing clonal macrophage involvement in HIV-associated and non-HIV-associated lymphomas or other cancers using genotypic analysis as well as a kit for such diagnostic method. The invention also relates to a method of treating macrophage-induced cancer. The invention also relates to a recombinant macrophage useful in vitro and in vivo methods of screening for therapeutic agents useful in treating macrophage-induced cancer.
The discovery that HIV lymphomas are frequently associated with clonal macrophage involvement and that the macrophage has HIV DNA integrated upstream of a known oncogene, c-fes (c-fes/fps), is disclosed. As described in detail below, macrophage clonality is associated with many HIV-related lymphomas. Macrophage clonality can be associated with non-HIV-related lymphomas as well. Expansion of macrophages may enhance growth of surrounding tissue by secretion of cytokines; the cytokine Interleukin-6 has been shown to cause growth of myeloma and hybridoma cells (Woodruff, C. et al.,
DNA and Cell Bioloqy
11:587-592). Diagnosis of macrophage clonality and treatment targeting macrophages offers a new direction in cancer therapy. Disclosed are diagnostic methods and kits as well as therapeutic methods useful in the battle to overcome clonal macrophage-induced HIV lymphomas and clonal macrophage-induced cancers in general.
Accordingly, in one aspect, the invention features a method of diagnosing the presence of clonally expanded macrophages in a suspected cancerous tissue of a mammal by first obtaining a sample of the tissue suspected of being cancerous followed by isolation of DNA from the tissue by standard techniques known to those skilled in the art of molecular biology. The presence of clonal DNA in the isolated DNA is determined by standard techniques including but not limited to HIV integration site analysis by IPCR (Shiramizu, B. et al.,
Cancer Res
(1994) 54:2069-2072); RFLP (Restriction Fragment Length Poly
Herndier Brian
McGrath Michael S.
Shiramizu Bruce
Borden Paula A.
Bozicevic Field & Francis LLP
Crouch Deborah
Field Bret E.
The Regents of the University of California
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