Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1992-12-31
2002-07-16
Clark, Deborah J. R. (Department: 1632)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S320100, C435S455000, C424S093200, C424S093210, C536S024500
Reexamination Certificate
active
06420172
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods and reagents for enhancing in vivo tumor cell immunity.
(The following is a general discussion of relevant art and not an admission that any is prior art to the claimed invention. All of the cited or referenced art is hereby incorported by reference.)
In general, tumors that arise de novo are poorly immunogenic, thereby escaping host antitumor responses (Hewitt et al., 33
Br. J. Cancer
241, 1976). The reasons for this poor immunogenicity are poorly understood. A major objective in the field of tumor immunotherapy is the development of strategies for enhancing tumor immunogenicity, with potential applications in both tumor prevention and cure.
Several experimental strategies have been reported for enhancing tumor immunogenicity, for example, use of mutagen or drug treatment (Van Pel and Boon, 79
Proc. Nat. Acad. Sci. USA
4718, 1982; Frost et al., 159
J. Exp. Med.
1491, 1984; and Frost et al., Maloy and Nicolson (eds.), in “Occult Nodal Metastasis in Solid Carcinoma”,
Cancer Research Monographs,
Vol. 5, New York, Praeger Publishers, 1987); by transfection with a foreign gene encoding an exogenous antigen such as influenza hemagglutinin (Fearon et al., 38
Cancer Research
2975, 1988); by transferring a gene expressing interleukin-2 (Fearon et al., 60
Cell
397, 1990); and by transferring a gene expressing interleukin-4 into a tumor (Tepper et al., 57
Cell
503, 1989, and Golumbek et al., 254
Science
713, 1991).
The role of cytokines and growth factors in tumor cell growth has been discussed in the literature. See, for example, Walsh et al., 155
Western Journal of Medicine
152, 1991; Foekens et al., 63
Cancer
2139, 1989; Koenuma et al., 80
Japanese Journal of Cancer Research
51, 1989; Antoniades et al.,
FASEB Journal Abstracts
4716, 1991; Aaronson, 254
Science
1146, 1991; Macaulay et al., 50
Cancer Research
2511, 1990; Korc-Grodzicki et al.,
Eighty
-
Second American Association for Cancer Research Proceedings
Vol. 32, Abstract 300, 1991; Culouscou et al., 40
International Journal of Cancer
646, 1987; Roholl et al., 16
Histopathology
455, 1990; Estrov et al., 9
Journal Clinical Oncology
394, 1991; Rodeck et al., 97
Journal Investigative Dermatology
20, 1991; and Theodorescu et al., 148
Journal of Cellular Physiology
380, 1991. Others have suggested a relationship between receptors for such cytokines and tumorigenicity. See, for example, Noguchi et al., 82
Japanese Journal of Cancer Research
1199, 1991; Campbell and Novak, 149
Journal of Cell Physiology
293, 1991; Foekens et al., 37
Journal Steroid Biochem. Molec. Biol.
815, 1990; Freiss et al., 173
Biochem. Biophys. Research Communications
919, 1990; and Berns et al., 52
Cancer Research
1036, 1992. Yet others have noted that antibodies to such factors may inhibit growth of tumors. See, for example, Gansler et al., 135
American Journal of Pathology
961, 1989, and Eppstein et al., 141
Journal of Cell Physiology
420, 1989. Still others have noted that drugs may inhibit tumor growth. See, for example, Upp et al., 115
American J. Surg.
29, 1988; Hajri et al., 27
Eur. J. Cancer
1247, 1991; Schally, 48
Cancer Res.
6977, 1988; and Longnecker, 22
Drug Intell. Clin. Pharmacol.
99, 1988.
Both IGF-I and IGF-II have previously been characterized extensively as growth, and to a lesser extent as differentiation, factors, and are presumed to play significant roles in embryonic and fetal development (see, for example, Froesch et al, 47
Ann. Rev. Physiol.
443, 1985; Whitman et al., 5
Ann. Rev. Cell. Biol.
93, 1989; Spaventi et al., 108
Development
491, 1990; Han et al., 236
Science
193, 1987; Rappolee et al., Spencer EM (ed.), in “Modern Concepts of Insulin-Like Growth Factors”, Elsevier Science Publishing Co. Inc., 1991; Shen et al., 83
Proc. Nat. Acad. Sci. USA
9179, 1986). In many instances, cells that express IGF's in embryonic or fetal forms do not continue to express the same cytokine in the adult form to an appreciable extent.
IGF-I and IGF-II are expressed at high levels in a range of tumor cell types (see, for example, Antoniades et al, 50
Intl. J. Cancer
215, 1992; Roholl et al., 16
Histopathology
455, 1990; Williams et al., 61
Mol. Cell Endocrinol.
139, 1989; Foekens et al., 63
Cancer
2139, 1989; Koenuma et al., 80
Jpn. J. Cancer Res.
51, 1989; Culouscou et al., 40
Intl. J. Cancer
646, 1987; Antoniades et al., 5
FASEB J.
A1184, 1991; Brunner et al., 16
Breast Cancer Res. Treat.
148, 1990; Brewer et al., 31
Proc. Annu. Meet. Am. Assoc. Cancer Res.
A247, 1990; and Macaulay et al., 50
Cancer Res.
2511, 1990). Tumor cells express either one or the other, or both. Also, many tumors express receptors for IGF-I (Rechler et al., 47
Ann. Rev. Physiol.
425, 1985, and Kiess et al., 124
Endocrinology
1727, 1989).
The prior tumor cell literature has focused on the potential role of the IGF's as growth factors driving the proliferation of tumor cells that produce them. In turn, this has led to attempts to inhibit growth of such tumor cells with anti-IGF-I or anti-IGF-II antibodies that are added exogenously. While some growth inhibition has been claimed using anti-IGF-I and anti-IGF-II antibodies in vitro (see, for example, Minuto et al., 48
Cancer Res.
3716, 1988; Huff et al., 46
Cancer Res.
4613, 1986; Blatt et al., 123
Biochem. Biophys. Res. Commun.
373, 1984) and in vivo (Gansler et al., 135
Am. J. Pathol.
961, 1989), tumor development in vivo was not blocked by the anti-IGF antibodies. Similarly, there have been attempts to use octreotide to inhibit growth of tumor cells. While some growth inhibition has been claimed using this agent (see, for example, Hajri et al., 27
Eur. J. Cancer
1247, 1991), tumor development in vivo was not blocked by octreotide.
SUMMARY OF THE INVENTION
Applicant has discovered that the immunogenicity of a tumor cell can be remarkably enhanced by inhibition of expression within that tumor cell of one or more molecular factors that affect a differentiation state (see below regarding how such factors can be readily identified), e.g., cytokines including, but not limited to, insulin-like growth factor I and II (IGF-I and IGF-II), platelet-derived growth factor (PDGF), macrophage colony stimulating factor (MCSF), granulocyte/macrophage colony stimulating factor (GMCSF), and interleukins II and III (IL-II and IL-III); nuclear transcription factors, such as those which bind directly to regulatory sequences in DNA, and other transcriptional factors (e.g., Id), which bind to transcriptional regulators and modulate their transcription regulatory function; other examples include basic helix-loop-helix (bHLH) proteins such as myoD protein, SCL protein, MYC protein, E12, E47, Myf-5 protein, myogenin, and human homologues of the Drosophila genes AS-C, da, h, and emc; leucine zipper protein, with (bZIP) and without (ZIP) basic domains,: such as Jun proteins, Fos proteins, ATF/CREB proteins; and cell surface receptors associated with differentiation control, erg, estrogen. Methods for identifying other genes whose inhibition enhances tumor cell immunogenicity are defined herein. The best candidate genes are those for which there is evidence that they influence the cell's differentiation state. The phrase “differentiation state” means the molecular repertoire of a cell at a given point in time.
The role of nuclear transcriptional factors as regulators of cellular differentiation states is discussed in the literature. Green et al, 10
EMBO J.
4153, 1991. Some of these transcriptional factors bind directly to regulatory sequences in deoxyribonucleic acid and thereby activate the associated gene. Other transcriptional factors, for example, Id, bind to other transcriptional regulators and thereby modulate their transcriptional regulatory function. The expression of nuclear transcriptional factors in both normal and neoplastic cells has been described.
One example of a class of nuclear transcriptional factors linked to differentiation control is helix-loop-helix (HL
Ilan Joseph
Tykocinski Mark L.
Chen Shin-Lin
Clark Deborah J. R.
Foley & Lardner
TIB Company, LLC
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