1. Metastasis
Metastasis is the spread of malignant tumors to secondary sites remote from the original or primary tumor. Metastasis presents a cancer clinician with difficulty in diagnosing and treating the malignant tumor because (a)metastases may be comprised of as little as one or a few cells thereby evading clinical diagnosis even with modern techniques; (b) often metastases have already been seeded by the time a patient is diagnosed with a malignant non-lymphoid tumor (Silverberg et al., 1989, CA Cancer J. Clin. 39:3-21); (c) treatment is more complex than simple surgical excision of the primary tumor; (d) systemic therapy for metatstatic non-lymphoid tumors, such as renal cell carcinoma (Rosenberg et al., 1985, N. Engl. J. Med. 313:1485-1492), remains ineffective with little survival advantage; and (e) not all malignant tumors have the same metastatic potential and no direct relationship has been established in determining whether any particular nonolymphoid tumor will develop metastasis.
2. T-Cell Surface Molecules, Interleukin-2, and the IL-2 Receptor.
Monoclonal antibodies have been used to characterize and classify T cell surface molecules such as the clusters of differentiation (CD) of human leukocyte antigens. The T cell receptor (TCR) is an integral membrane protein, expressed on the surface of T lymphocytes, occuring as a disulfide linked heterodimer which is non-covalently associated with CD3. TCR has been linked to autoimmune disease as anti-TCR antibodies have shown therapeutic potential for treating autoimmune disease (Basi et al., 1992, J. Immunol. Methods 155:175-191). Of the T cell surface molecules, a correlation between an increase in concentration of soluble CD8 in the serum of children with non-Hodgkins lymphoma is disclosed by Kung et al. (U.S. Pat. No. 5,006,459). The elevated levels of CD8 appear related to the stage of the lymphoma and responsiveness to therapy.
IL-2 and the IL-2 receptor (IL-2R) interact in regulating the T cell immune response. The IL-2R is present in three forms classified by their binding affinity for IL-2 and by the different combinations of two binding proteins (the .alpha. and .beta. chains). High affinity IL-2R contain both .alpha. and .beta. chains, intermediate affinity contain .beta. chains, and low affinity contain .alpha. chains (Leonard et al., 1990, Prog. Clin. Biol. Res., 352:179-187). IL-2R.alpha. is only expressed on activated T cells, and it has been shown that IL-2 exerts its T cell growth promoting effects via stimulation of the .alpha. chain. Kung et al. (supra) disclose the elevation of serum IL-2 receptors (IL2R) in patients with active lymphatic cancers such as leukemia and lymphoma; and further, the concentration of soluble ILR2 bears a direct relationship with the severity and prognosis of the lymphatic cancer. They also disclose that soluble ILR2 receptors were generally not elevated in patients with non-lymphatic cancers. In addition, the level of soluble ILR2 correlated poorly with the number of circulating IL-2R bearing lymphocytes.
Immunotherapy with lymphokines are being used as a systemic form of anticancer therapy in attempting to stimulate the host immune response against tumor cells. Different compositions comprising IL-2 have been described including: U.S. Pat. No. 5,229,109 to Grimm et al. disclosing low toxity IL-2 analogues; U.S. Pat. No. 5,089,261 to Nitecki et al., disclosing IL-2 conjugated to a polymer to reduce immunogenicity and to enhance solubility and circulating half-life; U.S. Pat. Nos. 5,061,488 and 5,126,129 to Wiltrout et al., describing compositions and methods involving a combination of flavone-8-acetic acid and recombinant IL-2; U.S. Patent No. 5,098,702 to Zimmerman et al. disclosing a combination of IL-2 and/or Interferon-.beta. and tumor necrosis factor against tumor cells; U.S. Pat. No. 4,939,093 to McGrogan et al. disclosing methods for the production of human IL-2-like polypeptides; and U.S. Pat. No. 4,789,658 to Yoshimoto et al., disclosing the production of human IL-2 and its use against diseases including neoplasms. U.S. Pat. No. 4,690,915 to Rosenberg discloses adoptive immunotherapy involving treating a patient with immune cells, lymphokine activated lymphocytes, with IL-2 immunotherapy.
Thus, the background and related art does not disclose or correlate the existence of IL-2R.alpha. with metastases or the metastatic potential of solid, nonolymphoid tumors. Further, no known methods exist for utilizing the presence of IL-2R.alpha. in establishing the prognosis of the metastatic potential of non-lymphoid tumors; or in the diagnosis of or targeting anticancer agents to their metastases. Nor does the background and related art disclose methods for administering anticancer therapy against non-lymphoid metastatic cells directly to the areas in organs where metastases develop (prometastatic territories), rather than conventional systemic administration. Additionally, it has not disclosed that TCR.beta. is expressed on non-lymphoid tumors and that TCR.beta. represents a target for methods of anticancer therapy directed against tumors expressing TCR.beta.. The methods of the present invention will greatly facilitate the diagnosis and anticancer therapy of individuals bearing non-lymphoid tumors, metastases thereof, or non-lymphoid tumors having a high probability of metastasis.
USPTO Backgrounds
USPTO Backgrounds