A method and composition for treatment of advanced cutaneous T cell lymphoma is provided which involves administration of recombinant interleukin-12.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method for treating advanced cutaneous T cell lymphoma in humans comprising administering to a human an effective amount of recombinant interleukin-12 so that symptoms of cutaneous T cell lymphoma are reduced.

Another object of the present invention is to provide a combination therapy for treatment of advanced cutaneous T cell lymphoma comprising recombinant interleukin-12 and an adjunct therapeutic agent which stimulates interferon-.gamma. production.

DETAILED DESCRIPTION OF THE INVENTION

Cytokines are intercellular messenger molecules that evoke biological responses after binding to receptors on responsive cells. A variety of cells of the immune system can secrete cytokines, with the principal producers being the T-helper cells (both type 1, Th1, and type 2, Th2) and macrophages. The binding of cytokines to their receptors on responsive cells leads to numerous physiologic responses including the development of cellular and humoral immunity, induction of the inflammatory response, regulation of hematopoiesis, control of cellular proliferation and differentiation, and induction of wound healing. The complexity of the cytokine pathways and the fact that they exhibit cross-regulation, where the cytokines secreted by one subset of Th cells can block production and activity of cytokines secreted by the other subset, has made it difficult to predict the effect of administration of a single cytokine to a patient.

For example, interferon-.gamma. is secreted by the Th1 subset of Th cells, as well as by NK cells. Increases in the level of interferon-.gamma. results in a depression of activity of Th2 cells. IL-12, which is secreted by macrophages and B-cells, can also inhibit activity of Th2 cells. However, IL-10, which is secreted by Th2 cells, results in a decrease in activity of Th1 cells, which secrete interferon-.gamma.. This interrelationship of the cytokine pathways makes it difficult to predict the efficacy of in vivo of administration of a single cytokine in modulating various disease states.

It has now been found, however, that administration of recombinant IL-12 in patients is a safe and effective therapy for advanced CTCL. IL-12 was administered both subcutaneously and intralesionally in a phase I clinical trial of advanced CTCL. A phase I clinical trial is designed to examine both efficacy and safety of a drug.

Patients in the phase I clinical trial were classified as having either extensive plaque (4 patients), SzS (2 patients), or extensive tumors with large cell transformation (2 patients). Patients received either 50, 100, or 300 ng/kg of recombinant IL-12, two times a week for up to 24 weeks. Doses were given both intralesionally and subcutaneously. Subcutaneous dosing resulted in complete responses in 2 of the 4 plaque patients, partial responses in 1 of the 4 plaque patients, and a partial response in 1 of the 2 SzS patients. The overall response rate with subcutaneous dosing (complete and partial responses) was 57%. A minor response was also seen in one of the plaque patients. By "complete response" it is meant complete disappearance of all evidence of disease both clinically and histologically. By "partial response" it is meant that there is at least a 50% decrease (but less than 100%) in size of all measured lesions as compared to their size at the start of therapy. By "minor response" it is meant that there is a 25 to 50% decrease in the size of all measured lesions as compared to their size at the start of therapy.

Following intralesional dosing with recombinant IL-12, individual plaque, erythema, or tumor regression was seen in most patients (8 out of 9); one patient with SzS dropped out of the trial for personal reasons. Biopsy of regressing lesions revealed a marked decrease in the density of the infiltrate in all cases. Increased numbers of cytotoxic T-cells were observed on immunohistochemical analysis in some biopsies.

Adverse effects associated with recombinant IL-12 treatment, either subcutaneously or intralesionally, were minor and included low grade fever and headache. One patient discontinued IL-12 at week 6 due to depression. These results demonstrated that IL-12 was a safe as well as an effective treatment for advanced CTCL. The results showed that IL-12 may augment antitumor responses. The fact the IL-12 was particularly effective in plaque patients was unexpected and unique.

Accordingly, the present invention provides a useful method for alleviating symptoms and treating CTCL in patients which comprises administering recombinant IL-12 to the patient. The method of the present invention is particularly useful in treating advanced CTCL, which includes patients presenting with plaque, Sezary Syndrome, or tumors with large cell transformation. IL-12 can be administered either systemically (e.g., subcutaneously, intravenously) or intralesionally and can be formulated in any pharmaceutically acceptable carrier which is known to those of skill in the art For example, an injectable formulation of recombinant IL-12 is made and sold by Genetics Institute (Cambridge, Mass.). An effective dose of recombinant IL-12 is administered repeatedly, for several weeks, until symptoms of advanced CTCL (such as plaques, tumors or erythroderma) regress or are reduced. An effective dose is one in which there is at least a partial response in the patient. In some patients a reduction of symptoms of advanced CTCL represents a total absence of those lesions after treatment. Dosage schedules and regimens are routinely designed by those of skill based upon results described above for the phase I trial. In a preferred embodiment, approximately 100 to 300 ng/kg of recombinant IL-12 is administered by subcutaneous or intravenous injection 2 to 3 times per week.

The present invention also provides combinational therapies for the treatment of CTCL. It has been found that CTCL may be treated by the combined use of recombinant IL-12 and adjunct therapeutic agents that also induce interferon-.gamma. production. Examples of adjunct therapeutic agents that also induce interferon-.gamma. production include, but are not limited to, retinoids, interleukin-2, interleukin-15, interleukin 18, interferon-.alpha. and interferon-.gamma..

In fact, experiments in peripheral blood monocytes from patients with advanced CTCL indicate that administration of IL-12 in combination with an adjunct therapeutic agent such as interleukin-18 synergistically augment interferon-.gamma. production and cytotoxic lymphocyte activity. In these experiments, PBMC from patients with advanced CTCL and normal healthy volunteers were cultured with medium alone, PHA, interleukin-18 or IL-12 alone, PHA plus interleukin-18 or IL-12, and PHA plus interleukin-18 and IL-12 for 20 48 hours and supernatants were assayed by ELISA for interferon-.gamma. as described by Rook et al. 1995. J. Immunol. 154:1491 1498. PBMC were also assayed for NK cell activity using CR51 labeled k562 cells as targets as described by Rook et al. 1995. J. Immunol. 154:1491 1498. Interleukin-18 and IL-12 each significantly increased interferon-.gamma. production by patient and normal PBMC. Interferon-.gamma. production was also synergistically augmented by combining interleukin-18 and IL-12 in culture. Similarly cultures combining interleukin-18 and IL-12 more markedly enhanced NK cell activity in comparison to interleukin-18 and IL-12 alone.

Experiments have also shown that clinically available retinoids, such as acitretin, 13-cis-retinoic acid, and all trans-retinoic acid, in concentrations ranging from 1 to 10 ng/ml, induce production of low levels (20 to 100 pg/ml) of interferon-.gamma. in PBMCs from normal volunteers. A number of clinical studies have shown that retinoids have clinical activity in the treatment of CTCL, with response rates ranging from 30% to 60% (Fuss, F. M. and T. M. Kuzel. 1995. Hematol. Oncol. Clin. North Am. 9:1127 1137). The highest response rates, however, are seen when patients have early stage disease, not advanced CTCL. Retinoids have been suggested as adjunct therapy for treatment of CTCL with interferons or PUVA. In studies in CTCL patients, the all trans-retinoic acid was the most potent retinoid for inducing interferon-.gamma. activity. Addition of anti-IL-12 neutralizing antibodies to the retinoid-cultured cells reduced the interferon-.gamma.-inducing activity of the retinoids (Rook, A. H. et al. 1996. Ann NY Acad. Sci. 795:310 318). Thus, at least a portion of the interferon-.gamma. activity of retinoids appears to be mediated through effects on IL-12. Therefore, patients with advanced CTCL can be administered lower doses of recombinant IL-12 in combination with a clinically available retinoid to alleviate or treat CTCL with fewer side effects from administration of IL-12. Dosages of the retinoid to use in the patients can be selected by one of skill based on clinical use of these drugs for other conditions.
 

Claim 1 of 1 Claim

1. A method for treatment of advanced cutaneous T cell lymphoma in a human comprising administering to a human 100 to 300 ng/ml of recombinant interleukin-12 in a pharmaceutically acceptable carrier and an adjunct therapeutic agent which stimulates interferon-.gamma. production.

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