Cutaneous T-cell lymphoma (CTCL) is a chronic incurable disease with significant morbidity and mortality. Treatment of CTCL depends on clinical stage and includes both topical and systemic therapies, including psoralene plus UVA irradiation (PUVA), total skin electron beam therapy (TSEBT), systemic chemotherapy, and three new drugs (vorinostat, romidepsin, and pralatrexate), which have been approved by the FDA based on overall response rates of 29% to 34%. Unfortunately, these interventions are associated with sometimes debilitating and dose-limiting side effects, and they are not curative. Partial responses, progression and relapses do often occur, and prolonged disease-free survival is rare except in patients whose CTCL is diagnosed and treated from an early stage. Fortunately, CTCL is highly responsive to radiotherapy, and TSEBT has evolved as a powerful treatment regimen. Current low-dose (8-10 Gy) TSEBT treatment regimens can generate very good responses with minimal toxicity. However, relapses occur, and radiation doses are gradually increased. High-dose (30-36 Gy) treatment regimens of are commonly used, resulting in complete response (CR) rates ranging from 98% in limited plaque stage to 36% in tumor stage. The CR rate is correlated with total radiation dose, but most patients will eventually relapse. However, high-dose TSEBT is generally not repeated more than twice due to its unavoidable side effects, namely significant toxicity, debilitating skin atrophy and necrosis.
In phase I and phase II clinical studies conducted independent of Neumedicines, interleukin-12 (IL-12) monotherapy was shown to be effective in CTCL, inducing tumor regression and achieving some complete responses. Recombinant human interleukin-12 (NM-IL-12) has also been shown to be effective as a mitigator of radiation-induced hematopoietic and skin toxicity in non-human primates. Hence, its inclusion in a combination therapy regimen with TSEBT is hypothesized to increase response rates while simultaneously lowering toxicity by (a) allowing a lower total radiodose of TSEBT and (b) inducing hematopoietic recovery of the multiple cells lines, as it did in primate studies, whose populations are diminished by radiotoxicity.
The company believes that if human trials show results similar to those seen in animal studies, NM-IL-12 could become an optimal adjuvant for radiation therapy in CTCL because: