Unsuccessful high dose IL-2 therapy followed immediately by near continuous low dose temozolomide can result in rapid durable complete and near-complete remissions in metastatic melanoma

 Abstract

Metastatic melanoma remains a disease with a very poor prognosis. High dose Interleukin-2 (HD IL-2) and temozolomide (TMZ) are both approved treatments for this malignancy but response rates remain poor. HD IL-2 is the only approved therapy that has been shown to induce durable complete responses albeit in a very small percentage of patients. The combination of TMZ followed by HD IL-2 as biochemotherapy has been studied previously but did not improve responses over what had been observed for HD IL-2 alone. In our clinical practice, we noted surprising rapid and dramatic responses to TMZ when given as therapy at 75 mg/m2 for 21 days per one month cycles in 6/9 (67%) sequentially treated patients who had just completed a full course of HD IL-2 and either had failed to respond (11%) or frankly progressed (89%). The TMZ therapy began on average within 6 weeks of stopping the IL-2. All responding patients had complete or near complete responses (CR and nearCR) to TMZ. The responses became evident rapidly, typically within 1 or 2 cycles of TMZ. Three patients remain alive and completely disease free, two are off of all therapy to date. Two patients recurred after initial CR and nearCR. One patient died from an acute myocardial infarction while in a CR. One patient had prolonged stable disease and 2 patients progressed. These were much better responses than what is typically observed for single agent TMZ; indeed, durable CR to TMZ that persists off therapy is an unrecognized phenomenon to our knowledge. TMZ is an oral atypical alkylating agent that in addition to having cytotoxic activity against melanoma has also been shown to decrease the T regulatory population of lymphocytes (T-regs). We hypothesize that the TMZ may be synergistic with HD IL-2 in a sequence-specific fashion by allowing the immune activation induced by the HD IL-2 to proceed without negative feedback applied by the T-reg population of cells whose major function is to inhibit an exuberant immune response. This postulated mechanism would result in the sequence-specific activity noted in our patients. Of interest, 3/6 responding patients and 1/3 stable/ non-responding patients also exhibited persistent polyarthralgias that began on TMZ suggesting the induction of autoimmunity which may be related to anti-melanoma effects. The durable CRs that persist after the cessation of treatment suggest that this sequence-specific combination should be studied further, ideally in a prospective trial of repeated courses of HD IL-2 followed strategically by continuous TMZ.

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Pages
1091 - 1097
doi
10.4161/cbt.10.11.13452
Type
Bedside-to-Bench Report
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Unsuccessful high dose IL-2 therapy followed immediately by near continuous low dose temozolomide can result in rapid durable complete and near-complete remissions in metastatic melanoma