Abstract
High-dose interleukin-2 (HD IL-2) has curative potential in metastatic melanoma (MM) and renal cell carcinoma (RCC). Radiotherapy (RT) kills cancer cells and induces immunomodulatory effects. Prospective trials exploring clinical and immunological properties of combined RT/HD IL-2 are still needed. We designed a phase II, single-arm clinical trial for patients with MM and RCC. The treatment schedule consisted of 3 daily doses of 6-12 Gy of RT to 1-5 non-index metastatic fields, before IL-2 at the first and third treatment cycle. HD IL-2 was administered by continuous infusion for 72 hours and repeated every 3 weeks for up to 4 cycles, thereafter every 4 weeks for a maximum of 2 cycles. The primary endpoint was the immunological efficacy of the combined RT/HD IL-2 treatment (assessed by IFN-γ ELISPOT). Nineteen out of 22 patients were evaluable for immunological and clinical response. Partial response occurred in 3 (15.7%) patients and stable disease was observed in 7 (36.8%). The disease control rate was 52.6% after a median follow up of 39.2 months. According to Common Terminology Criteria for Adverse Events 4.0 (CTCAE 4.0), the majority of toxicities were grade 1-2. Immunological responses were frequent and detected in 16 (84.2%) patients. Increased levels of IL-8 and IL-10 in melanoma, circulating effector memory CD4+ and intratumoral CD8+ T cells in both tumor types were detected after therapy. Overall the treatment was well tolerated and immunologically active. Immunomonitoring and correlative data on tumor and peripheral blood cell subsets suggest that this combination treatment could be a promising strategy for patients progressing after standard treatments.
Highlights
High-dose interleukin-2 (HD high-dose interleukin-2 (IL-2)) has been reported to obtain an objective clinical disease regression in 15-17% of patients with metastatic melanoma (MM) and renal cell carcinoma (RCC), with 6-8% of cases experiencing a durable complete response in all metastases [1,2,3]
One RCC patient received this treatment as first line therapy because refused all the other proposed treatments
We looked for predictive modulations of response to treatment by evaluating serum levels of VEGF and fibronectin, known to have a prognostic value in MM and RCC, and pro-inflammatory cytokines (IL-1b, IL-6, IL-8, IL-10, TNFa, IL-12 p70) known for their involvement in local and systemic immune response
Summary
High-dose interleukin-2 (HD IL-2) has been reported to obtain an objective clinical disease regression in 15-17% of patients with metastatic melanoma (MM) and renal cell carcinoma (RCC), with 6-8% of cases experiencing a durable complete response in all metastases [1,2,3]. Immunotherapy is being increasingly used for the treatment of numerous cancers and has considerably changed the therapeutic scenario of MM and RCC in recent years [4]. HD IL-2, one of the earliest immunotherapies, still has curative potential in a subset of patients and is an important option for those who develop side-effects or progress to previous treatments [7,8,9]. Fyfe et al reported findings on 255 patients with metastatic RCC undergoing HD IL-2 and enrolled in seven phase II clinical trials. Even if most of the severe side-effects are in general reversible, the management of these adverse events may often leads to hospitalization in an Intensive Care Unit (ICU) if the medical Oncology Unit is lacking an adequate trained staff
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