Radiotherapy and High-Dose Interleukin-2: Clinical and Immunological Results of a Proof of Principle Study in Metastatic Melanoma and Renal Cell Carcinoma

• DOI: 10.3389/fimmu.2021.778459
• Publication Date: 2021-10-27T05:46:17Z
• Authors: Jenny Bulgarelli; Claudia Piccinini; Elisabetta Petracci; Elena Pancisi; Anna Maria Granato; Francesco de Rosa; Massimo Guidoboni; Massimiliano Petrini; Valentina Ancarani; Giovanni Foschi; Antonino Romeo; Luca Tontini; Ugo De Giorgi; Cristian Lolli; Giorgia Gentili; Linda Valmorri; Alice Rossi; Fabio Ferroni; Carla Casadei; Pietro Cortesi; Laura Crudi; Laura Ridolfi
• Keywords: Adult; Male; renal cell carcinoma; IFN-γ ELISPOT assay; Skin Neoplasms; metastatic melanoma, renal cell carcinoma, radiotherapy, high dose IL-2, IFN-g ELISPOT assay, clinical immunomonitoring; Immunology; Antineoplastic Agents; Radiation Dosage; Proof of Concept Study; 03 medical and health sciences; 0302 clinical medicine; Humans; clinical immunomonitoring; Prospective Studies; Infusions, Intravenous; Carcinoma, Renal Cell; Melanoma; radiotherapy; Aged; IFN-γ ELISPOT assay; clinical immunomonitoring; high dose IL-2; metastatic melanoma; radiotherapy; renal cell carcinoma; Chemoradiotherapy; RC581-607; Middle Aged; Kidney Neoplasms; Recombinant Proteins; 3. Good health; Italy; high dose IL-2; Interleukin-2; Female; Dose Fractionation, Radiation; Immunologic diseases. Allergy; metastatic melanoma

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.