Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response

Journal of Translational Medicine

Massimo Guidoboni¹  Antonino Romeo³  Elisabetta Parisi³  Emanuela Scarpi²  Linda Valmorri²  Giorgia Gentili²  Ruggero Ridolfi¹  Francesco de Rosa¹  Laura Ridolfi¹ 

[1] Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy;Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy;Radiotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

关键词: Radiotherapy;    RCC;    Melanoma;    HD-IL-2;   

Others  :  1147951
DOI  :  10.1186/s12967-014-0262-6

 received in 2014-04-15, accepted in 2014-09-11,  发布年份 2014

【 摘 要 】

Background

Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines.

Methods/design

The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6¿12 Gy will be administered to at least one metastatic field on days ?3 to ?1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic/proinflammatory cytokines will also be quantified.

Discussion

This study aims to evaluate the potential immunological synergism between HD-IL-2 and XRT, and to identify biomarkers that are predictive of response to IL-2 in order to spare potentially non responding patients from toxicity.

Trial registration

EudraCT no. 2012-001786-32

ClinicalTrials.gov Identifier: NCT01884961 webcite

【 授权许可】

   
2014 Ridolfi et al.; licensee BioMed Central Ltd.

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