Article

Radio Frequency Ablation Combined with Interleukin-2 Induces an Antitumor Immune Response to Renal Cell Carcinoma in a Murine Model

Department of Urology, University Medical Center Utrecht, The Netherlands.
The Journal of urology (Impact Factor: 4.47). 06/2012; 188(2):607-14. DOI: 10.1016/j.juro.2012.03.116
Source: PubMed

ABSTRACT

Immune based therapy has gained renewed interest in the search for treatment strategies for metastasized renal cell carcinoma. We determined whether radio frequency ablation combined with interleukin-2 would induce a tumor specific immune response and serve as an in situ vaccine against renal cell carcinoma.
Mice with orthotopic renal tumors were treated with radio frequency ablation combined with interleukin-2, radio frequency ablation only, interleukin-2 only or no treatment as the control. Immunohistochemistry was done to determine which cells were present in the tumor after treatment. In vitro tumor specific cytotoxicity assays were performed with CD8+ T and natural killer cells derived from the spleen of treated mice. To study whether treatment could prevent metastasis or affect the growth of established metastases we induced lung metastasis intravenously before or after treatment and subsequently quantified it.
The number of natural killer, CD4+ and CD8+ T cells was significantly increased in the tumor tissue of radio frequency ablation/interleukin-2 treated mice (p <0.0001). Natural killer and CD8+ T cells showed strong antitumor activity in vitro after combination treatment. Lung metastatic formation was significantly prevented in mice that received combination therapy (p <0.0001). Lung metastases were significantly smaller after combination treatment (vs interleukin-2 p = 0.025).
Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy. This effect appears to be mediated by natural killer and CD8+ T cells. It may have an important role in the development of new immunotherapy strategies for renal cell carcinoma.

0 Followers
 · 
25 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Current immunomodulatory agents for stage III and IV melanoma exert different mechanisms of action that manifest in distinct adverse events. Objective: This systematic review aims to synthesize safety data from clinical trials on ipilimumab, vemurafenib, interferon (IFN) alfa-2b, dacarbazine and interleukin (IL)-2 to elucidate the severe adverse events associated with each melanoma therapy. Methods: Through a systematic search using MEDLINE, EMBASE and the Cochrane Central Register between January 1, 2010 and June 1, 2012, we identified 32 clinical trials with 5802 subjects that met the inclusion criteria. Results: Ipilimumab was associated with immune-mediated diarrhea and colitis, with an incidence rate of 0.0017 cases per 100 person-years. Patients receiving vemurafenib developed keratoacanthomas and cutaneous squamous cell carcinoma at an incidence rate of 0.0025 cases per 100 person-years. Treatment with IFN alfa-2b precipitated depression at an incidence rate of 0.0002 cases per 100 person-years. Dacarbazine was associated with respiratory toxicity and dyspnea, with incidence rates of 0.0001 and 0.00008 cases per 100 person-years, respectively. IL-2 treatment induced vascular leak syndrome (VLS), with symptoms of hypotension and oliguria, was observed at incidence rates of 0.17 and 0.15 cases per 100 person-years, respectively. Findings may serve as a foundation for future research in this area and guide clinical recommendations.
    No preview · Article · Jun 2013 · Journal of Dermatological Treatment
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA) in a preclinical mouse model. Experimental Design Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma. Results Treatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity. Conclusion Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with high-risk of local and systemic recurrence.
    Preview · Article · Nov 2015 · PLoS ONE