Abstract
419 Background: Targeted therapies achieve response rates up to 50% in metastatic RCC, but durable complete remissions are very rare. Therefore additional therapeutic options are warranted. Adoptive transfer (ACT) of tumor infiltrating lymphocytes (TIL) has revealed response rates of up to 72% in melanoma patients and may lead to consolidation of responses upon sunitinib in RCC. Recent data suggest that sunitinib influences lymphocyte infiltration and regulatory T cells (Treg) into tumor, dendritic cells (DC), and myeloid derived suppressor cells (MDSC) in animal models, but impaired proliferation and function of human T cells and was unable to improve human DC activity in vitro. Methods: We compared TIL grown from primary tumors pretreated with 2 courses sunitinib prior to cytoreductive nephrectomy to TIL generated from treatment-naïve RCC. Patients took part in a phase II trial of presurgical sunitinib registered under EudraCT 2006-006491-38 and gave written informed consent. From 6 pretreated primary tumors and 6 untreated controls sterile tumor material was obtained and digested with collagenase, hyaluronidase and DNase to obtain tumor single cell suspension. This TIL/tumor suspension was cultured for up to 25 days in 6000IU/ml interleukin 2 (IL-2) and rapidly expanded by anti-CD3+IL-2 stimulation. Results: TIL harvested after coculture with tumor cells yielded 36+/−SD fold expansion from non-pretreated tumors versus a 128+/−SD fold expansion from tumors from patients that had been pretreated with sunitinib (p=0.015). Phenotypic analysis of culture product indicated a higher content of natural killer (NK) cells from treatment naïve TIL cultures, while sunitinib pretreatment skewed towards NK T cells. Interferon-gamma-production was not different on a per cell level.Rapid expansion after culture using anti-CD3/IL-2 induced 100-200 fold expansion towards a content of more than 75% T cells with no significant differences between both groups. Conclusions: Sunitinib in vivo pretreatment improves TIL grow during initial culture and does not impair function or rapid expansion, allowing higher final yield of TIL for ACT studies in RCC.
Published Version
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