Treatment of metastatic renal cell carcinoma

Abstract

PurposeTo review the treatment of metastatic renal cell carcinoma (RCC), including the use of new targeted therapies. MethodsA search of MEDLINE (1966 to August 2008 and American Society of Clinical Oncology Meeting abstracts (2005 to May 2008) was preformed using the search terms bevacizumab, everolimus, interferonalfa (IFN-α), interleukin-2 (IL-2), sorafenib, sunitinib, temsirolimus, and RCC. Articles most pertinent to the treatment of metastatic RCC are reviewed. ResultsThe treatment of metastatic RCC has undergone a paradigm shift over the past 5 years from biologic response modifiers to new targeted therapies. Historically, response rates for the biological response modifiers, aldesleukin (IL-2), and IFN-α were approximately 15%. Recently, three targeted agents, sorafenib, sunitinib, and temsirolimus have been approved for the treatment of RCC. Additionally, bevacizumab has been investigated and shown to increase progression free survival in RCC. IL-2 remains the only agent to induce complete, durable remissions; however, many patients are not eligible for this therapy. Newer agents (sorafenib, sunitinib, and temsirolimus) have shown to be superior to IFN-α or placebo and bevacizumab combined with IFN-α has shown activity when compared to IFN-α alone. Unlike IL-2, the greatest benefit obtained with targeted therapies is in achieving stable disease (SD). Despite their benefit, targeted therapies have never been compared with each other in clinical trials and choosing the most appropriate agent remains challenging. To date, the optimal sequence or combination of treatments has not been defined; however, everolimus has recently demonstrated activity in patients progressing on targeted therapy. ConclusionsIL-2 remains the most active regimen in inducing complete responses; however, its use is accompanied by substantial morbidity and is limited to those with a good performance status. Targeted therapies are also efficacious in the treatment of RCC, with the major benefit being induction of SD. Future research will better define the sequencing of therapies, as well as, explore the activity of novel combination regimens.

High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention

“…In human cancer therapy, systemic IL-2 has shown some success, yet effects are in general not very predictable and limited to a small subgroup of patients (2,3). This might seem at odds with the strong and consistently observed positive effects that IL-2 exerted in our ex vivo treatment of TILs.…”

“…Among them are DGK inhibition and IL-2 application. Systemic IL-2 administration has a long history in the treatment of RCC yielding partial and sometimes complete responses in a subgroup of patients (2,3). Documented in this study is its potent capacity to restore the cytokine secretion and cytotoxic response of in vivo-repressed CD8-TILs at very low dose.…”

“…IL-2 is an activator of T effector cells and is used in immunotherapy of metastatic RCC leading to tumor regression and even complete responses in some patients (2,3). Ex vivo cultivation of tissue suspensions of RCCs in low-dose IL-2 led to reduced expression levels of DGK-a protein in CD8-TILs (Fig.…”

“…Among human tumors, renal cell carcinoma (RCC) displays clinical and experimental features indicating that it can be targeted by immune effector cells (1). Clinical evidence includes the observations of spontaneous remission and response to immunotherapy with long-lasting regression in some patients (2,3). Histologically, RCC has a large immune cell infiltrate of CD8 + T lymphocytes with some expressing TCRs that enable the T cells to recognize and kill tumor cells in vitro (4)(5)(6)(7).…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…Aldesleukin (Proleukin; Chiron) is a recombinant IL-2 used in the treatment of kidney cancer (Kintzel and Calis 1991;Bukowski et al 1997;Reeves and Liu 2009). Renal carcinomas shed soluble IL-2Ra that blocks normal IL-2 responses by titrating free IL-2 (Bien and Balcerska 2008).…”