Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated. Experimental Design: Patient peripheral blood levels of MDSC and regulatoryT-cell (Treg) and T-cell production of IFN-g were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well asT-cell production of IFN-g were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR -and CD15 + CD14-MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro. MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-g. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at z1.0 Ag/mL. Sunitinib did not induce MDSC maturation in vitro. Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.

Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system. Experimental Design: Type-1 (IFNg) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies. Results: After one cycle of treatment, there was a significant increase in the percentage of IFNgproducingTcells (CD3 + , P < 0.001; CD3 + CD4 + , P = 0.001), a reduction in interleukin-4 production (CD3 + cells, P = 0.05), and a diminished type-2 bias (P = 0.005).The increase in type-1response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1response after two cycles of treatment and a decrease in the percentage of Treg cells (r = -0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib onTreg cells are indirect. Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducingTreg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.

These data validate the model described by Motzer et al. Additional independent prognostic factors identified were prior radiotherapy and sites of metastasis. Incorporation of these additional prognostic factors into the Motzer et al model can help better define favorable risk, intermediate risk, and poor risk patients.

The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown benefit in patients with renal cell carcinoma, hepatocellular carcinoma (sorafenib), and gastrointestinal stromal tumor (sunitinib). Their efficacy in other malignancies is currently being investigated because of their broad range of activity. The effectiveness of these drugs is somewhat diminished by the development of a variety of toxicities, most notably hand-foot skin reaction (HFSR). Although HFSR does not appear to directly affect survival, it can impact qual-

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.