Purpose: Myeloid suppressor (Gr-1 + /CD11b + ) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8 + Tcells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist. Experimental Design: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1 + /CD11b + ) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-h. Results:This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4 + T cells, CD8 + T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8 + T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-h markedly enhanced antitumor efficacy. Conclusions: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.

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5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-A that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a ''vascular disrupting agent,'' there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-A; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8 + T cells. These CD8 + T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8 + T cells, and perforin knockout mice, but not in CD4 + T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8 + T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy. (Cancer Res 2005; 65(24): 11752-61)

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Background Proponents of flexible annuloplasty rings have hypothesized that such devices maintain annular dynamics. This hypothesis is based on the supposition that annular motion is relatively normal in patients undergoing mitral valve repair. We hypothesized that mitral annular dynamics are impaired in ischemic mitral regurgitation (IMR) and myxomatous mitral regurgitation (MMR). Methods and Results Philips iE33 echocardiographic module and X7-2t probe were used to acquire full volume rt-3DTEE loops in 11 normal subjects, 11 patients with IMR and 11 patients with MMR. Image analysis was performed using Tomtec Image Arena -4D-MV Assessment© - 2.1 (Munich, Germany). A midsystolic frame was selected for the initiation of annular tracking using the semi-automated program. Continuous parameters were normalized in time to provide for uniform systolic and diastolic periods. Both IMR (9.98±155 cm2) and MMR annuli (13.29±3.05 cm2) were larger in area than normal annuli (7.95±1.40 cm2) at midsystole. In general, IMR annuli were less dynamic than controls. In MMR, annular dynamics were also markedly abnormal with the mitral annulus dilating rapidly in early systole in response to rising ventricular pressure. Conclusions In both IMR and MMR, annular dynamics and anatomy are abnormal. Flexible annuloplasty devices used in mitral valve repair are, therefore, unlikely to result in either normal annular dynamics or normal anatomy.