pyrophosphate and Carcinoma--Renal-Cell

4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDA-responses may be needed for optimal clinical use of these agents.

Topics: Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mammary Neoplasms, Experimental; Mice; Oxygen; Stilbenes; Xenograft Model Antitumor Assays

We previously showed that Vdelta2 T cells infiltrate renal tumors and can be expanded as potent cytotoxic effectors from peripheral blood mononuclear cells of most renal cell carcinoma (RCC) patients, using a structural analog of nonconventional T-cell receptor gamma9delta2 ligand, bromohydrin pyrophosphate, and interleukin-2 (IL-2). In this study, we have further investigated the differentiation status and the migration potential of circulating and tumor-infiltrating Vgamma9Vdelta2 T lymphocytes from RCC patients. The repertoire of tumor-infiltrating and peripheral Vgamma9Vdelta2 T cells from RCC patients was characterized by a dominant CD27- CD45RA- subset. These effector memory Vgamma9Vdelta2 T cells were efficiently expanded using bromohydrin pyrophosphate combined with IL-15, but not IL-2. In addition, peripheral Vgamma9Vdelta2 T cells from RCC patients present a modified chemotactic pattern compared with donors. After ex vivo activation, peripheral expanded Vgamma9Vdelta2 T cells acquire low-migration capacities toward renal cells. Tumor-infiltrating Vgamma9Vdelta2 T cells migrated with higher efficiency toward primary renal tumor cells. The traffic toward tumor cells required the CXCL12/CXCR4 interaction. Altogether, these results outline that those Vgamma9Vdelta2 effectors exhibit differential migration capacities according to their localization, their differentiation status, and the tumor microenvironment parameters that may influence their use in immunotherapy.

Topics: Carcinoma, Renal Cell; Cell Movement; Cell Proliferation; Cells, Cultured; Chemokine CXCL12; Chemotaxis, Leukocyte; Diphosphates; Gene Expression Profiling; Humans; Immunologic Memory; Interleukin-15; Kidney Neoplasms; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Protein Array Analysis; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Chemokine; Receptors, CXCR4; T-Lymphocytes

The present study evaluated the treatment efficacy of the vascular disrupting agents CA4P and OXi4503 in an orthotopically transplanted human renal cell carcinoma xenograft model (Caki-1). Experiments used vascular casting, vessel density assessments as well as tumour necrosis measurements to evaluate the efficacy of these agents. After treatment with either agent, assessment of the vascular casts showed an almost total eradication of tumour blood vessels. Histological evidence further supported this observation, showing extensive central tumour necrosis with only a small viable rim of tumour cells remaining at the periphery. These results suggest that vascular disrupting agents CA4P and OXi4503 may have utility in the treatment of renal cell carcinoma, an encouraging result given that current conventional therapies have been currently largely unsuccessful in managing this disease.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Diphosphates; Female; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Silicon; Stilbenes; Transplantation, Heterologous

Metastatic renal cell carcinoma, inherently resistant to conventional treatments, is considered immunogenic. Indeed, partial responses are obtained after treatment with cytokines such as IL-2 or IFN-alpha, suggesting that the immune system may control the tumor growth. In this study, we have investigated the ability of the main subset of peripheral gammadelta lymphocytes, the Vgamma9Vdelta2-TCR T lymphocytes, to induce an effective cytotoxic response against autologous primary renal cell carcinoma lines. These gammadelta T cells were expanded ex vivo using a Vgamma9Vdelta2 agonist, a synthetic phosphoantigen called Phosphostim. From 11 of 15 patients, the peripheral Vgamma9Vdelta2 T cells were amplified in vitro by stimulating PBMCs with IL-2 and Phosphostim molecule. These expanded Vgamma9Vdelta2 T cells express activation markers and exhibit an effector/memory phenotype. They display a selective lytic potential toward autologous primary renal tumor cells and not against renal NC. The lytic activity involves the perforin-granzyme pathway and is mainly TCR and NKG2D receptor dependent. Furthermore, an increased expression of MHC class I-related molecule A or B proteins, known ligands of NKG2D, are detected on primary renal tumor cells. Interestingly, from 2 of the 11 positive cultures in response to Phosphostim, expanded-Vgamma9Vdelta2 T cells present an expression of killer cell Ig-like receptors, suggesting their prior recruitment in vivo. Unexpectedly, on serial frozen sections from three tumors, we observe a gammadelta lymphocyte infiltrate that was mainly composed of Vgamma9Vdelta2 T cells. These results outline that Vgamma9Vdelta2-TCR effectors may represent a promising approach for the treatment of metastatic renal cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Antigens; Carcinoma, Renal Cell; Cell Differentiation; Cell Line, Tumor; Cytotoxicity, Immunologic; Diphosphates; Female; Humans; Immunophenotyping; Kidney Neoplasms; Killer Cells, Natural; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Immunologic; Receptors, KIR; Receptors, Natural Killer Cell; T-Lymphocyte Subsets

The use of bone scans in the evaluation of renal cell carcinoma has become routine in many centers. In a retrospective analysis of 42 patients undergoing radical nephrectomy for renal cell carcinoma, we analyzed the cost-effectiveness of routine preoperative bone scans. Although these scans accurately predict metastatic disease to bone, they are not cost-effective as a routine preoperative tool because they do not alter outcome. In selected patients with bone pain and no other positive staging studies, preoperative bone scans may be of value in the decision to perform extirpative surgery.

Topics: Bone Neoplasms; Carcinoma, Renal Cell; Cost-Benefit Analysis; Diphosphates; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Middle Aged; Neoplasm Staging; Nephrectomy; Radionuclide Imaging; Retrospective Studies; Technetium; Technetium Tc 99m Pyrophosphate; Time Factors