Effective Tumor Destruction Research Articles

Radiofrequency Ablation of Liver Metastases from Colorectal Carcinoma

Most patients with colorectal carcinoma will develop liver metastases. Radiofrequency ablation (RFA) has been utilized in metastatic CRC to help improve the survival gap between resectable and unresectable tumor. The current use of RFA in selected patient populations is reviewed. RFA provides a survival benefit in patients with unresectable hepatic metastases from CRC compared with chemotherapy alone. It offers effective local tumor destruction in appropriately selected lesions and minimizes the morbidity and mortality of an open resection. Common complications are abdominal bleeding (1.6%), abdominal infection (1.1%), and injury to the biliary tree (1.0%). Mortality ranges from 0% to 0.5%. Trials are underway to compare chemotherapy plus local ablation to chemotherapy alone. RFA is a tool that should be utilized by experienced individuals to achieve optimal oncologic outcomes.

1051. Prostate Cancer-Targeted Suicide Gene Therapy Achieved Effective Tumor Destruction While Safeguarding Against Systemic Toxicity

Cancer gene therapy based on tissue-restricted expression of cytotoxic gene should achieve superior therapeutic index over an unrestricted method. This study compared the therapeutic effects of a highly augmented, prostate-specific gene expression method to a strong constitutive promoter-driven approach. Molecular imaging was coupled to gene therapy to ascertain real-time therapeutic activity. The imaging reporter gene (luciferase) and the cytotoxic gene (herpes simplex thymidine kinase) were delivered by adenoviral vectors injected directly into human prostate tumors grafted in SCID mice. Serial bioluminescence imaging, positron emission tomography (PET) and computed tomography (CT) revealed restriction of gene expression to the tumors when prostate-specific vector was employed. In contrast, administration of constitutive active vector resulted in strong signals in the liver. Liver serology, tissue histology, and frail condition of animals confirmed liver toxicity suffered by the constitutive active cohorts, while the prostate-targeted group was unaffected. The extent of tumor killing was analyzed by apoptotic staining and human prostate marker (PSA). Overall, the augmented prostate-specific expression system was superior to the constitutive approach in safeguarding against systemic toxicity, while achieving effective tumor-killing. Integrating non-invasive imaging into cytotoxic gene therapy will provide a useful strategy to monitor gene expression and therapeutic efficacy in future clinical protocols.

Metabolic Mechanisms of Tumor Resistance to T Cell Effector Function

Established tumors develop ways to elude destruction by the host immune system. Recent work has revealed that tumors can take advantage of the generation of metabolic dysregulation to inhibit immune responses. Effector T-cell functions are particularly sensitive to nutrient availability in the tumor microenvironment. In this review, we highlight experimental data supporting the importance of glucose, oxygen, tryptophan, and arginine for optimal T-cell function, and the mechanisms by which these nutrients may become depleted in the tumor microenvironment. These observations provide a conceptual framework for modulating metabolic features of the T cell-tumor interaction, toward the end of promoting more effective immune-mediated tumor destruction in vivo.

Vaccine-Stimulated, Adoptively Transferred CD8+ T Cells Traffic Indiscriminately and Ubiquitously while Mediating Specific Tumor Destruction

It has been suggested that antitumor T cells specifically traffic to the tumor site, where they effect tumor destruction. To test whether tumor-reactive CD8(+) T cells specifically home to tumor, we assessed the trafficking of gp100-specific pmel-1 cells to large, vascularized tumors that express or do not express the target Ag. Activation of tumor-specific CD8(+) pmel-1 T cells with IL-2 and vaccination with an altered peptide ligand caused regression of gp100-positive tumors (B16), but not gp100-negative tumors (methylcholanthrene 205), implanted on opposing flanks of the same mouse. Surprisingly, we found approximately equal and very large numbers of pmel-1 T cells (>25% of all lymphocytes) infiltrating both Ag-positive and Ag-negative tumors. We also found evidence of massive infiltration and proliferation of activated antitumor pmel-1 cells in a variety of peripheral tissues, including lymph nodes, liver, spleen, and lungs, but not peripheral blood. Most importantly, evidence for T cell function, as measured by production of IFN-gamma, release of perforin, and activation of caspase-3 in target cells, was confined to Ag-expressing tumor. We thus conclude that CD8(+) T cell-mediated destruction of tumor is the result of specific T cell triggering at the tumor site. The ability to induce ubiquitous homing and specific tumor destruction may be important in the case of noninflammatory metastatic tumor foci.

Role of alpha4 integrin and its ligand VCAM-1 in the specific extravasation of a tumor-specific TH2 clone into tumor tissue that initiates its rejection.

The effectiveness of anticancer immunotherapeutic strategies involving the transfer of tumor-specific T cells depends on appropriate lymphocyte-endothelial cell interactions that facilitate the migration of lymphocytes into tumor. Here, we investigated the molecular mechanisms underlying the migration of the antigen-specific Th2 CD4(+) T-cell clone YS1093 into S1509a tumor tissue. YS1093 is specific for the S1509a tumor but does not recognize the S713a tumor. Transfer of YS1093 cells into mice bearing both S1509a and S713a tumors caused only the S1509a tumor to regress. This regression was markedly inhibited by pretreating YS1093 cells with an anti-alpha4 integrin MAb and administering an anti-VCAM-1 MAb at T-cell transfer. Since vascular endothelial cells in S1509a tumor tissues express VCAM-1 and the MHC class II (I-E(k)) molecule restricting YS1093 activity, labeled YS1093 cells migrated specifically into the S1509a tumor, and this migration was also blocked by the anti-TCRbeta F(ab')(2) and anti-I-E(k) MAbs. Furthermore, in vitro assays revealed that anti-CD3 MAb-mediated TCR cross-linkage initiated the binding of alpha4 integrin on YS1093 cells to VCAM-1. This adhesive activity was completely blocked by the anti-alpha4 integrin MAb. These results strongly suggest that i.v.-transferred YS1093 cells act in tumor regression by specifically recognizing their tumor antigen peptide in the context of I-E(k) on vascular endothelial cells in the S1509a tumor, which activates the binding of alpha4 integrin to VCAM-1 on the endothelial cells, facilitating YS1093 extravasation into the tumor. It is likely that this initial migration of specific CD4(+) T cells into tumor tissues promotes the subsequent infiltration into the tumor of other immunocytes that effect tumor destruction.

591. Comparison of Plant-TK/AZT Versus HSV-TK/Ganciclovir Enzyme/Prodrug Systems in a Human Glioma Cell Line

Nucleoside analogs were among the first chemotherapeutic agents to be used for the medical treatment of malignant and viral diseases. Although these compounds are used as first line therapy for many cancer types, several disadvantages still remain. Therefore alternative strategies like gene therapy are being developed to improve their therapeutic properties. There are many barriers to overcome in developing clinically useful suicide therapy systems. Effective tumor destruction depends on the chemistry of the prodrugs, the interaction between enzyme and prodrug, and the choice of the gene therapy vector. The perfect prodrug should be rapidly activated, so issues like prodrug half-life, degradation or clearance mechanisms will not be limiting factors. On the other hand, highly efficient enzymes should prove beneficial since gene expression and gene transfer are usually not high in vivo. Because current delivery methods cannot transfer the gene to all tumor cells, the strong bystander effect, where activated prodrug can kill neighboring tumor cells that are not expressing the suicide gene, is also needed.

Regulation of p53 tumor specific immune responses in colorectal cancer patients

Anti-tumor specific immune responses are modulated during tumor development via different escape mechanisms abrogating the process of effective immunological tumor destruction. In this study we analyzed the p53 specific immune response in colorectal cancer patients (n = 24) depending on their UICC stage and characterized their regulatory T cell functions independent of the p53 mutational status.

Indications, Results and Prospects of Photodynamic Therapy in the Treatment of Gastrointestinal and Genitourinary Cancers

Photodynamic therapy has been applied predominantly to patients with cutaneous and bronchial malignancies for more than a decade. More recently major interest has been focused on the endoscopic application of photodynamic therapy to tumors in hollow organs. Combining the favorable properties of laser light and a tumor localizing photosensitizer provides effective tumor destruction with a minimum of risk for the patient. Photodynamic therapy in gastrointestinal and genitourinary cancer may be indicated as an alternative to conventional therapy, particularly in superficial malignancies and localized recurrent disease.