Sharon S Evans
Roswell Park Cancer Institute Corp
Project start date: 2010-01-01
Project end date: 2014-12-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Sharon S Evans
LEUKOCYTE-ENDOTHELIAL CELL ADHESION IN TUMOR IMMUNITY
Sharon S Evans, Associate Member
Roswell Park Cancer Institute Corp
elm & Carlton Streets
buffalo, Ny 14263
Grant 5R01CA079765-02 from National Cancer Institute IRG: RAD
Abstract: This proposal addresses the central hypothesis that significant antitumor responses can be achieved through the use of fever- range hyperthermia to stimulate L-selectin and alpha4beta7 integrin-dependent recruitment of immune effector cells to malignant tissues and tumor-draining lymph nodes. The hypothesis is formulated on the basis of new information demonstrating that fever range, long duration whole body hyperthermia (WBH) stimulates expression of endothelial ligands for two leukocyte homing receptors, L-selectin and alpha4beta7 integrin, on tumor vessels in the RIP-Tag5 transgenic mouse model. This finding is correlated with increased lymphocyte infiltration into beta islet tumors. Notably, pancreatic tumors that develop as a result of transgene expression of the SV40 T antigen (Tag) in RIP-Tag5 mice are normally devoid of infiltrating lymphocytes. Three independent approaches are proposed to address the central hypothesis (1) Strategies are designed to examine the direct role of L-selectin and alpha4beta7 integrin in targeting immune effector cells to pancreatic beta islet tumors in response to fever-range WBH in RIP-Tag5 single transgenic mice and in RIP- Tag5 double transgenic mice that have a high frequency of tumor- reactive cytotoxic T lymphocytes (CTL) as a result of coexpression of the B7.1 costimulatory molecule or a Tag-specific T cell receptor. The specific role of adhesion molecules in lymphocyte recruitment will be delineated by antibody blockade studies and using cell lines that restrictively bind to endothelium via L-selectin or alpha4beta7 integrin. (2) The molecular mechanisms underlying hyperthermia control of lymphocyte-endothelial adhesion will be investigated in cell lines using in vitro kinase assays and dominant negative approaches to examine the involvement of specific signal transduction pathways (i.e., MAPK, HSP90, JAK/STATs, Src kinases, and IL-6). (3) Studies are designed to determine if fever-range WBH, in combination with cytokines (IFN-alpha, IL-2), inhibits tumor progression in RIP-Tag transgenic mice by enhancing L- selectin and/or alpha4beta7 integrin-dependent accumulation of CTL in beta islet tumors. WBH effects on intratumoral localization of immune cells that produce Th1-cytokines (e.g., IFN-gamma) will also be examined since these cytokines are fundamental to the generation of cell-mediated tumor immunity. The proposed studies are expected to provide a framework for future evaluation of the efficacy of fever-range WBH as an adjuvant in the treatment of cancer in combination with immunotherapies designed to enhance the generation of tumor- specific CTL
Keywords: cell adhesion, leukocyte, neoplasm /cancer immunology, vascular endothelium T cell receptor, antineoplastic, biological signal transduction, cytotoxic T lymphocyte, disease /disorder model, hyperthermia therapy, integrin, interleukin 6, lymph node, natural killer cell, neoplastic cell, pancreatic islet neoplasm, protein structure /function, receptor expression, selectin, tumor progression immunocytochemistry, laboratory mouse, monoclonal antibody, tissue /cell culture, transgenic animal
Project start date: 1999-12-13
Project end date: 2002-11-30
5R01CA079765-02 (2001): $201492
1R01CA079765-01A1 (2000): $199672
Leukocyte-Endothelial Adhesion In Tumor Immunity
Sharon S Evans, Associate Member
Roswell Park Cancer Institute Corp
Grant 2R01CA079765-09A1 from National Cancer Institute IRG: RTB
Abstract: T cell-based cancer immunotherapy depends on the ability of blood-borne T cells to gain access to malignant tissues in order to initiate tumor-target destruction. While expansion of the pool of circulating effector T cells can be achieved therapeutically by adoptive T cell transfer, the overall success of immunotherapy strategies has been limited. Our studies have defined a paucity of trafficking molecules on tumor microvessels that are required for T cell entry into the tumor microenvironment. However, we have discovered that the tumor microenvironment can be exploited favorably by systemic thermal therapy (STT) to increase the adhesive properties of vascular endothelial cells that serve as gateways to tumor tissues. These observations lead us to hypothesize that systemic thermal therapy (STT) can improve the efficacy of adoptive T cell therapy by targeting the delivery of cytolytic T lymphocytes to primary and metastatic sites of tumor growth. The proposed studies are formulated on the basis of the identification of a novel lymphocyte-endothelial-interleukin-6 (IL-6) axis in murine tumor models that mediates the proadhesive activities of STT. A major adhesive target of STT is the vascular gatekeeper, intercellular adhesion molecule-1 (ICAM-1), which supports both firm arrest of T cells on vessel walls and transendothelial migration. In Aim 1 we plan to build on our previous findings to determine if STT acts through an IL-6-dependent mechanism to modify additional trafficking molecules (adhesion receptors, chemokines) that recruit T cells in a murine B16 melanoma model of adoptive immunotherapy. Complementary in situ imaging studies will investigate the contribution of endogenous human IL-6 in mobilizing adoptively transferred T cells in a preclinical xenograft model of human melanoma. In Aim 2 We will test the hypothesis that preconditioning of the host tissue environment by transient lymphodepletion amplifies the effects of STT on the trafficking of effector T cells to murine melanoma tumor tissues. The combinatorial effects of this multimodality therapy on ICAM-1-dependent entry of CD8 effector T cells in tumor tissues will be defined using antibody-blocking strategies and adhesion-deficient mice. A causal relationship between early T cell entry into tumor tissues and tumor cell apoptosis will be evaluated. Aim 3 will test the hypothesis that enhancement of the local chemokine availability on the tumor vascular landscape can collaborate with STT to enhance CD8 T cell trafficking to tumor tissues during adoptive transfer. The requirement for the chemokine/chemokine receptor pair, CXCL10/CXCR3, in mediating the transition of T cells from initial rolling interactions to ICAM-1-dependent firm arrest in tumor vessels will be probed using a sustained-release microsphere system for delivery of CXCL10. The proposed studies are expected to provide new insights into mechanisms of T cell delivery to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy. Despite considerable progress in the development of immunotherapy strategies in cancer, these therapies have had minimal overall impact and treatment options continue to be limited for advanced-stage patients. This proposal is formulated based on our findings that systemic thermal therapy is a novel approach to target the delivery of tumor-specific cytolytic T lymphocytes to the tumor microenvironment, thereby overcoming a significant barrier to T cell-based immunotherapy. The proposed studies are expected to provide needed insights into the dynamic mechanisms that underlie targeted delivery of effector T cells to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy
Project start date: 1999-12-13
Project end date: 2013-11-30
5R01CA079765-08 (2007): $323608
5R01CA079765-07 (2006): $328543
5R01CA079765-06 (2005): $331747
5R01CA079765-05 (2004): $327181
2R01CA079765-04A1 (2003): $322749
XENOGENEIC MODEL FOR HOMING OF HUMAN LYMPHOCYTES
Sharon S Evans, Associate Member
Roswell Park Cancer Institute
buffalo, Ny 14263
Grant 1R03RR008926-01 from National Center For Research Resources IRG: CM
Abstract: Strategies are proposed to evaluate the potential of severe combined immunodeficient (SCID) mice to serve as an in vivo model to study mechanisms involved in homing of human lymphocytes. Lymphocyte migration into peripheral lymph nodes is initiated by the interaction of the L-selectin homing receptor on lymphocytes with the vascular addressin on post-capillary high endothelial venules (HEV). To determine if addressin expression develops normally in immunodeficient mice, a direct comparison will be performed of the level of the peripheral lymph node addressin expressed on HEV of normal Balb/c and SCID. The MECA-79 monoclonal antibody, which binds to both the murine and human peripheral lymph node vascular addressin, will be used to detect the presence of this antigen by immunohistochemical staining and Western blot analysis. Experiments are also proposed to determine if murine SCID peripheral lymph node HEV are functionally capable of mediating L-selectin-dependent adhesion of human lymphocytes. This aim will be accomplished by (a) directly comparing human lymphocyte binding in vitro to peripheral lymph node HEV of normal Balb/c and SCID mice and (b) examining the effect of L-selectin-specific blocking antibodies on the adhesion of human lymphocytes to murine HEV. Non-blocking L-selectin-specific monoclonal antibodies will be used as a negative control. In addition, protocols are designed to evaluate L-selectin-dependent homing of human lymphocytes to peripheral lymph nodes of SCID mice in vivo. This aim will be accomplished by examining the tissue localization of xenotransfused human lymphocytes that express high or low levels of the L-selectin peripheral lymph node homing receptor. The role of the L-selectin lymphocyte homing receptor in mediating human lymphocyte localization to peripheral lymph nodes will be further determined by treating human lymphocytes with L- selectin-specific blocking antibodies prior to xenotransfusion into SCID mice. Successful development of an in vivo model to study human homing will represent a major advance to multiple disciplines. This model will provide a unique system in which to explore the role of L-selectin as well as other adhesion pathways in normal lymphocyte homing and in pathological processes such as inflammation and metastasis. Moreover, this model should prove useful for evaluating new therapeutic strategies in these pathological disorders
Keywords: cell migration, genetic model, heterologous transplantation, leukocyte adhesion molecule, lymphocyte, model design /development cell adhesion, gene expression, high endothelial venule, leukocyte transfusion, lymph node SCID mouse, human subject, immunocytochemistry, laboratory mouse, monoclonal antibody, tissue /cell culture, western blotting
Project start date: 1993-09-30
Project end date: 1995-09-29
1R03RR008926-01 (1993): $33060
MECHANISMS CONTROLLING LEUKOCYTE TRAFFICKING BY FEVER RANGE THERMAL STRESS
Sharon S Evans, Associate Member
Roswell Park Cancer Institute Corp Elm And Carlton Streets Buffalo, Ny 14263
Grant 1P01CA094045-01A20003 from National Cancer Institute IRG: NCI
Abstract: Revised ) Successful anti-tumor immunotherapy ultimately depends on the ability of immune effector cells to gain access to malignant tissues. In this project, adhesive interactions between tumor-specific cytotoxic T lymphocytes (CTL) and tumor microvessels are considered to be a locus of action for promoting tumor immunity. This research proposal addresses the hypothesis that the proinflammatory cytokine, interleukin-6 (IL-6), plays a central role in stimulating a4b7 integrin-dependent delivery of CTL to tumor tissues in response to fever-range thermal stress. This hypothesis is formulated on the basis of new information from our laboratory demonstrating that fever-range hyperthermia stimulates the binding function of the a4b7 integrin homing receptor in tumorspecific CD8+ human CTL by altering 11-6 bioactivity. Initial data indicate that fever-range whole body hyperthermia (WBH) also acts on blood vessels in murine tumor tissues to stimulate the expression of functional endothelial ligands for a4b7 integrin (i.e., MAdCAM- 1, VCAM-1). Experiments are designed to address the following specific aims (1) To define the requirement for IL-6 in recruitment of tumorreactive CTL to tumor tissues in response to fever-range whole body hyperthermia (WBH). The role of multiple lymphocyte-endothelial molecular pairs (a4b7 integrin/MAdCAM- 1, VCAM- 1; LFA-1/ICAM- 1; PSGL-1/E-selectin, P-selectin; CCR7/SLC; CXCR3/MIG, IP-10) will be investigated. These studies focus on a novel model system in which a4b7 integrin-dependent trafficking of human CTL to autologous lung tumor xenografts will be evaluated in SCID mice. (2) To identify novel IL-6 macromolecular soluble complexes induced by thermal stress that promotes a4b7 integrin-dependent leukocyte-endothelial cell adhesion. (3) To elucidate contributions of a4b7 integrin and endogenous IL- 6 in promoting tumor-specific cytotoxic immunity in response to combination fever range WBH and hsp110/grp170 vaccination. This project is highly interactive with Project 1 (John Subjeck) and Project 2 (Elizabeth Repasky) in which novel tumor vaccination strategies are developed using hsp 110 and grp 170 to initiate tumor-specific CTL responses in mouse models. Moreover, the success of this proposal is dependent on support from the core resources for administrative support and scientific leadership, hyperthermia treatment of mice, analysis of cytokine levels and CTL responses, and biostatistical analysis. Results of this integrated program are expected to support our long-term goal to develop new immunotherapies for the intervention in cancer.
Keywords: T lymphocyte, cell adhesion, cell motility, cytokine receptor, heat, interleukin 6, neoplasm /cancer immunology, stress, cytotoxic T lymphocyte, hypothermia, integrin, ligand, selectin, tumor infiltrating lymphocyte, SCID mouse, northern blotting, polymerase chain reaction
Project start date: 2003-07-20
Project end date: 2008-06-30
Sponsored Links Excellgen http://Excellgen.com
INFLAMMATORY CONTROL OF LYMPHOCYTE TRAFFICKING
Sharon S Evans, Professor Of Oncology
Roswell Park Cancer Institute Corp, Elm & Carlton Streets, Buffalo, Ny 14263
Grant 1R01AI082039-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: A critical component of the acute inflammatory response is the rapid mobilization of blood- borne lymphocytes into secondary lymphoid organs. These organs are the staging ground for lymphocyte encounters with antigens and foreign pathogens during the initiation of protective immunity. Significant progress has been achieved in defining the adhesion events that guide homeostatic steady-state trafficking of lymphocytes across vascular checkpoints in lymphoid organs. By contrast, the molecular basis of inducible trafficking of naive and central memory cells to lymphoid organs during inflammation is poorly understood. Extensive preliminary data lead us to hypothesize that the proinflammatory cytokine, interleukin-6 (IL-6), is a driving force in regulating lymphocyte migration into lymphoid organs during acute inflammation. The first aim will identify the cellular source of IL-6 that regulates the capture efficiency of vascular gateways in a model of systemic febrile inflammation. Reciprocal bone marrow chimeras with wild-type and IL-6-deficient mice will segregate whether IL-6 production by radiation-resistant stromal cells or radiation-sensitive hematopoietic cells is required for enhanced lymphocyte trafficking across vessel walls during febrile stress. Homing assays and intravital microscopy will further validate that a defined cellular source of IL-6 promotes lymphocyte influx into lymphoid organs. Aim 2 will focus on determining if IL-6 is also responsible for mobilizing the recruitment of naive cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our surprising discovery that IL-6 produced by mature dendritic cells modifies the adhesive properties of vascular entryways. The final aim will use genetic approaches to dissect the IL-6 downstream signal transduction pathways that regulate lymphocyte trafficking during local and systemic adaptive immune responses. The studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanisms required for accelerated lymphocyte trafficking during acute inflammation. Understanding the cytokine requirements for lymphocyte recruitment during acute inflammation may lead to novel intervention strategies in chronic inflammatory disorders as well as provide insights into vaccine approaches based on the ability of IL-6 to heighten adaptive immunity. This proposal addresses fundamental questions in immunology regarding the mechanisms governing trafficking of lymphocytes to lymphoid organs during acute inflammation, a function that is crucial for host protection against pathogens. The molecular mechanisms that mediate basal trafficking of lymphocytes to lymphoid organs are well defined, however, little is known about the means of augmenting lymphocyte trafficking during acute inflammation. The proposed studies are expected to provide important insights into the unique role of cytokines in dynamically regulating leukocyte trafficking at key vascular checkpoints. These studies further have the potential to lead to novel therapeutic targets for the promotion of immune surveillance as well as for the treatment of chronic inflammation
Keywords: ATGN; Acute; Address; Adhesions; Adhesives; Antigens; Assay; Autoimmune Diseases; Automobile Driving; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Basophilic Histiocyte; Basophils, Tissue; Bioassay; Biologic Assays; Biological Assay; Blood; Blood Vessels; Blood monocyte; Bone Marrow; CCL21; CCL21 gene; CD54 (ICAM 1); CD54 Antigens; CKb9; Cancers; Cells; Chimera; Chimera organism; Chronic; Cues; Cytokine Signal Transduction; Cytokine Signaling; Cytokines, Chemotactic; Data; Defect; Dendritic Cells; Differentiation Factor, B-Cell; Disease; Disorder; Drivings, Automobile; Endothelial Cells; Event; Fever; Genetic; Glycoprotein ICAM 1 (human clone pHRVr1 deblocked protein moiety reduced); HPGF; Hematopoietic; Hepatocyte-Stimulating Factor; High Endothelial Venule; Homing; Homologous Chemotactic Cytokines; Hybridoma Growth Factor; Hyperthermia; ICAM-1; IFN-beta 2; IFNB2; IL-6; IL6 Protein; INFLM; IVM; Image; Immune; Immune Surveillance; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunological Surveillance; Immunology; Immunology (Including BRMP); Immunology (NCI Program); In Situ; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Intercrines; Interleukin 6 (Interferon, Beta 2); Interleukin-6; Intervention; Intervention Strategies; Knockout Mice; Laboratories; Lead; Leukocyte Trafficking; Link; Lymph node proper; Lymphatic; Lymphocyte; Lymphocytic; Lymphoid; MAP-ERK Kinase; MAPK ERK Kinases; MECA-79 antigen; MEKs; MGC34555; MGI-2; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Maps; Marrow Mast Cell; Marrow monocyte; Mediating; Memory; Mice; Mice, Knock-out; Mice, Knockout; Mice, Mutant Strains; Modeling; Molecular; Murine; Mus; Mutant Strains Mice; Myeloid Differentiation-Inducing Protein; Null Mouse; Organ; PNAd; Pathway interactions; Pb element; Phase; Physiologic pulse; Plasmacytoma Growth Factor; Play; Probability; Process; Production; Property; Property, LOINC Axis 2; Pulse; Pyrexia; Radiation; Ras/Raf; Resistance; Reticular Cell; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Lymph Node; Role; SCYA21; SIS cytokines; SLC; STAT3; STAT3 gene; Signal Pathway; Signal Transduction Pathway; Site; Source; Staging; Stress; Stromal Cells; Surveillances, Immunologic; Surveillances, Immunological; T memory cell; T-Cells; T-Lymphocyte; TCA4; Thymus-Dependent Lymphocytes; Transgenic Organisms; Vaccines; Veiled Cells; autoimmune disorder; base; body system, allergic/immunologic; chemoattractant cytokine; chemokine; cytokine; density; disease/disorder; driving; driving force; febrile; febris; heavy metal Pb; heavy metal lead; host response; imaging; immunogen; immunopathology; immunoresponse; insight; interferon beta 2; interventional strategy; intravital microscopy; lymph cell; lymph gland; lymph nodes; malignancy; mast cell; mastocyte; memory T lymphocyte; migration; monocyte; mouse mutant; neoplasm/cancer; new therapeutic target; novel; organ system, allergic/immunologic; pathogen; pathway; peripheral lymph node addressin; public health relevance; ray (radiation); resistant; response; social role; thermal stress; thermo stress; thymus derived lymphocyte; trafficking; transgenic; vascular
Relevance: This proposal addresses fundamental questions in immunology regarding the mechanisms governing trafficking of lymphocytes to lymphoid organs during acute inflammation, a function that is crucial for host protection against pathogens. The molecular mechanisms that mediate basal trafficking of lymphocytes to lymphoid organs are well defined, however, little is known about the means of augmenting lymphocyte trafficking during acute inflammation. The proposed studies are expected to provide important insights into the unique role of cytokines in dynamically regulating leukocyte trafficking at key vascular checkpoints. These studies further have the potential to lead to novel therapeutic targets for the promotion of immune surveillance as well as for the treatment of chronic inflammation
Project start date: 2010-01-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
1R01AI082039-01A1 (2010): $465332
Sharon S Evans
Roswell Park Cancer Institute Corp
Project start date: 1999-12-13
Project end date: 2013-11-30
LEUKOCYTE-ENDOTHELIAL ADHESION IN TUMOR IMMUNITY
Sharon S Evans
Department/ Educational Institution Type:
Grant 5R01CA079765-11 from National Cancer Institute
Keywords: Address; Adhesion Molecule; adhesion receptor; Adhesions; Adhesives; adoptive cell immunotherapy; Adoptive Cellular Immunotherapy; Adoptive Immunotherapy; Adoptive Transfer; Antibodies; anticancer therapy; Apoptosis; Apoptosis Pathway; Area; arm; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; base; BCDF; Blocking Antibodies; Blood; Blood leukocyte; blood vessel neoplasm; Blood Vessel Tumor; Blood Vessels; Body Tissues; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); cancer immunotherapy; cancer therapy; Cancer Treatment; CD183; CD54 (ICAM 1); CD54 Antigens; CD8; CD8B; CD8B1; CD8B1 gene; Cell Adhesion Molecules; cell adhesion protein; Cell Death, Programmed; Cell Therapy; cell-based therapy; chemoattractant cytokine; Chemoattractants; chemokine; chemokine receptor; Chemotactic Factors; Chemotaxins; CKR-L2; clinical practice; clinical relevance; clinically relevant; CMKAR3; combination therapy; combinatorial; Combined Modality Therapy; combined modality treatment; combined treatment; complement chemotactic factor; CRG-2; Cutaneous Melanoma; CXCL10; CXCL10 gene; CXCR3; CXCR3 gene; Cytokines, Chemotactic; Cytolysis; density; design; designing; Development; Differentiation Factor, B-Cell; Endothelial Cells; Environment; Extravasation; febrile; febris; Fever; Frequencies (time pattern); Frequency; Funding; gatekeeper; Gatekeeping; Generalized Growth; Genetic; gIP-10; Glycoprotein ICAM 1 (human clone pHRVr1 deblocked protein moiety reduced); Goals; GPR9; Growth; heavy metal lead; heavy metal Pb; Hepatocyte-Stimulating Factor; Homologous Chemotactic Cytokines; host response; Hour; HPGF; Human; human disease; Human, General; Hybridoma Growth Factor; Hyperthermia; ICAM-1; IFI10; IFN-beta 2; IFNB2; IL-6; IL6 Protein; Image; imaging; Immune; Immune response; immune therapy; Immuno-Chemotherapy; Immunochemotherapy; Immunologically Directed Therapy; immunoresponse; Immunotherapy; Immunotherapy, Adoptive; Immunotherapy, Cancer, General; improved; In Situ; INP10; insight; Intercellular adhesion molecule 1; Intercrines; interferon beta 2; Interleukin 6 (Interferon, Beta 2); Interleukin-6; intravital microscopy; Investigation; IP-10; IP10; IP10-R; ITX; IVM; Laboratories; language translation; Lead; Leakage; Leukocytes; Link; lymph cell; Lymphocyte; Lymphocytic; Lysis; LYT3; Malignant; Malignant - descriptor; Malignant Cutaneous Melanoma; Malignant Melanoma; Malignant Melanoma of Skin; Malignant Melanoma of Skin Stage Unspecified; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow leukocyte; Mediating; melanoma; MGI-2; Mice; Microbeads; Microspheres; Mig-R; MigR; migration; MOB-1; Modeling; Multimodal Therapy; Multimodal Treatment; multimodality therapy; Multimodality Treatment; Murine; Mus; Myeloid Differentiation-Inducing Protein; Neoplasms in Vascular Tissue; neoplastic cell; new approaches; new therapeutics; next generation therapeutics; novel; novel approaches; novel strategies; novel strategy; novel therapeutics; ontogeny; Ovalbumin; Patients; Pb element; Plasmacytoma Growth Factor; pre-clinical; Pre-Clinical Model; preclinical; Preclinical Models; preconditioning; Prior Therapy; Property; Property, LOINC Axis 2; Pyrexia; Reaction; receptor; Receptor Protein; recruit; Recruitment Activity; Regimen; Research Specimen; response; Reticuloendothelial System, Blood; Reticuloendothelial System, Leukocytes; Role; SCID; SCID Mice; SCYB10; severe combined immune deficiency; Severe Combined Immunodeficient Mice; SIS cytokines; Site; site targeted delivery; Skin, Melanoma; social role; Specimen; Spillage; Staging; success; SYS-TX; System; System, LOINC Axis 4; Systemic Therapy; T-Cells; T-Lymphocyte; targeted delivery; Testing; Therapy, Cell; thermal stress; thermo stress; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Tissue Growth; Tissues; trafficking; Translating; Translatings; tumor; Tumor Cell; tumor growth; Tumor Immunity; Tumor Tissue; vascular; Vascular Endothelial Cell; Vascular Neoplasms; Vascular Tissue Tumor; Vascular Tumor; white blood cell; White Blood Cells; white blood corpuscle; White Cell; Work; Xenograft Model
Relevance: Despite considerable progress in the development of immunotherapy strategies in cancer, these therapies have had minimal overall impact and treatment options continue to be limited for advanced-stage patients. This proposal is formulated based on our findings that systemic thermal therapy is a novel approach to target the delivery of tumor-specific cytolytic T lymphocytes to the tumor microenvironment, thereby overcoming a significant barrier to T cell-based immunotherapy. The proposed studies are expected to provide needed insights into the dynamic mechanisms that underlie targeted delivery of effector T cells to the tumor microenvironment and offer a conceptual basis for novel therapeutic strategies in cancer immunotherapy
Project start date: 1999-12-13
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01CA079765-11 (2011): $288197
5R01CA079765-10 (2010): $311648