CLINICAL IMPACT OF B7-H IMMUNE CELL COREGULATORS IN RENAL CELL CARCINOMA
Dong Haidong
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01CA134345-04 from National Cancer Institute
Keywords: Accounting; Address; Adult; Affect; Aggressive behavior; Algorithms; Antibodies; Antigens; Area; Automobile Driving; base; Basic Science; Behavior; Biological Response Modifiers; Cancer Patient; Cancer Relapse; cancer risk; cell mediated immune response; Cell physiology; Cell Proliferation; Cell Survival; Cells; Cellular Immunity; Cessation of life; Clear Cell; Clinical; Clinical Sciences; Clinical Trials; clinically relevant; Combined Modality Therapy; Diagnosis; Disease; Disease Progression; Employee Strikes; Environment; Excision; experience; Fostering; Generations; Health; high risk; Histologic; Human; Immune; Immune response; Immune Targeting; Immunity; Immunobiology; immunogenic; immunogenicity; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; improved; In Situ; in vitro Assay; in vivo; inhibitor/antagonist; injured; Injury; insight; Intervention; Kidney; Killings; Ligands; Link; Malignant - descriptor; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Methods; Microscopic; Modeling; Molecular; molecular marker; Monitor; Morbidity - disease rate; Natural Killer Cells; Neoplasm Metastasis; neoplastic cell; novel; Operative Surgical Procedures; Organ; Outcome; outcome forecast; Patient Care; Patient Monitoring; Patient-Centered Care; Patients; Pharmaceutical Preparations; Plant Roots; Primary Neoplasm; prognostic; Proteins; Recurrent Malignant Neoplasm; Refractory; Regulation; Relapse; Renal carcinoma; Renal Cell Carcinoma; Reporting; Residual Cancers; Risk; Serum; Specificity; Specimen; stem; Stratification; Survival Rate; survivin; T-Lymphocyte; Testing; tool; Translating; tumor; tumor progression
Relevance: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney malignancy, killing nearly 13,000 patients annually. Current treatment options for metastatic ccRCC are limited as evident in 2 year survival rates of 10-20%. Advancing ccRCC patient care centers around several areas including better methods for identifying patients at high risk for metastatic relapse following surgery, more thorough understanding of molecular mechanisms that drive ccRCC metastatic progression, and developing rational mechanism-targeted therapies to treat metastatic ccRCC disease. We have determined that ccRCC tumors can aberrantly express several relatively novel immune cell coregulatory ligands, namely B7-H1, B7-H3, and B7-H4, the expression of which predict aggressive ccRCC behavior and increased cancer-related death. These observations raise the distinct possibility that human tumors, especially ccRCC, might employ B7-H ligands to blunt patients´ anti-tumor immune responses, thereby promoting malignant progression. Tumor- associated B7-H ligands may likely prove useful to refine prognostic algorithms to pinpoint high-risk patients who are most prone to ccRCC progression and death. However, whether tumor-associated B7-H ligands actually function as clinical inhibitors of cell-mediated antitumoral immunity to promote malignant progression remains to be determined, as does the rationale for B7-H blockade as immunotherapeutic means to improve treatment of advanced ccRCC (or any other malignancy for that matter). This proposal is singularly devoted to studies that, we believe, will directly improve clinical ccRCC patient care. Specifically, our studies will rigorously test the prognostic and immunotherapeutic potential of B7-H ligands aberrantly expressed by ccRCC. Specifically, we will address a most vital question: "Do B7-H ligands within clinical tumors truly function to impair antitumoral immunity in cancer patients?" Such findings will help to establish the merits (and limitations) of in vivo B7-H ligand blockade as a clinical immunotherapeutic approach to treat human forms of malignancy
Project start date: 2008-12-01
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01CA134345-04 (2012): $273715
Sponsored Links Excellgen http://Excellgen.com
CLINICAL IMPACT OF B7-H IMMUNE CELL COREGULATORS IN RENAL CELL CARCINOMA
Dong Haidong, Full Consultant & Associate Professor
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01CA134345-03 from National Cancer Institute
Abstract: Renal cell carcinoma (RCC) encompasses 90% of kidney cancers and 3% of adult cancers. In the U.S. alone, more than 30,000 new cases of RCC are diagnosed and nearly 13,000 patients die from RCC annually. RCC is categorized into three distinct histologic subtypes of which clear cell (ccRCC) is the most common and lethal form, accounting for nearly 90% of RCC-related deaths. The majority of patients now diagnosed with ccRCC will present with organ-confined tumors seemingly amenable to surgical extirpation. Yet, almost half of these patients will experience metastatic relapse after surgery. Treatment options for metastatic ccRCC are limited both in terms of scope and efficacy. Thus, key advances to improve ccRCC patient care will necessarily include 1) better methods to identify patients at high risk for metastatic relapse following surgery; 2) a better understanding of molecular mechanisms that drive ccRCC metastatic progression; and 3) rational, mechanism- targeted therapies to treat metastatic disease in ccRCC patients. Such improvements could emanate from the introduction of newer, more effective drugs or optimization of combination therapies. In this proposal, emphasis will be placed on the latter topic to gain a better understanding of key issues related to the immunobiology and immunotherapeutic treatment of advanced ccRCC. We have recently reported that ccRCC tumors can aberrantly express several relatively novel immune cell coregulatory ligands, namely B7-H1, B7-H3 and B7-H4. We have further shown that enhanced tumor expression of these B7-H ligands can predict aggressive ccRCC behavior including enhanced risk for cancer progression and cancer-related death. Collectively, these observations raise the distinct possibility that human tumors might employ B7-H ligands to disarm host antitumoral immunity in order to promote malignant progression. Thus, tumor-associated B7-H ligands will likely prove useful to refine prognostic algorithms to pinpoint high-risk patients who are most prone to ccRCC progression and death. However, whether tumor- associated B7-H ligands actually function as clinical inhibitors of cell-mediated antitumoral immunity to promote malignant progression remains to be determined. This proposal is singularly devoted to studies that, we believe, will directly improve clinical ccRCC patient care. Specifically, our studies will rigorously test the prognostic and immunotherapeutic potential of B7-H ligands aberrantly expressed by ccRCC. Specifically, we will address a most vital question "Do B7-H ligands within clinical tumors truly function to impair antitumoral immunity in cancer patients?" Such findings will help to establish the merits (and limitations) of in vivo B7-H ligand blockade as a clinical immunotherapeutic approach to treat human forms of malignancy. Unifying Hypothesis for Specific Aims 1- 4 The overall hypothesis for this proposal is that the aggressive behavior of ccRCC tumors stems, at least in part, from the ability of tumors to elaborate an array of homologous but spatially distributed B7-H ligands that act in concert to undermine cell-mediated immunity in cancer patients. We further postulate that the most aggressive of ccRCC tumors concurrently express increased levels of other proteins that promote tumor cell proliferation and survival and, may also serve as antigenic moieties to lure immune cells into a perilous intratumoral environment. Thus, each aim of our proposal has been crafted to be free-standing, each addressing key clinical and scientific issues pertaining to B7-H ligands and moving from a macroscopic to microscopic understanding of B7-H ligands as immune- regulators and immunotherapeutic targets for clinical ccRCC. Specific Aim 1. Test if putative immunosuppressive, tumor-associated B7-H ligands (B7-H1, B7-H3, B7-H4, and PD-1) can collaborate with each other, as well as with other molecular markers that assist in fostering tumor cell proliferation and survival (IMP3, CAIX, Ki-67, and survivin) to improve outcome prediction for ccRCC patients. Specific Aim 2. Test whether ccRCC metastases are enriched for prognostic B7-H related molecules (B7-H1, B7-H3, B7-H4, and PD-1) as well as IMP3, Ki-67, and survivin when compared against patient-matched primary tumors from which metastases arise. Specific Aim 3. Test if soluble B7-H (sB7-H) ligands can be detected in the sera of ccRCC patients to improve strategies to monitor and, perhaps, immunotherapeutically treat ccRCC patients. Specific Aim 4. Test if tumor-associated B7-H ligands inhibit T and NK cell-mediated immune responses within clinical ccRCC specimens using in situ IHC analysis in combination with in vitro assays of immune cell function. Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney malignancy, killing nearly 13,000 patients annually. Current treatment options for metastatic ccRCC are limited as evident in 2 year survival rates of 10-20%. Advancing ccRCC patient care centers around several areas including better methods for identifying patients at high risk for metastatic relapse following surgery, more thorough understanding of molecular mechanisms that drive ccRCC metastatic progression, and developing rational mechanism-targeted therapies to treat metastatic ccRCC disease. We have determined that ccRCC tumors can aberrantly express several relatively novel immune cell coregulatory ligands, namely B7-H1, B7-H3, and B7-H4, the expression of which predict aggressive ccRCC behavior and increased cancer-related death. These observations raise the distinct possibility that human tumors, especially ccRCC, might employ B7-H ligands to blunt patients´ anti-tumor immune responses, thereby promoting malignant progression. Tumor- associated B7-H ligands may likely prove useful to refine prognostic algorithms to pinpoint high-risk patients who are most prone to ccRCC progression and death. However, whether tumor-associated B7-H ligands actually function as clinical inhibitors of cell-mediated antitumoral immunity to promote malignant progression remains to be determined, as does the rationale for B7-H blockade as immunotherapeutic means to improve treatment of advanced ccRCC (or any other malignancy for that matter). This proposal is singularly devoted to studies that, we believe, will directly improve clinical ccRCC patient care. Specifically, our studies will rigorously test the prognostic and immunotherapeutic potential of B7-H ligands aberrantly expressed by ccRCC. Specifically, we will address a most vital question "Do B7-H ligands within clinical tumors truly function to impair antitumoral immunity in cancer patients?" Such findings will help to establish the merits (and limitations) of in vivo B7-H ligand blockade as a clinical immunotherapeutic approach to treat human forms of malignancy
Keywords: 21+ years old; Abscission; Accounting; Address; adenocarcinoma of kidney; Adenocarcinoma, Renal Cell; Adult; adult human (21+); Affect; Aggression; Aggressive behavior; Algorithms; Antibodies; Antigens; API4; Apoptosis Inhibitor 4; Apoptosis Inhibitor Survivin; Area; ATGN; Automobile Driving; Baculoviral IAP Repeat-Containing 5 (Survivin); Baculoviral IAP Repeat-Containing Protein 5; base; Basic Research; Basic Science; Behavior; Biological Response Modifiers; Biomodulators; BIRC5; Blood Serum; BRM; cancer metastasis; Cancer of Bladder; Cancer of Prostate; Cancer of Urinary Bladder; Cancer Patient; cancer progression; Cancer Relapse; cancer risk; Cancers; Carcinoma, Hypernephroid; Cell Function; Cell Growth in Number; cell mediated immune response; Cell Mediated Immunology; Cell Multiplication; Cell physiology; Cell Process; Cell Proliferation; Cell Survival; Cell Viability; Cell-Mediated Immunity; Cells; Cellular Function; Cellular Immunity; Cellular Physiology; Cellular Process; Cellular Proliferation; Cessation of life; Clear Cell; Clinical; clinical investigation; clinical relevance; Clinical Sciences; Clinical Trials; Clinical Trials, Unspecified; clinically relevant; combination therapy; Combined Modality Therapy; combined modality treatment; combined treatment; Cytotoxic cell; Death; Diagnosis; Disease; Disease Progression; disease/disorder; Disorder; driving; Drivings, Automobile; drug/agent; Drugs; Employee Strikes; Environment; EPR-1; Excision; experience; Extirpation; Forecast of outcome; Fostering; gene product; Generations; Grawitz Tumor; Health; high risk; Histologic; Histologically; host response; Human; Human, Adult; Human, General; Hypernephroma; IAP4; Immune; Immune Mediators; Immune Mediators/Modulators; Immune Regulators; Immune response; Immune Targeting; immune therapy; Immunity; Immunity, Cellular; Immunobiology; immunogen; immunogenic; immunogenicity; immunologic preparation; Immunologically Directed Therapy; Immunophysiology; immunoresponse; Immunosuppressants; immunosuppressive; Immunosuppressive Agents; Immunotherapeutic agent; immunotherapeutics; Immunotherapy; improved; In Situ; in vitro Assay; in vivo; inhibitor; inhibitor/antagonist; injured; Injury; insight; Intervention; Intervention Strategies; interventional strategy; ITX; K lymphocyte; Kidney; Kidney Cancer; Kidney Carcinoma; Killings; language translation; Ligands; Link; malignancy; Malignant; Malignant - descriptor; Malignant Bladder Neoplasm; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Malignant prostatic tumor; Malignant Tumor; Malignant Tumor of the Bladder; Malignant Tumor of the Prostate; Man (Taxonomy); Man, Modern; Mediating; Medication; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Renal Cell Cancer; Metastatic Renal Cell Carcinoma; Metastatic Tumor; Methods; Microscopic; Modeling; Molecular; molecular marker; Monitor; Morbidity; Morbidity - disease rate; Multimodal Therapy; Multimodal Treatment; multimodality therapy; Multimodality Treatment; Natural Killer Cells; Neoplasm Metastasis; neoplasm progression; neoplasm/cancer; neoplastic cell; neoplastic progression; Nephroid Carcinoma; NK Cells; novel; Operation; Operative Procedures; Operative Surgical Procedures; Organ; Outcome; outcome forecast; Patient Care; Patient Care Delivery; Patient Monitoring; Patient-Centered Care; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Plant Roots; Primary Neoplasm; Primary Tumor; Prognosis; prognostic; Prostate CA; Prostate Cancer; Prostatic Cancer; Proteins; Recurrent Cancer; Recurrent Malignant Neoplasm; Recurrent Malignant Tumor; Refractory; Regulation; Relapse; Removal; renal; Renal Adenocarcinoma; Renal Cancer; Renal carcinoma; Renal Cell Cancer; Renal Cell Carcinoma; Renal Cell Carcinoma, Stage Unspecified; Reporting; Research Specimen; resection; Residual Cancers; Risk; root; Secondary Neoplasm; Secondary Tumor; Serum; Specificity; Specimen; stem; Stratification; Strikes; Strikes, Employee; Subcellular Process; surgery; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Survival Rate; survivin; T-Cells; T-Lymphocyte; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; tool; Translating; Translatings; tumor; Tumor Cell; Tumor Cell Migration; tumor progression; Urinary Bladder Malignant Tumor; Urinary System, Kidney
Relevance: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney malignancy, killing nearly 13,000 patients annually. Current treatment options for metastatic ccRCC are limited as evident in 2 year survival rates of 10-20%. Advancing ccRCC patient care centers around several areas including better methods for identifying patients at high risk for metastatic relapse following surgery, more thorough understanding of molecular mechanisms that drive ccRCC metastatic progression, and developing rational mechanism-targeted therapies to treat metastatic ccRCC disease. We have determined that ccRCC tumors can aberrantly express several relatively novel immune cell coregulatory ligands, namely B7-H1, B7-H3, and B7-H4, the expression of which predict aggressive ccRCC behavior and increased cancer-related death. These observations raise the distinct possibility that human tumors, especially ccRCC, might employ B7-H ligands to blunt patients´ anti-tumor immune responses, thereby promoting malignant progression. Tumor- associated B7-H ligands may likely prove useful to refine prognostic algorithms to pinpoint high-risk patients who are most prone to ccRCC progression and death. However, whether tumor-associated B7-H ligands actually function as clinical inhibitors of cell-mediated antitumoral immunity to promote malignant progression remains to be determined, as does the rationale for B7-H blockade as an immunotherapeutic means to improve treatment of advanced ccRCC (or any other malignancy for that matter). This proposal is singularly devoted to studies that, we believe, will directly improve clinical ccRCC patient care. Specifically, our studies will rigorously test the prognostic and immunotherapeutic potential of B7-H ligands aberrantly expressed by ccRCC. Specifically, we will address a most vital question: "Do B7-H ligands within clinical tumors truly function to impair antitumoral immunity in cancer patients?" Such findings will help to establish the merits (and limitations) of in vivo B7-H ligand blockade as a clinical immunotherapeutic approach to treat human forms of malignancy
Project start date: 2008-12-01
Project end date: 2014-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01CA134345-03 (2011): $55