PREDICTORS OF CLINICAL OUTCOME AFTER THERAPEUTIC VACCINATION IN FOLLICULAR LYMPHO
Eric Richard
University Of Texas Md Anderson Can Ctrcity: Houston country: United States (us)
Grant 5R01CA155143-02 from National Cancer Institute
Abstract: The generation of specific anti-tumor immune effectors (antibodies and T-cells) is a necessary condition for clinical efficacy of cancer vaccines; however, the efficacy of these effectors, and perhaps even their generation by vaccination, may be opposed by any of several immunosuppressive mechanisms that have been found in tumor microenvironments and in the peripheral blood of cancer patients. In a recently completed randomized, double-blind, controlled, multicenter phase III clinical trial, patient-specific tumor-derived idiotype (Id) protein was conjugated with a carrier protein (keyhole-limpet hemocyanin, KLH) and administered together with an adjuvant (granulocyte-macrophage colony stimulating factor, GM-CSF) to patients with advanced stage, previously untreated follicular lymphoma (FL), in complete remission following standard induction chemotherapy. Vaccination with Id-KLHCSF significantly prolonged disease-free survival (DFS), compared with the control group that received a non-specific immune stimulant (KLHCSF). The objective of this proposal is to identify predictors of clinical outcome after therapeutic idiotype vaccination in patients with FL, and use them to identify mechanisms affecting vaccine efficacy. Predictors will be found by correlating DFS with the results of immunologic and genomic studies on cryopreserved pre- and post vaccine serum and peripheral blood mononuclear cells, and viable tumor biopsy samples obtained at initial diagnosis, available from all treated patients from both arms of this trial. We propose four Specific Aims 1) determine whether the induction of antitumor humoral and/or cellular immune responses correlates favorably with clinical outcome following idiotype vaccination in FL, 2) determine whether the state of the immune system prior to vaccination and the cellular elements in the tumor microenvironment affect the induction of antitumor immune responses and clinical outcome following Id vaccination in FL, 3) determine whether the gene expression profiles of neoplastic and/or non-neoplastic cells in the tumor microenvironment at diagnosis predict clinical outcome following idiotype vaccination in FL, and 4) determine whether immune-response related gene polymorphisms predict clinical outcome following idiotype vaccination in FL. The overall goal of this project is to provide a deeper understanding of the interaction between the immune system and cancer cells, and suggest potential targets to improve results in future cancer vaccine trials. The proposed studies are likely to have substantial impact on the development of the cancer vaccine field in general and lymphoma vaccines in particular
Keywords: Adjuvant; Affect; Antibodies; arm; B-Cell Lymphomas; B-Lymphocytes; Biopsy Specimen; cancer cell; Cancer Patient; Cancer Vaccine Related Development; Cancer Vaccines; Carrier Proteins; Cells; chemotherapy; Clinical; clinical efficacy; Clinical Trials; Control Groups; Development; Diagnosis; Disease; Disease remission; Disease-Free Survival; Double-Blind Method; Evaluation; Follicular Lymphoma; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic Polymorphism; Genomics; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Neoplasms; Immune; Immune response; Immune system; immunogenic; Immunoglobulin Idiotypes; Immunoglobulins; Immunologic Monitoring; Immunologics; Immunosuppressive Agents; Immunotherapy; improved; In complete remission; Incidence; Indium; Integration Host Factors; Keyhole Limpet Hemocyanin; Lead; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Molecular Profiling; neoplastic; neoplastic cell; Non-Hodgkin`s Lymphoma; novel therapeutics; Outcome; Patient Selection; Patients; peripheral blood; Peripheral Blood Mononuclear Cell; Phase; Phase I/II Trial; Phase III Clinical Trials; pre-clinical; Proteins; public health relevance; Randomized; Relapse; Residual state; response; Serum; Single Nucleotide Polymorphism; Specimen; Staging; Surface; T-Lymphocyte; Therapeutic; Therapeutic Studies; tumor; Tumor Antigens; Tumor-Derived; Vaccination; vaccination strategy; vaccine efficacy; Vaccine Therapy; Vaccines; Variant
Relevance: The overall goal of this project is to provide a deeper understanding of the interaction between the immune system and cancer cells, and suggest potential targets to improve results in future cancer vaccine trials. The proposed studies are likely to have substantial impact on the development of the cancer vaccine field in general and lymphoma vaccines in particular
Project start date: 2011-03-01
Project end date: 2015-02-28
Budget start date: 1-MAR-2012
Budget end date: 28-FEB-2013
5R01CA155143-02 (2012): $494701
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Eric Richard
A CELL-BASED ASSAY TO FIND INHIBITORS OF CHRONIC ACTIVE B-CELL RECEPTOR SIGNALING
Eric Richard, Associate Professor
University Of Texas Md Anderson Can Ctrcity: Houston country: United States (us)
Grant 5R03DA031086-02 from Office Of The Director, National Institutes Of Health
Abstract: Certain cell lines of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which responds poorly to standard therapy, have recently been discovered by the candidate and former colleagues to rely on the B-cell receptor (BCR) for activation of the canonical NFB pathway and other pathways essential for their survival. The principal goal of the application is to collaborate with the Molecular Libraries Probe Production Centers Network (MLPCN), using a cell-based primary assay already established by the MLPCN, to find small-molecule inhibitors of this process termed "chronic active BCR signaling" (CABS). The assay will be performed in a CABS-dependent line, and in combination with counterscreens and secondary assays, will be used to identify inhibitors of CABS that can be optimized to serve as chemical probes of its poorly- understood mechanisms, and candidates for drug development as targeted therapy against ABC-DLBCL. The proposed project would be a continuation of ´s previous investigations into how the NFB pathway is constitutively activated in ABC-DLBCL, identifying potential therapeutic targets of increasing specificity. Finding chemical probes of CABS would advance ´s immediate career goals of making further discoveries about this pathway, and becoming established as an independent investigator. Finding serious candidates for drug development would advance ´s long-term goals of extending his research findings into the clinical arena, in keeping with his having recently joined a department which excels in the development and clinical testing of new therapies. Many different types of cancer depend on specific and abnormally-activated biological pathways, and inhibitors of these pathways have the potential to provide highly effective targeted therapies with reduced side effects. When a critical pathway is found in a cancer cell line, the line can be engineered to conveniently "report" on that pathway´s activity level, and thus be used to screen large libraries of chemical compounds for inhibitors of the pathway. This project will use this approach to find inhibitors of a critical pathway activated in one type of cancer of B cells (lymphomas) that responds poorly to standard therapy, helping in studies of this pathway and possibly providing candidates for development as targeted therapy
Keywords: Adverse effects; B-Cell Lymphomas; B-Lymphocytes; base; Biological; Biological Assay; Cancer cell line; cancer type; career; Cell Line; Cells; Chemicals; Chronic; Clinical; counterscreen; Critical Pathways; Development; drug development; Engineering; Failure (biologic function); Goals; high throughput screening; inhibitor/antagonist; Investigation; large cell Diffuse non-Hodgkin`s lymphoma; Lead; Lymphoma; Molecular Bank; Pathway interactions; Process; Production; public health relevance; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Reporting; repository; Research; research clinical testing; Research Personnel; Signal Transduction; small molecule; small molecule libraries; Specificity; therapeutic target; therapy development; tool
Relevance: Many different types of cancer depend on specific and abnormally-activated biological pathways, and inhibitors of these pathways have the potential to provide highly effective targeted therapies with reduced side effects. When a critical pathway is found in a cancer cell line, the line can be engineered to conveniently "report" on that pathway´s activity level, and thus be used to screen large libraries of chemical compounds for inhibitors of the pathway. This project will use this approach to find inhibitors of a critical pathway activated in one type of cancer of B cells (lymphomas) that responds poorly to standard therapy, helping in studies of this pathway and possibly providing candidates for development as targeted therapy
Project start date: 2010-07-15
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-09-129
5R03DA031086-02 (2011): $38315