Effect On IL-2R Antibody On Regulatory T-cells In Patients With Malignant Gliomas
John H Sampson, Associate Professor
Surgeryduke University
Grant 5R21CA132891-02 from National Cancer Institute IRG: ZRG1
Project start date: 2008-01-04
Project end date: 2009-12-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to John H Sampson
NEUROIMMUNOLOGY OF VACCINES IN ADOPTIVE T-CELL THERAPY FOR BRAIN TUMOR
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 1R21NS068057-01 from National Institute Of Neurological Disorders And Stroke
Abstract: The most common malignant primary brain tumor, glioblastoma (GBM), remains uniformly fatal despite surgical resection, incapacitating radiation therapy, and myelodepleting temozolomide (TMZ) chemotherapy. Adjuvant immunotherapy promises to induce robust tumor-specific immune responses that eliminate neoplastic cells with unparalleled specificity, but TMZ-induced lymphopenia would be expected to curtail the induction and persistence of productive antitumor immune responses. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of remaining lymphocytes. Thus, T-cells that predominate during this recovery period have a competitive advantage and may become disproportionately over-represented in the recovering lymphocyte population. We and others have identified this as an opportunity to enhance the preferential expansion and maintenance of ex vivo expanded and adoptively transferred anti-tumor T-cells. While high-dose IL-2 has been utilized in most human clinical trials of adoptive immunotherapy for maintenance and expansion of transferred lymphocytes, recent studies in murine models have demonstrated capacity to achieve T cell maintenance and anti-tumor efficacy using in vivo vaccination in the absence of exogenous cytokine supplementation. Given the documented neurotoxicity of IL-2 in patients with GBM, the capacity to facilitate in vivo engraftment of tumor-specific lymphocytes using concomitant vaccination is of paramount interest. Furthermore, our preliminary data demonstrate that vaccines given during the recovery from TMZ-induced lymphopenia result in dramatically enhanced humoral responses and antigen- specific T-cell frequencies in mice and humans. Although our preliminary data uses T-cells from mice with transgenic T-cell receptors to evaluate the combination of vaccine and adoptive immunotherapy in the context of TMZ, such approaches are not easily translated into human studies. Dendritic cells (DCs) loaded with the total antigenic content of tumor cells in the form of RNA (TTRNA), however, provide an innovative strategy that we and others have safely and successfully to expand tumor-specific lymphocytes against a broad repertoire of tumor antigens. Our OVERALL GOAL then is to evaluate the combination of adoptive cellular therapy and TTRNA-loaded DC vaccines during recovery from serial lymphodepletion with TMZ in a murine brain tumor model prior to clinical studies in humans. Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Vaccines are an attractive adjuvant approach to therapy for these tumors, but are thwarted by the chemotherapy used for these tumors that kills lymphocytes that might respond to these vaccines. This effect of the chemotherapy, however, actually helps maintain anti-tumor lymphocytes infused immediately after the chemotherapy so we will evaluate the combined efficacy of vaccines and transferred antitumor lymphocytes in this proposal
Keywords: 0-11 years old; 21+ years old; 2H-1, 3, 2-Oxazaphosphorin-2-amine, N, N-bis(2-chloroethyl)tetrahydro-, 2-oxide; 2H-1, 3, 2-oxazaphosphorin-2-amine, N, N-is(2-chloroethyl)tetrahydro-, 2-oxide; 3, 4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo[5, 1-d]-1, 2, 3, 5-tetrazin-4(3H)-one; ATGN; Abscission; Accounting; Active Immunotherapy; Adjuvant; Adoptive Cellular Immunotherapy; Adoptive Immunotherapy; Adult; Adverse effects; Antigens; Astrocytic Neoplasm; Astrocytic Tumor; Astrocytoma; Astrocytoma, Grade IV; Astroglioma; Autoimmune; Autoimmune Process; Autoimmune Status; Autoimmunity; Brain Neoplasia; Brain Neoplasms; Brain Tumors; CTX; CYCLO-cell; Cancer Cause; Cancer Etiology; Cancer Radiotherapy; Carloxan; Cell Growth and Maintenance; Cell Maintenance; Cell Therapy; Cessation of life; Child; Child Youth; Children (0-21); Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Co-Stimulator; Combined Vaccines; Costimulator; Coupled; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamide; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Data; Death; Dendritic Cell Vaccine; Dendritic Cells; Dose; EAE; Encephalomyelitis, Allergic; Endoxan; Endoxana; Enduxan; Engraftment; Epidermal Thymocyte Activating Factor; Essex brand of temozolomide; Excision; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Extirpation; Fosfaseron; Frequencies (time pattern); Frequency; Gene Products, RNA; Genoxal; Genuxal; Glioblastoma; Glioma, Astrocytic; Goals; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Half-Life; Half-Lifes; Hematopoietic; Human; Human, Adult; Human, Child; Human, General; IL-15; IL-2; IL-7; IL15; IL15 Protein; IL2; IL2 Protein; IL7 Protein; ITX; Immune response; Immunity; Immunologically Directed Therapy; Immunotherapy; Immunotherapy, Adoptive; Interleukin 2; Interleukin 2 Precursor; Interleukin 7 Precursor; Interleukin II; Interleukin-15; Interleukin-15 Precursor; Interleukin-2; Interleukin-7; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Killings; Ledoxina; Lymphocyte; Lymphocyte Count; Lymphocyte Mitogenic Factor; Lymphocyte Number; Lymphocytic; Lymphocytopenia; Lymphopenia; Lymphopoietin-1; MGC9721; MHC Receptor; Maintenance; Maintenances; Major Histocompatibility Complex Receptor; Malignant; Malignant - descriptor; Malignant Melanoma; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medical; Mice; Mitogenic Factor; Mitoxan; Modeling; Murine; Mus; Neosar; Operation; Operative Procedures; Operative Surgical Procedures; Opportunistic Infections; Patients; Population; Primary Brain Neoplasms; Procytox; Quality-Adjusted Life Years; RNA; RNA, Non-Polyadenylated; Radiation therapy; Radiation, Whole-Body; Radiotherapeutics; Radiotherapy; Receptors, Antigen, T-Cell; Recovery; Regimen; Removal; Ribonucleic Acid; Risk; Safety; Schering brand of temozolomide; Schering-Plough brand of temozolomide; Sendoxan; Specificity; Supplementation; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Syklofosfamid; T cell growth factor; T memory cell; T-Cell Growth Factor; T-Cell Receptor; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; Temodal; Temodar; Therapeutic; Therapy, Cell; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Total Body Irradiation; Total Lymphocyte Count; Toxic effect; Toxicities; Transgenic Organisms; Translating; Translatings; Treatment Side Effects; Tumor Antigens; Tumor Cell; Tumor-Associated Antigen; United States; Vaccination; Vaccines; Vaccines, Combination; Vaccines, Combined; Veiled Cells; Whole-Body Irradiation; Zytoxan; adoptive cell immunotherapy; adult human (21+); autoimmune encephalomyelitis; cell-based therapy; chemotherapy; children; clinical investigation; cytokine; design; designing; glioblastoma multiforme; host response; imidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; immune therapy; immunogen; immuurology; immunoresponse; improved; in vivo; innovate; innovation; innovative; interest; irradiation; language translation; lymph cell; melanoma; memory T lymphocyte; methazolastone; neoplastic cell; neuroimmunology; neuron toxicity; neuronal toxicity; neurotoxicity; new approaches; novel; novel approaches; novel strategies; novel strategy; public health relevance; resection; response; self recognition (immune); side effect; spongioblastoma multiforme; surgery; temozolomide; therapy adverse effect; thymus derived lymphocyte; transgenic; treatment adverse effect; tumor; tumor-specific antigen; tumors in the brain; vaccine efficacy; youngster
Relevance: Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Vaccines are an attractive adjuvant approach to therapy for these tumors, but is thwarted by the chemotherapy used for these tumors that kills lymphocytes that might respond to these vaccines. This effect of the chemotherapy, however, actually helps maintain anti-tumor lymphocytes infused immediately after the chemotherapy so we will evaluate the combined efficacy of vaccines and transferred antitumor lymphocytes in this proposal
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-06-181
1R21NS068057-01 (2010): $235500
PRE-CLINICAL TRANSLATION OF REGULATORY T-CELL INHIBITION IN BRAIN TUMORS
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 1R21NS067980-01 from National Institute Of Neurological Disorders And Stroke
Abstract: The most common malignant primary brain tumor, glioblastoma (GBM), remains uniformly fatal despite surgical resection and incapacitating radiation therapy. Temozolomide (TMZ) chemotherapy has shown a survival benefit in patients with GBM, but median survival remains <15 months. Immunotherapy represents a promising additional approach, but the profound lymphopenia induced by TMZ would curtail the induction of vaccine-induced antitumor immune responses. Recently, however, non-myeloablative lymphodepletion, such as that produced by TMZ, has emerged as a potent adjuvant to adoptive T-cell immunotherapy. Following periods of lymphopenia there is a homeostatic proliferation of lymphocytes designed to recover normal lymphocyte counts. Thus, T-cells that predominate during this recovery period, including those anti-tumor T-cells provided through adoptive transfer, become disproportionately represented in the recovering lymphocyte population. Unfortunately, immunosuppressive regulatory T-cells (TRegs) also undergo homeostatic proliferation after lymphodepletion. Moreover, attempts at eliminating TRegs from adoptively transferred cells are thwarted because these immunosuppressive cells are re-generated de novo from the transferred cells. While antibodies specific for the high-affinity interleukin (IL)-2 receptor alpha (IL-2R1) (CD25) have been shown to abrogate TReg function in animal models, effector T-cell functions are also inhibited. Effector T-cells may not always be dependent on IL-2 signaling, however. During homeostatic proliferation, effector T-cells enjoy a reduced activation threshold and can differentiate into effector memory T-cells directly driven by surges in cytokines that share receptors with IL-2 such as IL-7 and IL-15. Signaling through these cytokines, then, may uniquely bypass the need for IL-2 signaling in effector T-cells in this context. If so, lymphodepletion may provide a unique context wherein adoptively transferred effector T-cells may not require IL-2 signaling and may not be susceptible to inhibition by IL-2R blocking antibodies while TRegs may remain susceptible to this mode of inhibition because of their unique dependence on IL-2 specifically. Consistent with this, our preliminary studies have shown that unarmed IL-2R1-specific antibodies given to mice during recovery from transient lymphopenia, while capable of functionally inactivating TRegs actually dramatically enhance effector T-cell responses. In this proposal, we will test the HYPOTHESIS that during hematopoietic recovery from treatment-induced lymphopenia the generation of de novo TRegs from adoptively transferred anti- tumor T-cells can be selectively inhibited by anti-IL2R1 antibodies leading to enhanced antitumor immunity without induction of limiting autoimmunity. If correct, the translatability of this approach is high because daclizumab, a commercially-available, humanized IL-2R1-specific antibody, functions identically to the antibody used for TReg inactivation studies in mice. Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Immunotherapy is an attractive alternative approach to therapy for these tumors, but is thwarted by immunosuppressive cells that are over represented in patients with cancer. Antibodies that block a critical receptor on these inhibitory cells, however, may be able to be used to reduce their recovery after chemotherapy
Keywords: 0-11 years old; 21+ years old; 3, 4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo[5, 1-d]-1, 2, 3, 5-tetrazin-4(3H)-one; Abscission; Accounting; Adjuvant; Adoptive Cellular Immunotherapy; Adoptive Immunotherapy; Adoptive Transfer; Adult; Affinity; Alpha Interleukin 2 Receptor; Animal Model; Animal Models and Related Studies; Anti-Tac; Anti-Tac Humanized Monoclonal Antibody; Anti-Tac Monoclonal Antibody; AntiTac; Antibodies; Astrocytic Neoplasm; Astrocytic Tumor; Astrocytoma; Astrocytoma, Grade IV; Astroglioma; Autoimmune Status; Autoimmunity; Blocking Antibodies; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Bypass; CD25; Cancer Cause; Cancer Etiology; Cancer Radiotherapy; Cancer Treatment; Cancers; Cell Communication and Signaling; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Central Nervous System; Cessation of life; Child; Child Youth; Children (0-21); Clinical; Co-Stimulator; Costimulator; Dacliximab; Daclizumab; Daclizumab (Zenapax, Humanized Anti-Tac, HAT, Humanized Anti-IL-2R); Death; Defect; Dependence; Dose; Environment; Epidermal Thymocyte Activating Factor; Essex brand of temozolomide; Excision; Extirpation; Frequencies (time pattern); Frequency; Generations; Glioblastoma; Glioma, Astrocytic; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Hematopoietic; High Affinity Interleukin-2 Receptor; Human; Human, Adult; Human, Child; Human, General; IL-15; IL-2; IL-2Ralpha; IL-7; IL15; IL15 Protein; IL2; IL2 Protein; IL2 Receptors; IL2R; IL2RA; IL2RA gene; IL7 Protein; ITX; Immune response; Immunity; Immunologically Directed Therapy; Immunosuppressants; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Inflammatory Infiltrate; Interleukin 2; Interleukin 2 Precursor; Interleukin 2 Receptor; Interleukin 2 Receptor, Alpha; Interleukin 7 Precursor; Interleukin II; Interleukin-15; Interleukin-15 Precursor; Interleukin-2; Interleukin-7; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Interleukins; Intracellular Communication and Signaling; Lead; Lesion; Low Affinity Interleukin 2 Receptor; Lymphocyte; Lymphocyte Count; Lymphocyte Mitogenic Factor; Lymphocyte Number; Lymphocytic; Lymphocytopenia; Lymphopenia; Lymphopoietin-1; MA to TAC(IL-2 Receptor); MGC9721; Maintenance; Maintenances; Malignant; Malignant - descriptor; Malignant Melanoma; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Medical; Mice; Mitogenic Factor; Moab, Clinical Treatment; Modality; Modeling; Monoclonal Antibodies; Murine; Mus; Nervous System, CNS; Neuraxis; Operation; Operative Procedures; Operative Surgical Procedures; Organ; Patients; Pb element; Population; Primary Brain Neoplasms; Quality-Adjusted Life Years; Radiation therapy; Radiotherapeutics; Radiotherapy; Receptor Protein; Receptors, IL-2; Recovery; Regulatory T-Lymphocyte; Removal; Schering brand of temozolomide; Schering-Plough brand of temozolomide; Signal Transduction; Signal Transduction Systems; Signaling; Specificity; Subcellular Process; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; T cell growth factor; T cell response; T memory cell; T-Cell Growth Factor; T-Cell Growth Factor Receptors; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; TCGF Receptors; TCGFR; Temodal; Temodar; Testing; Therapeutic; Therapeutic Effect; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Total Lymphocyte Count; Toxic effect; Toxicities; Translations; Tumor Cell; Tumor Immunity; Tumor-Infiltrating Lymphocytes; United States; Vaccines; adoptive cell immunotherapy; adult human (21+); alpha-subunit, receptor, interleukin-2; anticancer therapy; biological signal transduction; cancer therapy; chemotherapy; children; cytokine; design; designing; glioblastoma multiforme; heavy metal Pb; heavy metal lead; host response; imidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; immune therapy; immunoresponse; immunosuppressive; interleukin-2Ralpha; irradiation; lymph cell; lymphocyte proliferation; malignancy; melanoma; memory T lymphocyte; methazolastone; model organism; neoplasm/cancer; neoplastic cell; peripheral blood; pre-clinical; preclinical; public health relevance; receptor; resection; response; self recognition (immune); spongioblastoma multiforme; surgery; temozolomide; thymus derived lymphocyte; tumor; tumors in the brain; unspecified interleukin; youngster
Relevance: Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Immunotherapy is an attractive alternative approach to therapy for these tumors, but is thwarted by immunosuppressive cells that are over represented in patients with cancer. Antibodies that block a critical receptor on these inhibitory cells, however, may be able to be used to reduce their recovery after chemotherapy
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PAR-08-232
1R21NS067980-01 (2010): $235500
ENHANCING GLIOMA IMMUNOTHERAPY WITH TEMODAR-INDUCED LYMPHOPENIA AND A MULTIVALENT
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Abstract: Seeinstructions) Project 2. Enhancing Glioma Immunotherapy with Temodar-lnduced Lymphopenia and a Multivalent Vaccine. John H. Sampson, M.D., Ph.D., M.H.Sc., Project Leader Despite the demonstrated capacity for the immune system to eliminate tumor cells with exquisite precision in preclinical models, active immunotherapy against human neoplasms has met with relatively few clinical successes. However, our vaccines targeting the tumor-specific epidermal growth factor receptor mutation, EGFRvlll, when given during recovery from temozolomide (TMZ)-induced lymphopenia have produced strong humoral and CD8+ and CD4+ T-cell responses that are accompanied by radiographic responses in all patients with residual disease and a median survival that exceeds 32 months. Vaccination eliminates EGFRvlll-expressing tumor cells. This illustrates the effectiveness of immunologic targeting, but EGFRvlll-negative tumor recurrence in this setting underscores the need to develop an effective therapy that addresses the heterogeneity of antigen expression in GBM. We believe that the potent and specific immune responses generated against EGFRvlll in our studies were potentiated by TMZ. The homeostatic proliferation that occurs after TMZ-induced lymphodepletion reduces the threshold for lymphocyte activation and proliferation. Our murine models have demonstrated that vaccine responses can be dramatically enhanced in TMZ-pretreated mice in a dose-dependent manner and dose-intensified TMZ regimens in patients with GBM have resulted in dramatically enhanced cellular and humoral responses to vaccination. These results have highlighted the potential to leverage the recovery from TMZ-induced lymphopenia as a potentially novel mechanism to enhance active immunotherapy against GBM. In an attempt to broaden the response seen when targeting EGFRvlll in this context, we propose to evaluate total tumor-RNA loaded dendritic cell vaccines. Mechanistic understanding of the effects of TMZ on the induction and maintenance of antitumor immunity will be explored in relevant murine astrocytoma models in order to rationally develop enhanced immunotherapeutic treatments for patients with GBM. RELEVANCE (See instructions) Treatment for malignant primary brain tumors is ineffective and represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the USA. The only major side effect of temozolomide, the only successful chemotherapeutic for this disease, is bone marrow suppression. We believe this suppression may dramatically enhance antitumor immunity and will investigate this possibility
Keywords: 3, 4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo[5, 1-d]-1, 2, 3, 5-tetrazin-4(3H)-one; ATGN; Active Immunotherapy; Address; Adjuvant Therapy; Adverse effects; Anthelone U; Antibodies; Antigen Targeting; Antigens; Antitumor Response; Astrocytic Neoplasm; Astrocytic Tumor; Astrocytoma; Astrocytoma, Grade IV; Astroglioma; Autoimmune Responses; Autoimmune Status; Autoimmunity; Blast Transformation; Blastogenesis; Bone Marrow Suppression; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cancer of Brain; Candida; Cells, CD4; Clinical; Data; Dendritic Cell Vaccine; Dendritic Cells; Disease; Disorder; Doctor of Medicine; Doctor of Philosophy; Dose; EAE; EGF; EGFR; ERBB Protein; ERBB1; Effectiveness; Encephalomyelitis, Allergic; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone; Essex brand of temozolomide; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Frequencies (time pattern); Frequency; Gene Expression; Gene Products, RNA; Genetic Alteration; Genetic Change; Genetic defect; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioblastoma; Glioma; Glioma, Astrocytic; Goals; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; HER1; Hematopoietic; Heterogeneity; Human; Human Urinary Gastric Inhibitor; Human, General; ITX; Immune response; Immune system; Immunity; Immunization; Immunologic Stimulation; Immunologic, Immunochemical; Immunological Stimulation; Immunologically Directed Therapy; Immunologics; Immunostimulation; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Immunotherapeutic agent; Immunotherapy; Instruction; LYT3; Lymphoblast Transformation; Lymphocyte Activation; Lymphocyte Stimulation; Lymphocyte Transformation; Lymphocytopenia; Lymphopenia; M.D.; Maintenance; Maintenances; Malignant; Malignant - descriptor; Malignant Glial Neoplasm; Malignant Glial Tumor; Malignant Glioma; Malignant Neuroglial Neoplasm; Malignant Neuroglial Tumor; Malignant Tumor of the Brain; Malignant neoplasm of brain; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medical; Mice; Modeling; Monilia; Murine; Mus; Mutation; Natural immunosuppression; Neoplasms; Neoplasms of Neuroglia; Neuroglial Neoplasm; Neuroglial Tumor; Newly Diagnosed; Normal Tissue; Normal tissue morphology; Patients; Ph.D.; PhD; Phase; Pre-Clinical Model; Preclinical Models; Primary Brain Neoplasms; Principal Investigator; Programs (PT); Programs [Publication Type]; Protocols, Treatment; Quality-Adjusted Life Years; RGM; RNA; RNA, Non-Polyadenylated; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Recovery; Recurrence; Recurrent; Regimen; Regulatory T-Lymphocyte; Residual Tumors; Ribonucleic Acid; Risk; Safety; Schering brand of temozolomide; Schering-Plough brand of temozolomide; Sensitization, Immunologic; Sensitization, Immunological; Specificity; T cell response; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; Temodal; Temodar; Thymus-Dependent Lymphocytes; Transforming Growth Factor alpha Receptor; Translating; Translatings; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tumor Antigens; Tumor Cell; Tumor-Associated Antigen; Tumors; Tumors of Neuroglia; Tumors, Residual; Urogastrone; Vaccinated; Vaccination; Vaccines; Variant; Variation; Veiled Cells; autoimmune encephalomyelitis; beta-Urogastrone; body system, allergic/immunologic; c-erbB-1; c-erbB-1 Protein; cell mediated immune response; chemotherapy; disease/disorder; effective therapy; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; genome mutation; glioblastoma multiforme; helper T cell; host response; imidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; immune therapy; immunogen; immunogenicity; immunologic preparation; immunoresponse; immunosuppression; immunotherapeutics; improved; innovate; innovation; innovative; language translation; meetings; methazolastone; neoplasia; neoplastic cell; neoplastic growth; new approaches; novel; novel approaches; novel strategies; novel strategy; organ system, allergic/immunologic; programs; proto-oncogene protein c-erbB-1; residual disease; response; safety testing; self recognition (immune); side effect; spongioblastoma multiforme; success; temozolomide; therapy adverse effect; thymus derived lymphocyte; treatment adverse effect; tumor; tumor-specific antigen; vaccine-induced immunity
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
5P50NS020023-27_8625 (2010): $247202
NINDS RESEARCH EDUCATION PROGRAMS FOR RESIDENTS AND FELLOWS IN NEUROSURGERY
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Durham, Nc 27705
Grant 5R25NS065731-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Program The brain is the most frequent site of crippling and incurable human disease. Although basic discoveries in the neurosciences are being made at an unprecedented pace, these discoveries cannot be leveraged to reduce the burden of human disease unless they are responsibly translated into human studies and critically evaluated in the context of clinical practice. While many residency training programs in Neurology or Neurosurgery provide training in the basic sciences, the later demands of clinical practice rarely permit these specialists to excel in basic science research. Neurologist and Neurosurgeons, however, have unique access to the human brain and spinal cord and to patients with neurologic disease. As such, they are ideally positioned to translate basic science discoveries into the clinical arena concurrent with their clinical practice. Formal training in the principles, costs, and responsible conduct of translational and clinical research is lacking in most medical school curricula and is non-existent in traditional residency training programs, however. Thus, there is a clear need to enhance the interest and capability of Neurologists and Neurosurgeons in training to proceed on to academic careers as clinician-scientists who will fill the need to translate basic discoveries into novel treatments designed to reduce the burden of neurological disease. The overall goal of this translational and clinical research training program is to ensure that a diverse group of residents and fellows in the clinical neurosciences become highly-trained clinician-scientists with sufficient knowledge of clinical investigation principles and regulations to become competent, responsible, and independently-funded investigators capable of translating basic discoveries into clinical practice. The program proposed here will provide a unique and rigorous, but proven, approach to engage and educate physicians focused within the neurosciences. The program will integrate didactic training within the context of the Clinical Research Training Program, a formal degree program with a thesis requirement within the School of Medicine, and mentorship by a multidisciplinary faculty with significant experience in translational and clinical research and training. Emphasis will be placed on critical interpretation of the literature, statistical methodologies, and mechanisms of funding. The Program Director and an External Advisory Board will review program and trainee performance quarterly, as well as review applicants and mentors. Trainees will be recruited during and after residency training from a local, national, and international pool. The brain is the most frequent site of crippling and incurable human disease. Important basic discoveries in the neurosciences are not being translated into clinical practice where they could reduce the burden of human neurologic disease because Neurologists and Neurosurgeons lack the requisite skills to conduct high-quality and responsible clinical and translational research. This proposal describes a program to enhance the interest and capability of Neurologists and Neurosurgeons as clinician-scientists who will fill the need to translate basic discoveries into novel treatments for human neurologic diseases
Keywords: Articulation; Basic Research; Basic Science; Brain; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Communities; Conflict of Interest; Curriculum; Development; Disease; Disorder; Doctor of Medicine; Education; Educational Curriculum; Educational aspects; Encephalon; Encephalons; Enrollment; Ensure; Faculty; Funding; Funding Mechanisms; Goals; Heterogeneity, Population; Human; Human, General; International; Investigators; Joints; Knowledge; Lead; Literature; M.D.; Man (Taxonomy); Man, Modern; Measurable; Medulla Spinalis; Mentors; Mentorship; Method LOINC Axis 6; Methodology; National Institute of Neurological Disorders and Stroke; Nervous System Diseases; Nervous System, Brain; Neurologic; Neurologic Disorders; Neurological; Neurological Disorders; Neurologist; Neurology; Neurosciences; Neurosurgeon; Patient Participation; Patients; Pb element; Performance; Physicians; Population Heterogeneity; Position; Positioning Attribute; Program Description; Program Reviews; Programs (PT); Programs [Publication Type]; Recruitment Activity; Regulation; Research; Research Personnel; Research Training; Researchers; Residencies; Resolution; Schools, Medical; Science of neurosurgery; Scientist; Site; Specialist; Spinal Cord; Training; Training Programs; Translating; Translatings; Translational Research; Translational Research Enterprise; Translational Science; Translations; Universities; base; career; clinical investigation; clinical practice; cost; design; designing; disease/disorder; diverse populations; enroll; experience; heavy metal Pb; heavy metal lead; heterogeneous population; human disease; interest; intervention design; language translation; medical schools; multidisciplinary; nervous system disorder; neurological disease; neurosurgery; novel; patient oriented research; patient oriented study; programs; public health relevance; recruit; skills; surgeon, neuro-; therapy design; translation research enterprise; treatment design
Relevance: The brain is the most frequent site of crippling and incurable human disease. Important basic discoveries in the neurosciences are not being translated into clinical practice where they could reduce the burden of human neurologic disease because Neurologists and Neurosurgeons lack the requisite skills to conduct high-quality and responsible clinical and translational research. This proposal describes a program to enhance the interest and capability of Neurologists and Neurosurgeons as clinician-scientists who will fill the need to translate basic discoveries into novel treatments for human neurologic diseases
Project start date: 2009-03-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: RFA-NS-09-001
5R25NS065731-02 (2010): $1
3R25NS065731-02S1 (2010): $54482
GENE TARGETED THERAPY OF BRAIN TUMORS
John H Sampson
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 5R21NS067975-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Primary malignant brain tumors, like glioblastoma (GBM), remain universally fatal. Like most neoplasms, they develop through the acquisition of multiple genetic alterations that lead to a heterogeneous deregulation of cell signaling pathways. Despite this complexity, recent advances in gene expression technology have been successful at providing more accurate prognostic information to patients. Still, they have little impact on patient care because they do not alter treatment choice. Innovative approaches pioneered by our group, however, offer an opportunity to identify more elaborate structure in the patterns of gene expression in these tumors by extrapolating the findings obtained with defined cell culture manipulations in vitro, such as activation of a given cell signaling pathway, to the complexity of human cancers in vivo. The resulting "gene signatures" can be thought of as a "fingerprint" shared between experimental cell cultures and patient tumors. To the degree to which they are shared, we believe these signatures have the potential to be used as guides for directing the use of targeted therapeutic agents to treat human cancers. In support of this hypothesis, we have recently shown that these gene signatures accurately predict oncogenic pathway activation and response to targeted therapeutics in various murine and human tumors. The advantage of targeting therapy to susceptible tumors is well illustrated by the examples of trastuzumab for HER2-expressing breast cancer and imatinib for Philadelphia chromosome chronic myeloid leukemia. Similarly, support for the basic concept that genetic analysis can inform targeted therapy in GBM has recently been provided in two retrospective studies - one demonstrating that O6-methylguanine-DNA methyltransferase promoter methylation can inform the use of temozolomide chemotherapy in GBM and the other identifying a significant association between clinical response to epidermal growth factor receptor (EGFR) inhibitors in patients and tumors that co-express PTEN and EGFRvIII. These studies provide evidence that molecular analysis could be used to select patients with GBM that are more likely to respond to a given therapy. These observations combined with the dismal results of studies using various single agents in GBM, suggests that the complexity and heterogeneity of GBM will need to be matched with an equally complex therapeutic combination. This is not much different than in other biologic systems, for example AIDS, leukemia, or bacterial infections, where the potency of combinatorial therapy has been evident in many early and dramatic treatment successes. Therefore, our OVERALL GOAL in this proposal is to enhance the efficacy of targeted combinatorial therapeutics for patients with brain tumors. Brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma, and treatment for these tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. Innovative analysis of genetic "fingerprints" in these and other tumors may allow therapy to be enhanced by matching specific susceptibilities of the tumor to targeted therapeutic agents. This proposal tests this "personalized" medicine approach in human tumors grown in mice as a prelude to human clinical studies
Keywords: 0-11 years old; 21+ years old; 3, 4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo[5, 1-d]-1, 2, 3, 5-tetrazin-4(3H)-one; AGT; AIDS; AIDS Virus; Accounting; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Adult; Anthelone U; Anti-ERB-2; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-p185-HER2; Assay; Astrocytoma, Grade IV; BZS; Bacterial Infections; Behavior; Bioassay; Biologic Assays; Biological Assay; Biology; Blood (Leukemia); Brain Neoplasia; Brain Neoplasms; Brain Tumors; Cancer Cause; Cancer Etiology; Cancer Genes; Cancer Radiotherapy; Cancer of Brain; Cancer of Breast; Cancer-Promoting Gene; Cancers; Cell Communication and Signaling; Cell Culture Techniques; Cell Line; Cell Lines, Strains; Cell Signaling; CellLine; Cells; Cessation of life; Characteristics; Child; Child Youth; Children (0-21); Chronic Myeloid Leukemia; Chronic Myeloid Leukemia t(9;22) (q34;q11), BCR/ABL Positive; Clinical; Clinical Research; Clinical Study; Complex; DNA-6-O-Methylguanine[protein]-L-Cysteine S-Methyltransferase; Death; Disease; Disorder; EC 2.1.1.63; EGF; EGFR; EGFR Blocker; EGFR Inhibitor; EGFR Tyrosine Kinase Inhibitor; EGFR-TK Inhibitor; EGFRvIII; ERBB Protein; ERBB1; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Inhibitor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epidermal Growth Factor-Urogastrone; Essex brand of temozolomide; Expression Profiling; Expression Signature; Fingerprint; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic analyses; Genetic defect; Genome; Genomics; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioblastoma; Glioma; Goals; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Guanine-O(6)-Alkyltransferase; HER1; HER2 Monoclonal Antibody; HIV; HTLV-III; Heterogeneity; Heterograft; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human Urinary Gastric Inhibitor; Human, Adult; Human, Child; Human, General; Imatinib; Immunologic Deficiency Syndrome, Acquired; In Vitro; Intracellular Communication and Signaling; Investigators; LAV-HTLV-III; Language; Lead; Leukemia, Granulocytic, Chronic; Leukemias, General; Lymphadenopathy-Associated Virus; MGMT; MHAM; MMAC1; Malignant Melanoma; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Brain; Malignant Tumor of the Breast; Malignant neoplasm of brain; Malignant neoplasm of breast; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Medical; Medicine; Methods; Methylated-DNA Protein-Cysteine Methyltransferase; Methylated-DNA-Protein-Cysteine S-Methyltransferase; Methylation; Mice; MoAb HER2; Molecular; Molecular Analysis; Molecular Fingerprinting; Molecular Profiling; Murine; Mus; Mutation; Myelocytic Leukemia, Chronic; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Chronic; Neoplasms; Neoplasms of Neuroglia; Neuroglial Neoplasm; Neuroglial Tumor; O(6)-AGT; O(6)-Alkylguanine-DNA Alkyltransferase; O(6)-MeG-DNA Methyltransferase; O(6)-Methylguanine DNA Transmethylase; O(6)-Methylguanine Methyltransferase; O(6)-Methylguanine-DNA Methyltransferase; O6-Alkylguanine DNA Alkyltransferase; Oncogenes; Oncogenic; Operation; Operative Procedures; Operative Surgical Procedures; PTEN; PTEN gene; PTEN1; Pathway interactions; Patient Care; Patient Care Delivery; Patients; Pattern; Pb element; Ph 1 Chromosome; Ph` Chromosome Positive Chronic Myelocytic Leukemia; Ph` Chromosome Positive Chronic Myelogenous Leukemia; Ph` Chromosome Positive Chronic Myeloid Leukemia; Ph` Positive Chronic Granulocytic Leukemia; Ph1 Chromosome; Ph1 Chromosome Positive Chronic Myelocytic Leukemia; Ph1 Chromosome Positive Chronic Myelogenous Leukemia; Ph1 Chromosome Positive Chronic Myeloid Leukemia; Ph1 Positive Chronic Granulocytic Leukemia; Philadelphia Chromosome; Philadelphia Chromosome Positive CML; Philadelphia Chromosome Positive Chronic Granulocytic Leukemia; Philadelphia Chromosome Positive Chronic Myelocytic Leukemia; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Chronic Myeloid Leukemia; Phosphatase and Tensin Homolog; Predisposition; Process; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Methylation; Quality-Adjusted Life Years; Radiation therapy; Radiotherapeutics; Radiotherapy; Receptor Protein; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Research Personnel; Researchers; Resistance; Retrospective Studies; SUBGP; Schering brand of temozolomide; Schering-Plough brand of temozolomide; Science of Medicine; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Structure; Subgroup; Surgical; Surgical Interventions; Surgical Procedure; Susceptibility; System; System, LOINC Axis 4; Targetings, Gene; Technology; Temodal; Temodar; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Transfection; Transforming Genes; Transforming Growth Factor alpha Receptor; Transplantation, Heterologous; Trastuzumab; Tumor Cell; Tumor Cell Line; Tumors; Tumors of Neuroglia; United States; Urogastrone; Virus-HIV; Work; Xenograft; Xenograft procedure; Xenotransplantation; adult human (21+); alkylguanine DNA alkyltransferase; bacterial disease; base; beta-Urogastrone; biological signal transduction; c-erb-2 Monoclonal Antibody; c-erbB-1; c-erbB-1 Protein; chemotherapy; children; combinatorial; cultured cell line; disease/disorder; epidermal growth factor receptor VIII; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; genetic analysis; genome mutation; glioblastoma multiforme; heavy metal Pb; heavy metal lead; imidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; in vivo; innovate; innovation; innovative; irradiation; leukemia; malignancy; malignant breast neoplasm; melanoma; methazolastone; methylguanine DNA methyltransferase; molecuar profile; molecular signature; neoplasia; neoplasm/cancer; neoplastic cell; neoplastic growth; new approaches; novel approaches; novel strategies; novel strategy; pathway; prognostic; proto-oncogene protein c-erbB-1; receptor; resistance mechanism; resistant; resistant mechanism; response; rhuMAb HER2; spongioblastoma multiforme; success; surgery; temozolomide; therapeutic target; tumor; tumors in the brain; vector control; youngster
Relevance: Brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma, and treatment for these tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. Innovative analysis of genetic "fingerprints" in these and other tumors may allow therapy to be enhanced by matching specific susceptibilities of the tumor to targeted therapeutic agents. This proposal tests this "personalized" medicine approach in human tumors grown in mice as a prelude to human clinical studies
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-06-181
5R21NS067975-02 (2010): $194754
1R21NS067975-01 (2009): $233754
RNA-BASED IMMUNOTHERAPY TARGETING ANTIGENS UNIQUE TO BRAIN TUMOR STEM CELLS
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Durham, Nc 27705
Grant 3R01CA135272-02S1 from National Cancer Institute
Abstract: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications A subset of cells in glioblastoma multiforme (GBM) have been identified that enjoy a unique capacity to regenerate tumors. These brain tumor stem cells (BTSC) have been segregated by the neural stem cell marker, CD133, and are widely believed to be the cells responsible for resistance to conventional therapies. An effective means of specifically eliminating these cells may reduce the need for intensive and non-specific conventional therapy and lower the risk of tumor recurrence. In our original proposal, we offered vaccines consisting of dendritic cells (DCs) loaded with amplified total tumor RNA derived from BTSCs as an innovative strategy to induce cellular and humoral antitumor immune responses against these BTSCs. Recently, temozolomide (TMZ), a myelosuppressive chemotherapy, has shown a survival benefit in patients with GBM. Unfortunately, the lymphopenia induced by TMZ would be predicted to curtail the induction of productive antitumor immune responses by such vaccines. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of the host´s remaining lymphocytes, which enjoy a lowered threshold for activation. As a result, anti-tumor lymphocytes that encounter their cognate antigen during this recovery phase, perhaps in the form of a vaccine, may have a competitive advantage and become over-represented in the recovering lymphocyte population. Our preliminary data demonstrate that peptide vaccines targeting a tumor-specific antigen, when given during the recovery from TMZ-induced lymphopenia, produced dramatically enhanced humoral responses and increased antigen-specific T-cell frequencies in mice and humans. Furthermore, increasing the dose of TMZ or treating with serial cycles of TMZ generated progressively higher T-cell frequencies in response to vaccination. These results highlight vaccination during hematopoietic recovery from serial TMZ as a novel strategy for enhancing antitumor immunity that needs to be investigated in the context of vaccines targeting BTSCs. Our Competitive Supplement would propose then to investigate the effects of TMZ on the efficacy of vaccines consisting of DCs loaded with TTRNA derived from BTSCs. Consistent with the goals of the American Recovery and Reinvestment Act, this Supplement would accelerate the tempo of our research in this area and allow for job creation and retention. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. A subset of malignant primary brain tumor cells (BTSCs), called brain tumor stem cells, enjoy a unique capacity to regenerate tumors and to resist conventional therapies. In this proposal we will see if targeting antigens preferentially or uniquely expressed by BTSCs in the context of chemotherapy-induced myelosuppression will enhance the efficacy of immunotherapy without inducing autoimmunity. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page
Keywords: 0-11 years old; 21+ years old; 3, 4-dihydro-3-methyl-4-oxoimidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide; 8-carbamoyl-3-methylimidazo[5, 1-d]-1, 2, 3, 5-tetrazin-4(3H)-one; ATGN; Accounting; Adult; Affinity; American; American Heart Association; Animal Care Assistants; Animal Care Technicians; Animal Experimental Use; Animal Experimentation; Animal Research; Animal Technicians; Animals, Laboratory; Antigen Targeting; Antigens; Area; Assay; Astrocytoma, Grade IV; Autoimmune Status; Autoimmunity; Award; Backcrossings; Bioassay; Biologic Assays; Biological Assay; Biology; Blood Precursor Cell; Bone Marrow; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Cancer Biology; Cause of Death; Cell Communication and Signaling; Cell Line, Tumor; Cell Signaling; Cells; Cessation of life; Child; Child Youth; Children (0-21); Clinical; Colony-Forming Units, Neoplastic; Commit; Complementary DNA; DNA, Complementary; Data; Death; Dendritic Cell Vaccine; Dendritic Cells; Doctor of Philosophy; Dose; EGFR; EGFRvIII; ERBB Protein; ERBB1; Education; Educational aspects; Employee; Employment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Essex brand of temozolomide; Evaluation; Experimental Animal Model; Face; Fellowship; Frequencies (time pattern); Frequency; Funding; Future; Gene Products, RNA; Generations; Genetic Alteration; Genetic Change; Genetic defect; Glioblastoma; Goals; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Grant; HER1; Harvest; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Hour; Human; Human, Adult; Human, Child; Human, General; ITX; Immune response; Immunity; Immunologic Monitoring; Immunologically Directed Therapy; Immunology procedure; Immunosurveillance; Immunotherapeutic agent; Immunotherapy; In Vitro; Intracellular Communication and Signaling; Jobs; Laboratories; Laboratory Animal Science; Laboratory Animals; Length; Lymphocyte; Lymphocyte Function; Lymphocytic; Lymphocytopenia; Lymphopenia; Malignant; Malignant - descriptor; Malignant Melanoma; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medical; Messenger RNA; Methods and Techniques; Methods, Other; Mice; Microdissection; Minority; Modeling; Molecular; Monitoring, Immune; Monitoring, Immunologic; Monitoring, Immunological; Mother Cells; Murine; Mus; Mutation; Myelosuppression; NIH; National Institutes of Health; National Institutes of Health (U.S.); Natural regeneration; Neural Stem Cell; Occupations; Organ Harvestings; Parents; Patients; Peptide Vaccines; Ph.D.; PhD; Phase; Philanthropic Fund; Population; Position; Positioning Attribute; Postdoc; Postdoctoral Fellow; Predisposition; Primary Brain Neoplasms; Procedures; Professional Postions; Progenitor Cell Transplantation; Progenitor Cells; Progenitor Cells, Hematopoietic; Protocols, Treatment; Puerto Rico; Quality-Adjusted Life Years; RGM; RNA; RNA analysis; RNA, Messenger; RNA, Non-Polyadenylated; Radiation Surgery; Radiosurgery; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Recovery; Recruitment Activity; Recurrence; Recurrent; Regeneration; Regimen; Research; Research Associate; Resistance; Reticuloendothelial System, Bone Marrow; Ribonucleic Acid; Risk; Safety; Salaries; Schering brand of temozolomide; Schering-Plough brand of temozolomide; Scholarship; Schools; Screening procedure; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Source; Specialist; Specificity; Stem Cell Transplantation; Stem Cells, Neoplastic; Stem cell transplant; Stem cells; Stereotactic External Beam Irradiation; Stereotactic Radiosurgery; Stereotaxic Radiosurgery; Susceptibility; T-Cells; T-Lymphocyte; Techniques; Temodal; Temodar; Therapeutic; Thymus-Dependent Lymphocytes; Time; Training; Transforming Growth Factor alpha Receptor; Transgenic Organisms; Treatment Efficacy; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tumor Antigens; Tumor Cell; Tumor Cell Line; Tumor Stem Cells; Tumor-Associated Antigen; United States; United States National Institutes of Health; Universities; Vaccination; Vaccines; Veiled Cells; Veterinary Assistants; Veterinary Nurses; Veterinary Technicians; Wages; Work; adult human (21+); base; biological signal transduction; c-erbB-1; c-erbB-1 Protein; cDNA; career; chemotherapy; children; conference; conventional therapy; epidermal growth factor receptor VIII; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; experience; experiment; experimental research; experimental study; facial; genome mutation; glioblastoma multiforme; host response; imidazo[5, 1-d]-1, 2, 3, 5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; immune therapy; immunogen; immunogenicity; immunologic assay; immunologic assay/test; immunologic preparation; immunoresponse; immunotherapeutics; implantation; in vivo; innovate; innovation; innovative; interest; intradermal injection; lymph cell; mRNA; meetings; melanoma; methazolastone; neoplastic cell; nerve stem cell; neural progenitor cells; neuronal progenitor; neuronal progenitor cells; new approaches; novel approaches; novel strategies; novel strategy; parent grant; post-doc; post-doctoral; pre-clinical; pre-doc; pre-doctoral; preclinical; predoc; predoctoral; prevent; preventing; progenitor; proto-oncogene protein c-erbB-1; public health relevance; recruit; regenerate; research study; resistant; response; screening; screenings; self recognition (immune); self-renewal; spongioblastoma multiforme; stem cell biology; symposium; temozolomide; therapeutic efficacy; therapeutically effective; thymus derived lymphocyte; transgenic; tumor; tumor-specific antigen; tumors in the brain; vaccine efficacy; youngster
Relevance: Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. A subset of malignant primary brain tumor cells (BTSCs), called brain tumor stem cells, enjoy a unique capacity to regenerate tumors and to resist conventional therapies. In this proposal we will see if targeting antigens preferentially or uniquely expressed by BTSCs in the context of chemotherapy-induced myelosuppression will enhance the efficacy of immunotherapy without inducing autoimmunity. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page
Project start date: 2008-08-01
Project end date: 2011-09-29
Budget start date: 30-SEP-2009
Budget end date: 29-SEP-2011
PFA/PA: PA-07-070
3R01CA135272-02S1 (2009): $407160
CMV-SPECIFIC ANTI-TUMOR IMMUNE RESPONSE IN ASTROCYTOMAS
John H Sampson, Associate Professor
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5P50CA108786-040003 from National Cancer Institute IRG: ZCA1
Abstract: Malignant gliomas (MGs) are univerally fatal, and effective therapy is limited by collateral damage to normal tissue. Immunotherapy directed against tumor-specific antigens may allow neoplastic cells to be targeted more precisely, and our dendritic cell (DC)-based vaccinations targeting of a mutated tumor-specific epidermal growth factor receptor have produced immunologic and radiographic responses in patients with MGs. The discovery that MGs, but not surrounding normal brain, serve as a refuge for Cytomegalovirus (CMV) reactivation provides an unparalleled opportunity to subvert, as a tumor-specific antigen, the highly immunogenic CMV protein, pp65. Despite the numerous advantages of targeting CMV antigens in MGs with DC-based vaccines, a number of factors clearly limit ant/tumor immune responses in these patients. Innovative complementary strategies that eliminate CD25+ regulatory T cells or block cytotoxic 3; lymphocyte antigen-4-induced T cell tolerance may enhance such immune responses, but the indiscriminate application of these potent adjuvants carries the risk of inducing autoimmune encephalomyelitis. In order to understand the limitations and risks of targeting CMV antigens in MGs, we have developed a novel murine astrocytoma cell line that supports infection with murine CMV and is tumorigenic in syngeneic mice. Our preliminary murine studies demonstrate that these tumors in the brain can be targeted with RNA-loaded DCs. We have also shown that DCs from patients with MGs that are loaded with pp65mRNA, induce interferon-gamma, production from CD4+ and CDS+ T-cells in an antigen-specific manner and incite T-cells to kill malignant astrocytes infected with human CMV. Interestingly, we have also found that CMV-specific T-cells preferentially accumulate at the tumor site in patients with MGs. We believe that our murine model system and the complementary human studies proposed will allow selection and translation of the most effective strategies for targeting CMV-associated antigens in patients with MGs, without the induction of autoimmunity. In this project, we will use the murine model, in combination with in vitro human studies to evaluate the safety of, and to gain a better understanding of the mechanisms involved in the therapeutic targeting of CMV-associated proteins in malignant gliomas. The results will then be used to rationally design and conduct a clinical CMV-targeted clinical trial.
Keywords: astrocytoma, cytomegalovirus, neoplasm /cancer immunotherapy, neoplasm /cancer vaccine, therapy design /development, vaccine development, T lymphocyte, clinical trial phase I, clinical trial phase II, dendritic cell, human therapy evaluation, nonhuman therapy evaluation, vector vaccine, biotechnology, human subject, laboratory mouse, patient oriented research
Sponsored Links Excellgen http://Excellgen.com
Dendritic Cell Immunotherapy Of Malignant Gliomas
John H Sampson, Associate Professor
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5R01CA097222-05 from National Cancer Institute IRG: ZRG1
Abstract: Despite aggressive surgical resections, high-dose radiation therapy, and toxic chemotherapy, the vast majority of patients with malignant brain tumors survive less than one year making conventional therapy for malignant brain tumors the most expensive therapy per quality-adjusted life-year saved currently provided. Moreover, the failure of these treatment modalities to be tumor-specific at the molecular level, results in inevitable damage to surrounding normal brain that incapacitates patients treated with these traditional modalities. The inherent specificity of immunologic recognition offers the prospect of targeting malignant cells more precisely. Several studies have documented the exceptional ability of dendritic cells (DCs) to activate the immune system and produce encouraging human antitumor responses. The epidermal growth factor mutation, EGFRvIII, found on the majority of malignant gliomas, represents a tumor-specific target for such an approach. Our preclinical results demonstrate that DCs loaded with a KLH conjugate of an EGFRvIII peptide induce potent humoral and cell-mediated immune responses. Although anti-EGFRvIII, DC-based immunotherapy will allow antigen-specific immune responses to be clearly monitored and potentially optimized, we believe that human antitumor responses will likely be enhanced and the spectrum and utility of this paradigm expanded by targeting additional antigens. However, existing techniques for identifying potential targets are labor intensive, do not systematically assess the entire neoplastic genome, and do not assess the potential risk of autoimmunity posed by targeting these antigens. Serial analysis of gene expression (SAGE) is a contemporary approach to gene expression analysis that allows rapid identification of genes that are over-expressed in neoplastic cells. SAGE databased mining and rapid expression screening has allowed our group to identify a large number of genes uniquely expressed in malignant gliomas that may function as specific tumor antigens. To select those with immunologic relevance and those that are unlikely to induce autoimmune reactivity, we have developed a unique system based on the loading of autologous DCs with genes or gene fragments. Using this technique, we have demonstrated that DCs loaded with tumor-specific RNAs can specifically activate autologous T cells without activating autoreactive T cells. The hypothesis to be tested in this project is that malignant gliomas can be selectively targeted for therapeutic immunotherapy without the induction of autoimmunity using DCs loaded with the tumor-specific EGFRvIII and other additional genes found by SAGE to be uniquely expressed by malignant gliomas.
Keywords: dendritic cell, epidermal growth factor, glioma, growth factor receptor, human therapy evaluation, neoplasm /cancer immunotherapy, receptor expression, antigen antibody reaction, antitumor antibody, autoimmunity, clinical trial phase I, colony stimulating factor, dosage, gene mutation, immunity, immunosuppression, interleukin 4, monocyte, tumor antigen, clinical research, human subject, leukapheresis, patient oriented research, serial analysis of gene expression
Project start date: 2002-09-30
Project end date: 2008-08-31
5R01CA097222-05 (2006): $300762
5R01CA097222-04 (2005): $308000
5R01CA097222-03 (2004): $305300
5R01CA097222-02 (2003): $305300
1R01CA097222-01 (2002): $299633
Intracerebral Infusion Of Radiolabeled Specific Antibody
John H Sampson, Associate Professor
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5R01CA097611-05 from National Cancer Institute IRG: ZRG1
Abstract: Despite aggressive surgical resections, high-dose radiation therapy, and chemotherapy delivered at toxic doses, the vast majority of patients with malignant brain tumors survive less than one year making conventional therapy for malignant brain tumors the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. Moreover, the failure of these treatment modalities to be tumor-specific at the molecular level, results in inevitable damage to surrounding normal brain that incapacitates patients treated with these traditional modalities. The inherent specificity of immunologic recognition offers the prospect of targeting malignant cells more precisely. Within our program, direct injection of 131-I-labeled, operationally-specific, monoclonal antibodies (MAbs) into brain tumor resection cavities delivers extremely high radiation doses to tumor cells around the resection cavity and has produced promising results in Phase II clinical trials. These MAbs diffuse only short distances beyond the cavity, however. Therefore, most of the radiation extending beyond the cavity is not specifically targeted to tumor cells and the radiation dose delivered beyond the cavity declines exponentially from the cavity interface. As a result tumor cells that are known to infiltrate the brain for significant distances beyond the cavity are sub-optimally treated and lethal tumors always recur within 2 cm of the radiated re section cavity. Continuous microinfusion is a promising technique that allows homogeneous delivery of even large molecular weight molecules at high concentrations throughout large areas of the brain. Although this technique may enhance the delivery of 131-I-labeled MAbs and other therapeutic agents to diffusely infiltrating malignant brain tumors and reduce recurrence rates, the parameters that govern this technique and its limitations have not been defined. One of the major goals of this proposal is to define these parameters. In addition, this proposal is designed to investigate whether targeted radiotherapy might be improved through the use of human chimeric MAbs with increased biostability and the use of high linear energy transfer radioisotopes, such as 211-At, with greater relative biological effectiveness.The hypothesis to be tested in this proposal is that continuous microinfusion will widely deliver operationally tumor-specific monoclonal antibodies conjugated to 131-I or the alpha-emitter 211-At such that they will be specific and potent therapeutic agents against malignant brain tumors with major reductions in toxicity to normal brain.
Keywords: antibody specificity, brain neoplasm, human therapy evaluation, injection /infusion, monoclonal antibody, neoplasm /cancer radioimmunotherapy, radiotracer, clinical trial phase I, dosage, drug screening /evaluation, neurotoxicology, nuclear medicine, tenascin, biotechnology, clinical research, human subject, patient oriented research
Project start date: 2002-09-30
Project end date: 2008-08-31
5R01CA097611-05 (2006): $300762
5R01CA097611-04 (2005): $308000
Sponsored Links Excellgen http://Excellgen.com
5R01CA097611-03 (2004): $308000
5R01CA097611-02 (2003): $308000
1R01CA097611-01 (2002): $308000
MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW
John H Sampson, Associate Professor
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5K23RR016065-05 from National Center For Research Resources IRG: RIRG
Abstract: Adapted from s ) The brain is the most frequent site of crippling and incurable human disease, and malignant primary brain tumors alone are more common than Hodgkin s disease, and cause more deaths than cancer of the bladder or kidney, leukemia, or melanoma. Conventional therapy for malignant brain tumors is ineffective and incapacitating, and represents the most expensive medical therapy per quality- adjusted life-year saved currently provided in the U.S. At the investigators institution, direct injection of (131)I-labeled, operationally-specific, monoclonal antibodies (MAbs) into brain tumor resection cavities delivers extremely high radiation doses to tumor cells around the resection cavity and has produced promising results in Phase II clinical trials. However, these MAbs diffuse only short distances beyond the cavity. Therefore, most of the radiation extending beyond the cavity is not specifically targeted to tumor cells and the radiation dose delivered beyond the cavity declines exponentially from the cavity interface. As a result, tumor cells that are known to infiltrate the brain for significant distances beyond the cavity are subopitimally treated and lethal tumors always recur within 2cm of the radiated resection cavity. Continuous microinfusion is a promising technique that allows homogeneous delivery of even large molecular weight molecules at high concentrations throughout large areas of the brain. Although this technique may enhance the delivery of (131)I-labeled MAbs and other therapeutic agents to diffusely infiltrating malignant brain tumors and reduce recurrence rates, the parameters that govern this technique and its limitations have not been defined. One of the major goals of this proposal is to define these parameters. In addition, this proposal is designed to investigate whether targeted radiotherapy might be improved through the use of human chimeric MAbs with increased biostability and the use of high linear energy transfer radioisotopes, such as (211)At, with greater relative biological effectiveness. The hypothesis to be tested in this proposal is that continuous microinfusion will widely deliver operationally tumor-specific MAbs conjugated to (131)I or the alpha-emitter (211)At such that they will be specific and potent therapeutic agents against malignant brain tumors with major reductions in toxicity to normal brain over conventional whole brain radiotherapies.
Keywords: brain neoplasm, combination cancer therapy, human therapy evaluation, monoclonal antibody, neoplasm /cancer immunotherapy, neoplasm /cancer radiation therapy, chimeric protein, clinical trial phase I, cytotoxicity, drug delivery system, glioma, neoplasm /cancer relapse /recurrence, neoplastic cell, outcomes research, radiation dosage, tenascin, tumor antigen, tumor progression, clinical research, human subject, linear energy transfer, microinjection, radionuclide
Project start date: 2000-09-01
Project end date: 2005-08-31
5K23RR016065-05 (2004): $125496
5K23RR016065-04 (2003): $125496
5K23RR016065-02 (2001): $125253
1K23RR016065-01 (2000): $125172
RNA-BASED IMMUNOTHERAPY TARGETING ANTIGENS UNIQUE TO BRAIN TUMOR STEM CELLS
John H Sampson, Associate Professor
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 5R01CA135272-03 from National Cancer Institute
Abstract: A subset of cells in glioblastoma multiforme (GBM) has been identified that enjoy a unique capacity to regenerate tumors. These brain tumor stem cells (BTSC) can be segregated by the neural stem cell marker, CD133, and are widely believed to be the cells responsible for resistance to conventional therapies. An effective means of specifically eliminating these cells may reduce the need for intensive and non-specific conventional therapy and lower the risk of tumor recurrence. EGFRvIII is a tumor-specific mutation found on BTSC. We have successfully targeted EGFRvIII using a peptide vaccine that allowed rapid translation to an ongoing Phase III trial. EGFRvIII expression is heterogeneous, however, and the recurrence of EGFRvIII-negative tumors suggests that BTSC can rely on other oncogenic pathways. While our data suggests that targeting tumor-specific mutations in BTSC may be important, few highly-conserved tumor-specific mutations like EGFRvIII will be identified and antigen defined vaccine approaches will ultimately be limited. Dendritic cells (DCs) loaded with amplified total tumor RNA is an innovative strategy to induce cellular and humoral antitumor immune responses. Although CD133(+) BTSC are a minority subpopulation of GBM that cannot be reliably isolated or propagated in sufficient quantities to serve as an antigen source for human vaccination protocols, we have been able to reproducibly amplify the RNA content from as few as 500 sorted CD133(+) tumor cells to generate RNA libraries sufficient for clinical scale DC-based vaccination. In order to focus the immunologic response on antigens preferentially or uniquely expressed within BTSC and limit the potential for autoimmune reactivity against shared antigens expressed in normal cells, we will evaluate approaches to enrich for antigens preferentially or uniquely expressed in BTSC by using full length cDNA affinity based substractive hybridization or an innovative strategy that leverages the ability of the DNA mismatch binding protein, MutS, to isolate cDNAs that contain tumor-specific mutations. These various preparations will be evaluated for differential toxicity and efficacy in an inbred transgenic murine malignant astrocytoma model, in which a subpopulation of CD133(+) tumor cells with BTSC qualities have been identified and CD8(+) and CD4(+) epitopes have been found. If efficacy is seen, the least toxic strategy will be translated into a Phase I study within the context of our existing clinical trial platform. Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. A subset of malignant primary brain tumor cells (BTSCs), called brain tumor stem cells, enjoy a unique capacity to regenerate tumors and to resist conventional therapies. In this proposal we will see if targeting antigens preferentially or uniquely expressed by BTSCs will enhance the efficacy and reduce toxicity of immunotherapy
Keywords: 0-11 years old; 21+ years old; ATGN; Accounting; Adult; Affinity; Anaplastic Astrocytic Neoplasm; Anaplastic Astrocytic Tumor; Anaplastic astrocytoma; Anthelone U; Antigen Targeting; Antigenic Determinants; Antigens; Astrocytoma, Grade III; Astrocytoma, Grade IV; Autoimmune; Autoimmune Process; Autoimmune Status; Autoimmunity; Binding Determinants; Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; CD8; CD8B; CD8B1; CD8B1 gene; Cause of Death; Cell surface; Cells; Cessation of life; Child; Child Youth; Children (0-21); Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Phase II; Clinical Trials, Phase III; Clinical Trials, Unspecified; Colony-Forming Units, Neoplastic; Complementary DNA; DNA; DNA mismatch repair protein mutS; DNA, Complementary; Data; Death; Dendritic Cells; Deoxyribonucleic Acid; EGF; EGFRvIII; Early-Stage Clinical Trials; Encephalon; Encephalons; Epidermal Growth Factor; Epidermal Growth Factor-Urogastrone; Epitopes; Figs; Figs - dietary; Gene Products, RNA; Genes; Genetic Alteration; Genetic Change; Genetic defect; Glioblastoma; Grade III Astrocytic Neoplasm; Grade III Astrocytic Tumor; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Heterogeneity; Human; Human Urinary Gastric Inhibitor; Human, Adult; Human, Child; Human, General; ITX; Immune response; Immunocompetent; Immunologic, Immunochemical; Immunologically Directed Therapy; Immunologics; Immunotherapeutic agent; Immunotherapy; LYT3; Lead; Length; Libraries; Malignant; Malignant - descriptor; Malignant Astrocytoma; Malignant Melanoma; Mammals, Mice; Man (Taxonomy); Man, Modern; Medical; Mesenchymal Progenitor Cell; Mesenchymal Stem Cells; Messenger RNA; Methods and Techniques; Methods, Other; Mice; Minority; Modeling; Molecular; Molecular Target; Murine; Mus; MutS DNA mismatch-binding protein; Mutation; Natural regeneration; Nervous; Nervous System, Brain; Neural Stem Cell; Normal Cell; Oncogenic; Pathway interactions; Patients; Pb element; Peptide Vaccines; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase 3 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Phase III Clinical Trials; Physiologic pulse; Predisposition; Preparation; Primary Brain Neoplasms; Property; Property, LOINC Axis 2; Proteins; Protocol; Protocols documentation; Pulse; Quality-Adjusted Life Years; RNA; RNA library; RNA, Messenger; RNA, Non-Polyadenylated; RT-PCR; RTPCR; Radiation; Recurrence; Recurrent; Regeneration; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic Acid; Risk; Safety; Sorting - Cell Movement; Source; Stem Cells, Neoplastic; Susceptibility; Techniques; Testing; Therapeutic; Toxic effect; Toxicities; Transgenic Organisms; Translating; Translatings; Translations; Transplantation; Tumor Antigens; Tumor Cell; Tumor Stem Cells; Tumor-Associated Antigen; United States; Urogastrone; Vaccination; Vaccines; Veiled Cells; adult human (21+); base; beta-Urogastrone; cDNA; chemotherapy; children; clinical investigation; conventional therapy; epidermal growth factor receptor VIII; gene product; genome mutation; glioblastoma multiforme; heavy metal Pb; heavy metal lead; host response; immune therapy; immunogen; immunogenicity; immunologic preparation; immunoresponse; immunotherapeutics; innovate; innovation; innovative; language translation; mRNA; malignant astrocyte; melanoma; neoplastic cell; nerve stem cell; neural; neural progenitor cells; neuronal progenitor; neuronal progenitor cells; novel; pathway; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase 3 study; phase 3 trial; phase I trial; phase II trial; phase III trial; protocol, phase I; protocol, phase II; protocol, phase III; public health relevance; ray (radiation); regenerate; relating to nervous system; resistant; response; reverse transcriptase PCR; self recognition (immune); self-renewal; sorting; spongioblastoma multiforme; study, phase II; study, phase III; transgenic; transplant; tumor; tumor-specific antigen; tumors in the brain; vaccination strategy; youngster
Project start date: 2008-08-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-07-070
5R01CA135272-03 (2010): $523631
5R01CA135272-02 (2009): $256854