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1.
Immunity ; 44(1): 179-193, 2016 Jan 19.
Article in English | MEDLINE | ID: mdl-26789923

ABSTRACT

Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen-specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrated that the clonal abundance of CD4(+) T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor-specific CD4(+) T cell population. However, through clonally derived help, this population acquired a polyfunctional effector phenotype and antitumor immunity was enhanced. Conversely, development of effector function was attenuated at low precursor frequencies due to irreversible T cell exhaustion. Our findings assert that the differential effects of T cell clonal abundance on phenotypic outcome should be considered during the design of adoptive T cell therapies, including use of engineered T cells.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Melanoma, Experimental/immunology , Tumor Escape/immunology , Adoptive Transfer , Animals , Cell Separation , Flow Cytometry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
2.
Adv Cancer Res ; 128: 1-68, 2015.
Article in English | MEDLINE | ID: mdl-26216629

ABSTRACT

Using the immune system to control cancer has been investigated for over a century. Yet it is only over the last several years that therapeutic agents acting directly on the immune system have demonstrated improved overall survival for cancer patients in phase III clinical trials. Furthermore, it appears that some patients treated with such agents have been cured of metastatic cancer. This has led to increased interest and acceleration in the rate of progress in cancer immunotherapy. Most of the current immunotherapeutic success in cancer treatment is based on the use of immune-modulating antibodies targeting critical checkpoints (CTLA-4 and PD-1/PD-L1). Several other immune-modulating molecules targeting inhibitory or stimulatory pathways are being developed. The combined use of these medicines is the subject of intense investigation and holds important promise. Combination regimens include those that incorporate targeted therapies that act on growth signaling pathways, as well as standard chemotherapy and radiation therapy. In fact, these standard therapies have intrinsic immune-modulating properties that can support antitumor immunity. In the years ahead, adoptive T-cell therapy will also be an important part of treatment for some cancer patients. Other areas which are regaining interest are the use of oncolytic viruses that immunize patients against their own tumors and the use of vaccines against tumor antigens. Immunotherapy has demonstrated unprecedented durability in controlling multiple types of cancer and we expect its use to continue expanding rapidly.


Subject(s)
Antineoplastic Agents/therapeutic use , Immunotherapy , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/immunology , Animals , B7-H1 Antigen/antagonists & inhibitors , Humans , Signal Transduction/drug effects , T-Lymphocytes/drug effects
3.
Blood ; 123(14): 2172-80, 2014 Apr 03.
Article in English | MEDLINE | ID: mdl-24558202

ABSTRACT

Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4(+) T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies.


Subject(s)
Anaphylaxis/immunology , Antibodies, Monoclonal/adverse effects , Glucocorticoid-Induced TNFR-Related Protein/agonists , Animals , Antibodies, Monoclonal/administration & dosage , Antigens, Differentiation/administration & dosage , B-Lymphocytes/physiology , CD4-Positive T-Lymphocytes/physiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Glucocorticoid-Induced TNFR-Related Protein/genetics , Glucocorticoid-Induced TNFR-Related Protein/immunology , Injections, Intraperitoneal , Interleukin-4/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Tumor Cells, Cultured
4.
Curr Opin Immunol ; 24(2): 217-24, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22245556

ABSTRACT

Modulation of co-inhibitory and co-stimulatory receptors of the immune system has become a promising new approach for immunotherapy of cancer. With the recent FDA approval of CTLA-4 blockade serving as an important proof of principal, many new targets are now being translated into the clinic. Preclinical research has demonstrated that targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR), a member of TNF receptor superfamily, by agonist antibodies or natural ligand, can serve as an effective anti-tumor therapy. In this review, we will cover this research and the rationale that has led to initiation of two phase 1 clinical trials targeting GITR as a new immunotherapeutic approach for cancer.


Subject(s)
Glucocorticoid-Induced TNFR-Related Protein/immunology , Immunotherapy , Neoplasms/therapy , Animals , Humans , Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Up-Regulation
5.
Physiol Genomics ; 28(1): 67-75, 2006 Dec 13.
Article in English | MEDLINE | ID: mdl-17062651

ABSTRACT

Mycobacterium avium subspecies paratuberculosis (MAP) and Mycobacterium avium subspecies avium (MAA) represent two closely related intracellular bacteria with vastly different associated pathologies. MAA can cause severe respiratory infections in immune compromised humans but is nonpathogenic in ruminants and is more readily controlled by the bovine immune system than MAP. MAP causes a fatal wasting syndrome in ruminants, typified by granulomatous enteritis localized in the small intestine. MAP has also been cited as a potential cause of human Crohn's disease. We used a bovine immune-specific microarray (BOTL-5) to compare the response of mature bovine monocyte-derived macrophages (MDM cells) to MAP and MAA. Statistical analysis of microarray data revealed 21 genes not appreciably expressed in resting MDM cells that were activated following infection with either MAA or MAP. Further analysis revealed 144 genes differentially expressed in MDM cells following infection with MAA and 99 genes differentially expressed following infection with MAP. Of these genes, 37 were affected by both types of mycobacteria, with three being affected in opposite directions. Over 41% of the differentially expressed genes in MAA and MAP infected MDM cells were members of, regulated by, or regulators of the MAPK pathways. Expression of selected genes was validated by quantitative real-time reverse transcriptase PCR and in several key genes (i.e., IL-2 receptor, tissue inhibitor of matrix metalloproteinases-1, and Fas-ligand) MAA was found to be a stronger activating factor than MAP. These gene expression patterns were correlated with prolonged activation of p38 MAPK and ERK1/2 by MAA, relative to MAP.


Subject(s)
Gene Expression , Macrophages/metabolism , Macrophages/microbiology , Mycobacterium avium subsp. paratuberculosis/pathogenicity , Mycobacterium avium/pathogenicity , Animals , Cattle , Gene Expression Profiling , MAP Kinase Signaling System , Mycobacterium avium/immunology , Mycobacterium avium subsp. paratuberculosis/immunology , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction
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