Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: The subject matter disclosed herein is generally directed to novel CD8+ and CD4+ T cell subtypes associated with effector, suppressive or regulatory T cell functions. Moreover, the subject matter disclosed herein is generally directed to methods and compositions for use of the subtype. Also, disclosed herein are gene signatures and markers associated with the subtype and use of said signatures and markers. Further disclosed are therapeutic methods of using said gene signatures and immune cell subtype. Further disclosed are pharmaceutical compositions comprising populations of CD4+ and/or CD8+ TILs or populations of immune cells depleted for a specific subtype. Further disclosed are interactions with other T cell subtypes.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: The subject matter disclosed herein is generally directed to novel CD8+ tumor infiltrating lymphocyte (TIL) subtypes associated with response to immunotherapy treatment. Specifically, the subtypes are associated with checkpoint blockade therapy. Moreover, the subject matter disclosed herein is generally directed to methods and compositions for use of the subtypes. Also, disclosed herein are gene signatures and markers associated with the subtypes and use of said signatures and markers. Further disclosed are therapeutic methods of using said gene signatures and immune cell subtypes. Further disclosed are pharmaceutical compositions comprising populations of CD8+ TILs enriched for a specific subtype.

Abstract: Described herein are compositions and methods for the modulation of T-cell tolerance, which can be upregulated or down regulated by concurrent enhancement or inhibition of CEACAM1/TIM3 interactions. As described herein, the discovery that CEACAM1 is a direct ligand of TIM3 and vice versa has been shown in cis and in trans. In addition, as demonstrated herein, CEACAM1 and TIM3 are co-regulated during the course of T-cell activation.

Abstract: Described herein are compositions and methods for the modulation of T-cell tolerance, which can be upregulated or down regulated by concurrent enhancement or inhibition of CEACAM1/TIM3 interactions. As described herein, the discovery that CEACAM1 is a direct ligand of TIM3 and vice versa has been shown in cis and in trans. In addition, as demonstrated herein, CEACAM1 and TIM3 are co-regulated during the course of T-cell activation.

Abstract: Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network as well as novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module.

Abstract: Described herein are methods and compositions for treatment of immune-related diseases or disorders and/or therapy monitoring based on the level of TIGIT, Flg2 and/or IL-33 expression and/or activity. In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of cancer and/or infections (e.g., chronic viral infection, intracellular and/or extracellular bacterial infection, and/or fungal infection). In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of autoimmune diseases and/or inflammation (e.g., caused by parasitic infection). In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of asthma, allergy, and/or atopy. Methods for identifying patients who are more likely to be responsive to and benefit from an immunotherapy that targets TIGIT, Fg12 and/or IL-33 are also described herein.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: Described herein are methods and compositions for treatment of immune-related diseases or disorders and/or therapy monitoring based on the level of TIGIT, Flg2 and/or IL-33 expression and/or activity. In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of cancer and/or infections (e.g., chronic viral infection, intracellular and/or extracellular bacterial infection, and/or fungal infection). In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of autoimmune diseases and/or inflammation (e.g., caused by parasitic infection). In some embodiments, the methods and compositions described herein are directed to treatment and/or therapy monitoring of asthma, allergy, and/or atopy. Methods for identifying patients who are more likely to be responsive to and benefit from an immunotherapy that targets TIGIT, Fgl2 and/or IL-33 are also described herein.

Abstract: Described herein are novel compositions comprising MT1 and/or MT2 modulators (i.e., inhibitors or activators), and methods using these agents for targeting different T-cell populations, for example, type 1 regulatory (Tr1) CD4+ cells and exhausted CD8+ T-cells cells. Aspects of the invention relate to inhibitors of MT1 and/or MT2 to increase the differentiation of CD4+ cell Trl1 CD4+ cells and increase in the activity of Tr1 cells, e.g., to increase IL-10 production. In alternative embodiments, MT1 and/MT1 inhibitors can be used to increase proliferation and/or activity of exhausted CD8+ T-cells and to decrease CD8+ T-cell exhaustion (e.g., decrease functionally exhausted or unresponsive CD8+ immune cells). Accordingly, aspects of the present invention relate to compositions and methods comprising inhibitors of MT1 and/or MT2 useful in the treatment of chronic immune conditions, such as persistent infections, cancer, and autoimmune disease.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: Described herein are compositions and methods for the modulation of T-cell tolerance, which can be upregulated or down regulated by concurrent enhancement or inhibition of CEACAM1/TIM3 interactions. As described herein, the discovery that CEACAM1 is a direct ligand of TIM3 and vice versa has been shown in cis and in trans. In addition, as demonstrated herein, CEACAM1 and TIM3 are co-regulated during the course of T-cell activation.

Abstract: Described herein are novel compositions comprising bispecific and multispecific polypeptide agents, and methods using these agents for targeting cells, such as functionally exhausted or unresponsive immune cells, that co-express the inhibitory receptors PD-1 and TIM-3. These compositions and methods are useful for the treatment of chronic immune conditions, such as persistent infections or cancer.

Abstract: The invention provides novel methods of treating neurological disorders, including neurodegenerative disorders such as MS. The invention also provides novel methods of treating cancers, including glial tumors such as glioblastoma multiforme. The invention further provides vaccines and related uses.