Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

The present invention relates to sustained-release formulations and dosage forms of ruxolitinib, or a pharmaceutically acceptable salt thereof, which are useful in the treatment of Janus kinase-associated diseases such as myeloproliferative disorders.

The emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). LSCs are heterogeneous for their phenotypes and their sensitivity to chemotherapeutic agents in vivo. Using in silico and functional approaches, the inventors uncovered that CALCRL is overexpressed in LSCs compared with normal hematopoietic cells. They further demonstrated that the CALCRL ligand adrenomedullin (ADM) is highly expressed in AML cells and that increased transcript level was markedly associated with decreased complete remission rates, 5-year overall and event7free survival. The inventors also showed that CALCRL depletion strongly affected leukemic growth in vivo and increased mice survival. Targeting ADM phenocopies the biological and anti-leukemic effects of the CALCRL depletion. These data highlight the critical role of ADM and disclose a promising therapeutic target to specifically eradicate R-LSCs and overcome relapse in AML.

The emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). LSCs are heterogeneous for their phenotypes and their sensitivity to chemotherapeutic agents in vivo. Using in silico and functional approaches, the inventors uncovered that CALCRL is overexpressed in LSCs compared with normal hematopoietic cells. They further demonstrated that the CALCRL ligand adrenomedullin (ADM) is highly expressed in AML cells and that increased transcript level was markedly associated with decreased complete remission rates, 5-year overall and event7free survival. The inventors also showed that CALCRL depletion strongly affected leukemic growth in vivo and increased mice survival. Targeting ADM phenocopies the biological and anti-leukemic effects of the CALCRL depletion. These data highlight the critical role of ADM and disclose a promising therapeutic target to specifically eradicate R-LSCs and overcome relapse in AML.

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

The present invention relates to combination therapies useful for the treatment of cancer. In particular, the invention relates to the combined use of a PD-1 inhibitor, a TGFβ inhibitor, an ATM inhibitor and radiation to treat cancer.

The present invention relates to combination therapies useful for the treatment of cancer. In particular, the invention relates to the combined use of a PD-1 inhibitor, a TGFβ inhibitor, an ATM inhibitor and radiation to treat cancer.

Disclosed are compounds, compositions and methods for treating diseases, disorders, or medical conditions that are affected by the modulation of DHODH. Such compounds are represented by Formula (I) as follows:

##STR00001##

wherein R.sup.1a, R.sup.1b, R.sup.2, and R.sup.3, are defined herein.

Disclosed are compounds, compositions and methods for treating diseases, disorders, or medical conditions that are affected by the modulation of DHODH. Such compounds are represented by Formula (I) as follows:

##STR00001##

wherein R.sup.1a, R.sup.1b, R.sup.2, and R.sup.3, are defined herein.