The present invention provides cell which co-expresses a chimeric antigen receptor (CAR) and a dominant negative C-terminal Src kinase (dnCSK). The present invention also provides nucleic acid constructs, vectors and methods for making such a cell and the use of such a cell in the treatment of diseases such as cancer by adoptive immunotherapy.

The present invention provides methods for inhibiting Fyn kinase, using 5-3-pyridin-2-amine, 6-3-imidazo[1,2-a] pyrazine, 6-3-imidazo[1,2-b] pyridazine, N-(5-imidazo [2,1-b][1,3,4] thiadiazol-2-yl)-amine, 4-3-1H-pyrazolo[3,4-b] pyridine, and N-(3-imidazo [1,2-b] pyridazin-6-yl) amine compounds and methods of treatment, prevention, inhibition or amelioration of diseases and conditions associated with Fyn kinase using such compounds.

Provided are engineered T-cell receptors comprising fusion proteins comprising a transmembrane domain and an intracellular domain capable of providing a stimulatory signal or an inhibitory signal, and immune cells comprising same.

In the present invention it is shown that the inactivation of the Pyk2 gene does not alter hippocampal development but prevents hippocampal-dependent memory tasks and LTP. Inventors clearly provide evidence for multiple roles of Pyk2 in spine morphology and postsynaptic structure. Thus, the inventors used direct overexpression of PYK2 by AAV-mediated gene transfer into the brain of Huntington's and Alzheimer's mouse models and found that overexpression of PYK2 in these 2 models improves synaptic properties and spine density deficits which is also accompanied by a rescue of spatial memory. Accordingly it was demonstrated that PYK2 may restore cognitive functions in neurodegenerative diseases. Thus the present invention relates to methods and pharmaceutical compositions for the treatment of neurodegenerative disease. In particular the present invention relates to a method of treating neurodegenerative disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a vector which comprises a nucleic acid molecule encoding for PYK2 polypeptide.

The disclosure features isolated polynucleotides, such as mRNAs, encoding a polypeptide that disrupts immune cell activity, such as T cell or B cell activity, including mRNAs comprising one or more modified nucleobase. The immune cell disruptor polynucleotides encode a polypeptide that comprises a first domain that mediates association of the polypeptide with an immune cell component and a second domain that mediates inhibition of immune cell activity when the polypeptide is expressed in the immune cell. The disclosure also features methods of using the same, for example, for inhibiting immune responses when administered to a subject, such as to inhibit autoimmune reactions.

A trigger-responsive immune-inactivating signaling polypeptide disclosed herein can include a modulating domain and an immune-inactivating moiety, such as a dominant negative signaling moiety or constitutively active signaling moiety. A modulating domain can be characterized by an ability to adopt a first state and a second state, and to transition between the first state and the second state when exposed to a trigger. When the modulating domain is in its first state, the immune-inactivating signaling moiety can be inhibited, and when the modulating domain is in its second state, the inhibition can be relieved. Further disclosed herein are compositions for the delivery of a trigger-responsive immune-inactivating signaling polypeptide. Also, methods for using a trigger-responsive immune-inactivating signaling polypeptide, including to regulate an activity of immune system cells, are disclosed.

In certain embodiments methods of treating X-Linked Hyper-IgM Syndrome (XHIM) in a mammal am provided where the methods comprise: i) providing differentiated T cells and/or stem/progenitor cells from the mammal; ii) performing a targeted insertion of a corrective CD40L cDNA at the CD40LG gene locus in said cells to provide a corrected CD40LG gene wherein said targeted insertion places said corrective CD40L cDNA downstream and operably linked to the endogenous CD40LG enhancer/promoter, and iii) introducing said cells into said mammal where said corrected CD40LG gene is expressed in a physiologically regulated manner.

There is provided an effector immune cell which expresses a cell surface receptor or receptor complex which specifically binds an antigen recognition receptor of a target immune cell; which effector immune cell is engineered such that when a synapse is formed between the effector immune cell and the target immune cell, the capacity of the effector immune cell to kill the target immune cell is greater than the capacity of the target immune cell to kill the effector immune cell. There is also provided the use of such a cell in methods for treating cancer, preventing allograft rejection and GVHD.

The present invention provides a nucleic acid molecule comprising a polynucleotide sequence encoding a chimeric receptor, particularly a chimeric antigen receptor (CAR), wherein said chimeric receptor comprises an endodomain comprising (i) a STAT5 association motif, and a JAK1 and/or JAK2 binding motif and (ii) a JAK3 binding motif, wherein (i) and (ii) are connected by a linker or hinge.

Provided are methods for the identification of mutant kinases that are resistant to inhibition by a kinase inhibitor. In some embodiments, the methods may be used to assess a test compound or kinase inhibitor for the risk of the development of resistance in vivo, e.g., during clinical administration to treat a disease such as a cancer.