The present disclosure provides synthetic modular polypeptide libraries and nucleic acids encoding such synthetic modular polypeptide libraries. Also provided are methods of making synthetic modular polypeptide libraries and nucleic acids encoding synthetic modular polypeptide libraries. Methods of screening a synthetic modular polypeptide library to identify a selected phenotype associated with a member of a synthetic modular polypeptide library are also provided where such methods find use in both in vitro and in vivo assays.

The present invention discloses a chimeric antigen receptor (CAR) comprising an antigen binding domain specific for BDCA2, a population of engineered cells expressing said CAR and a pharmaceutical composition thereof. Said engineered cells are for treatment of cancer in a subject, wherein the cancerous cells of said cancer express BDCA2 such as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).

The present invention discloses cell lines and recombinant growth factor receptors useful in adoptive cell therapy (ACT), wherein the recombinant growth factor receptor can act as a molecular switch enabling cells expressing the rGFR protein to be expanded in-vitro or in-vivo. Thus the invention provides a T or NK cell, comprising a recombinant growth factor receptor (rGFR) comprising: (i) an extracellular (EC) domain; (ii) a thrombopoietin receptor transmembrane (TM) domain; and (iii) a growth factor receptor intracellular (IC) domain.

The present disclosure provides synthetic modular polypeptide libraries and nucleic acids encoding such synthetic modular polypeptide libraries. Also provided are methods of making synthetic modular polypeptide libraries and nucleic acids encoding synthetic modular polypeptide libraries. Methods of screening a synthetic modular polypeptide library to identify a selected phenotype associated with a member of a synthetic modular polypeptide library are also provided where such methods fmd use in both in vitro and in vivo assays.

The present invention discloses cell lines and recombinant growth factor receptors useful in adoptive cell therapy (ACT), wherein the recombinant growth factor receptor can act as a molecular switch enabling cells expressing the rGFR protein to be expanded in-vitro or in- vivo. Thus the invention provides a T or NK cell, comprising a recombinant growth factor receptor (rGFR) comprising: (i) an extracellular (EC) domain; (ii) a thrombopoietin receptor transmembrane (TM) domain; and (iii) a growth factor receptor intracellular (IC) domain.

The present invention provides a chimeric antigen receptor having a structure of scFv(X)-(Y)CD 3zeta-MN.X comprises a tumor targeting antibody or a ligand or receptor capable of specifically binding to a tumor. Y is an intracellular region of a costimulatory receptor selected from ICOS, CD28, CD27, HVEM, LIGHT, CD40L, 4-1BB, OX40, DR3, GITR, CD30, SLAM, CD2, and CD226; M is an intracellular region of a gamma chain family cytokine receptor, the cytokine receptor being selected from IL2Ra, IL2Rb, IL4Ra, IL7Ra, IL9Ra, IL15Ra, and IL21Ra. N is an intracellular region of IL2Rg. The present invention further provides a CAR-T cell constructed from the recombinant expression vector of said chimeric antigen receptor, a preparation method therefor and the use thereof. The CAR-T cell of the present invention significantly improves tumor killing capacity and amplification capacity.

The present invention provides gene editing systems comprising gene editing dimerization switches comprising a first and second gene editing switch domain that allow for the regulation of a gene editing function by the introduction, e.g., administration, of a gene editing dimerization molecule having the ability to bring together a first gene editing switch domain and a second gene editing switch domain. A regulated gene editing function provides, e.g., less off-target side effects, and increases the therapeutic window.

The present invention also provides improved FKBP/FRB-based dimerization switches wherein the FRB switch domain or the FKBP switch domain, or both the FRB and FKBP switch domains, comprise one or more mutations that optimize performance, e.g., that alter, e.g., enhance the formation of a complex between the first switch domain, the second switch domain, and the dimerization molecule, rapamycin, or a rapalog, e.g., RAD001.

Recombinant paramyxoviruses including a viral genome encoding a heterologous gene are provided. In several embodiments, the recombinant paramyxovirus is a recombinant parainfluenza virus, such as a recombinant PIV3 including a viral genome encoding a heterologous respiratory syncytial virus F ectodomain linked to the transmembrane domain and the cytoplasmic tail of the F protein from the PIV3. Nucleic acid molecules including the genome of a recombinant paramyxoviruses are also provided. The recombinant viruses may advantageously be used in vaccine formulations, such as for vaccines against parainfluenza virus and respiratory syncytial virus.

The present disclosure relates to methods, compositions and uses involving immunotherapies and inhibitors of a target protein tyrosine kinase in which the kinase is not IL-2-inducible T cell kinase (ITK) and/or is selected from Bruton's tyrosine kinase (BTK), tec protein tyrosine kinase (TEC), BMX non-receptor tyrosine kinase (Etk), TXK tyrosine kinase (TXK) and/or receptor tyro-sine-protein kinase ErbB4 (ErbB4). The provided methods, compositions and uses include administration of one or more such inhibitor with another agent, such as an immunotherapeutic agent targeting T cells and/or genetically engineered T cells, such as CAR-expressing T cells. Also provided are methods of manufacturing engineered cells, cells, compositions, methods of administration, nucleic acids, articles of manufacture and kits. In some aspects, features of the methods and cells provide for improved activity, efficacy, persistence, expansion and/or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.

The present disclosure provides methods and compositions related to the modification of immune effector cells to increase therapeutic efficacy. In some embodiments, immune effector cells modified to reduce expression of one or more endogenous target genes, or to reduce one or more functions of an endogenous protein to enhance effector functions of the immune cells are provided. In some embodiments, immune effector cells further modified by introduction of transgenes conferring antigen specificity, such as exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs) are provided. Methods of treating a cell proliferative disorder, such as a cancer, using the modified immune effector cells described herein are also provided.