Abstract: This application discloses in part methods and compositions for mutating immune cells (e.g., CAR-T cells) and determining mutated immune cell cancer killing efficacy in vivo.

Abstract: Single domain VHH polypeptides (antibodies) that bind mesothelin, VHH polypeptide products, methods, cells, pharmaceutical compositions, and kits. The VHH polypeptides may be recombinantly produced and expressed. Provided are also chimeric antigen receptor (CAR) polypeptides comprising the VHH polypeptides and CAR immune effector cells comprising the expressing the same.

Abstract: Compositions and methods that are useful for identification of VHH antibodies that bind a target antigen.

Abstract: Described in several example embodiments herein are engineered bifunctional receptors that can include an E3 ligase binding domain and a target binding domain operatively coupled to the E3 ligase binding domain. In some embodiments, the engineered bifunctional receptors are capable of targeted degradation of a target protein. Also described in several example embodiments herein are compositions, formulations, and cells that can include or generate the engineered bifunctional receptors and uses thereof.

Abstract: The disclosure features compositions containing chimeric antigen receptor (CAR) immune cells that have been modified to reduce and/or eliminate expression or activity of a natural killer cell lectin A (NKG2A) polypeptide and/or a cluster of differentiation 94 (CD94) polypeptide, and methods for use thereof to treat a neoplasia.

Abstract: The invention features pseudotyped viral particles (e.g., lentiviral or gammaretroviral particles) and compositions and methods of use thereof, where the viral particles comprise a VHH domain.

Abstract: The invention features pseudotyped viral particles (e.g., lentiviral or gammaretroviral particles) and compositions and methods of use thereof, where the viral particles comprise a VHH domain.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that modulates one or more biomarkers, such as inhibits one or more biomarkers listed in Table 1 and/or increases one or more biomarkers listed in Table 4, in combination with an immunotherapy.

Abstract: The present invention relates, in part, to methods of treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an agent that inhibits or promotes the copy number, the expression level, and/or the activity of one or more biomarkers listed in Table 1 or a fragment thereof. Also provided herein are methods of detecting ADAR1 or ISG15 dependency in a high proliferation cell (e.g., a cancer cell). Also provided are methods of detected increased interferon signaling pathway activity in a high proliferation cell (e.g., a cancer cell). Included herein are methods of treating cancer with inhibitors of ADAR1 or ISG15. Methods of screening for such inhibitors are also provided herein. Methods of identifying the likelihood of a cancer to be responsive to an ADAR1 inhibitor are also provided.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that inhibits one or more biomarkers listed in Table 1 in combination with an immunotherapy.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that modulates one or more biomarkers, such as inhibits one or more biomarkers listed in Table 1 and/or increases one or more biomarkers listed in Table 4, in combination with an immunotherapy.

Abstract: The present disclosure provides vectors, methods and kits for for delivery and stable expression of CRISPR/Cas components capable of inducing genetic modification of cells, followed by recombinase-mediated excision of some or all of these components after the cells have been successfully genetically modified. The disclosed vectors and methods provide for reduced immunogenic effects arising from one or more CRISPR/Cas components. The disclosed vectors comprise coding sequences that encode a Cas protein, detectable markers and a guide RNA. The disclosed vectors provide for the subsequent genomic excision of the CRISPR/Cas components after successful genetic modification, as mediated by recombinase recognition of recombination sites flanking one or more of the disclosed coding sequences. The present disclosure further provides methods of generating a population of genetically modified tumor cells for screening a candidate target gene for cancer immunotherapy.

Abstract: The invention provides in vivo methods for identifying cancer-associated immunotherapy targets.

Abstract: The present invention relates, in part, to methods of treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an agent that inhibits or promotes the copy number, the expression level, and/or the activity of one or more biomarkers listed in Table 1 or a fragment thereof. Also provided herein are methods of detecting ADAR1 or ISG15 dependency in a high proliferation cell (e.g., a cancer cell). Also provided are methods of detected increased interferon signaling pathway activity in a high proliferation cell (e.g., a cancer cell). Included herein are methods of treating cancer with inhibitors of ADAR1 or ISG15. Methods of screening for such inhibitors are also provided herein. Methods of identifying the likelihood of a cancer to be responsive to an ADAR1 inhibitor are also provided.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that inhibits one or more biomarkers listed in Table 1, such as regulators of TNF signaling/NF-?B activation (e.g., RIPK1, BIRC2, TBK1, TRAF3, RNF31, RBCK1, OTULIN, TRAF6, TAB2, and TNIP1), in combination with an immunotherapy.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that inhibits one or more biomarkers listed in Table 1 in combination with an immunotherapy.

Abstract: The present invention relates, in part, to methods of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of an agent that inhibits one or more biomarkers listed in Table 1, such as regulators of ubiquitin proteasome pathway (e.g., STIP1 homology and U-Box containing protein 1 (STUB 1), ubiquilin-1 (UBQLN1), and heat shock protein 90 kDa beta member 1 (HSP90B 1)), in combination with an immunotherapy.

Abstract: The invention provides in vivo methods for identifying cancer-associated immunotherapy targets.