Abstract: Provided are methods, kits and compositions related to toxicity associated with administration of cell therapy for the treatment of diseases or conditions, e.g., cancer, including methods for use in predicting and treating a toxicity. In some embodiments, the toxicity is a neurotoxicity or cytokine release syndrome (CRS), such as a severe neurotoxicity or a severe CRS. The methods generally involve detecting a parameter of a biomarker or individually a parameter of each biomarker in a panel of biomarkers, such as a concentration, amount or activity, and comparing the detected parameter to a reference value for the parameter to determine if the subject is at risk for developing the toxicity, such as neurotoxicity or CRS or severe neurotoxicity or severe CRS.

Abstract: The present disclosure relates to anti-ROR1 binding proteins, including those that bind to a ROR1 or portion thereof such as an intracellular C terminal portion of a ROR1 protein, and the use of such binding proteins in immunohistochemical and diagnostic methods. Related kits and methods of using the binding proteins are also provided, as are methods of treatment of subjects having diseases or conditions determined to be candidates for such treatments by the binding proteins or methods of this disclosure.

Abstract: The present disclosure relates to methods for using BCMA-specific binding molecules (such as a BCMA-specific chimeric antigen receptor or antibody) in combination with ?-secretase inhibitors, which can be done concurrently or sequentially, to treat or prevent a B-cell related proliferative disease, such as a cancer or autoimmune disease, or the like. A BCMA-specific binding molecule in combination with ?-secretase inhibitor can be used in, for example, adoptive immunotherapy.

Abstract: Stem cells are modified to express an extracellular component including a tag cassette. The tag cassette can be used to detect, enrich, isolate, activate, track, deplete, or eliminate modified cells. The cells can be administered before or following differentiation into a more committed cell type.

Abstract: Provided are methods, kits and compositions related to toxicity associated with administration of cell therapy for the treatment of diseases or conditions, e.g., cancer, including methods for use in predicting and treating a toxicity. In some embodiments, the toxicity is a neurotoxicity or cytokine release syndrome (CRS), such as a severe neurotoxicity or a severe CRS. The methods generally involve detecting a parameter of a biomarker or individually a parameter of each biomarker in a panel of biomarkers, such as a concentration, amount or activity, and comparing the detected parameter to a reference value for the parameter to determine if the subject is at risk for developing the toxicity, such as neurotoxicity or CRS or severe neurotoxicity or severe CRS.

Abstract: The present disclosure relates to immune cells that express an exogenous neoantigen and an immunogenicity enhancer, or to T cells that express an exogenous neoantigen, and their use in treating a disease or disorder, such as cancer for tumor associated neoantigens. Related expression constructs, kits, host cells, pharmaceutical compositions, and methods are also provided.

Abstract: Engineered trimeric CD70 proteins for use in ex vivo T cell manufacturing are described. Use of the proteins during manufacturing creates expanded T cell populations with enhanced properties such as earlier proliferation in culture; selective expansion of nave and memory T cell subsets; longer persistence in vivo following administration to a subject; and improved therapeutic effect. Use of the proteins as therapeutics provide anti-cancer and anti-viral effects. The proteins can also be used as agonistic cell culture reagents in in vitro uses.

Abstract: Provided are methods and compositions directed to the treatment of an individual having cancer by (i) administering to the individual an adoptive cellular immunotherapy composition comprising CAR T cells and (ii) administering to the individual an interleukin-15 receptor agonist, such as, for example, a long-acting interleukin-15 receptor agonist.

Abstract: The instant disclosure provides biomarkers and methods for identifying subjects at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both after adoptive immunotherapy to guide preemptive intervention, modified therapy, or the like. For example, adverse event biomarkers may be measured in a subject before pre-conditioning chemotherapy, before immunotherapy (e.g., adoptive immunotherapy infusion comprising a chimeric antigen receptor (CAR)-modified T cell), or shortly after pre-conditioning chemotherapy and/or immunotherapy. Exemplary biomarkers include temperature, cytokine levels and endothelial activation biomarkers, such as angiopoietin-2, von Willebrand factor (vWF), ratio of angiopoietin-2 to angiopoietin-1, and ratio of ADAMTS13 to vWF. Also provided are methods of treating subjects identified as at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both to minimize such potential adverse events.

Abstract: The present disclosure provides fusion proteins with improved signaling properties. Disclosed embodiments include fusion proteins that comprise an extracellular component comprising a target-binding domain, a transmembrane domain, and an intracellular component comprising a SH2 domain or a functional portion or variant thereof, and have improved signaling in response to antigen-binding, including of solid-tumor antigens with low levels of expression. Recombinant host cells expressing the fusion proteins, and polynucleotides encoding the fusion proteins, are also provided, as are compositions and methods comprising the same.

Abstract: The instant disclosure provides biomarkers and methods for identifying subjects at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both after adoptive immunotherapy to guide preemptive intervention, modified therapy, or the like. For example, adverse event biomarkers may be measured in a subject before pre-conditioning chemotherapy, before immunotherapy (e.g., adoptive immunotherapy infusion comprising a chimeric antigen receptor (CAR) modified T cell), or shortly after pre-conditioning chemotherapy and/or immunotherapy. Exemplary biomarkers include temperature, cytokine levels and endothelial activation biomarkers, such as angiopoietin 2, von Willebrand factor (vWF), ratio of angiopoietin 2 to angiopoietin 1, and ratio of ADAMTS13 to vWF. Also provided are methods of treating subjects identified as at risk of developing cytokine release syndrome (CRS), neurotoxicity, or both to minimize such potential adverse events.

Abstract: Disclosed are protein switches that can sequester bioactive peptides and/or binding domains, holding them in an inactive (“off”) state, until combined with a second designed polypeptide called the key, which induces a conformational change that activates (“on”) the bioactive peptide or binding domain only when the protein switch components are co/localized when bound to their targets, components of such protein switches, and their use.

Abstract: Hematopoeitic stem/progenitor cells (HSPC) and/or non-T effector cells are modified to express an extracellular component including a tag cassette. The tag cassette can be used to activate, promote proliferation of, detect, enrich, isolate, track, deplete and/or eliminate modified cells. The cells can also be modified to express a binding domain.

Abstract: The present disclosure relates to tagged chimeric effector molecules and receptor molecules thereof for genetically engineering a host cell, wherein the recombinant host cell can be identified, isolated, sorted, induced to proliferate, tracked or eliminated. For example, a T cell may be recombinantly modified for use in adoptive immunotherapy.

Abstract: Binding proteins and high affinity recombinant T cell receptors (TCRs) specific for KRAS G12V or Her2-ITD neoantigens are provided herein. Compositions and recombinant host cells encoding and/or expressing the binding proteins and/or high affinity recombinant TCRs are also provided. The compositions and recombinant host cells may be used to treat a subject having non-small cell lung cancer (NSCLC), colorectal cancer, pancreas cancer, ovarian cancer, breast cancer, biliary tract cancer, an indication wherein a KRAS G12V neoantigen is a therapeutic target, or an indication wherein a Her2-ITD neoantigen is a therapeutic target. Related vaccines, vaccine therapies, and vaccination regimens are also provided.

Abstract: The disclosure provides in some aspect methods and compositions related to culturing and engineering T cells that maintain less differentiated state. The T cells are cultured in conditions that induce Notch signaling The resulting T cells exhibit maintenance of a less differentiated state for prolonged periods and have reduced susceptibility to exhaustion. Also provided are the cells produced by the methods, as well as related compositions and methods of use for adoptive therapy.

Abstract: The present disclosure provides binding proteins, such as TCRs, that specifically bind various tumor associated antigens (including human BRAFV600E epitope), cells expressing such antigen specific binding proteins, nucleic acids encoding the same, and compositions for use in treating diseases or disorders in which cells express BRAFV600E, such as in cancer.

Abstract: The present invention provides methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring genetically modified tumor specific CD8+ T cells in the presence of tumor-specific, subset specific genetically modified CD4+ T cells, wherein the CD4+ T cells confer and/or augment a CD8+ T cells ability to sustain anti-tumor reactivity and increase and/or maximize tumor-specific proliferation of the tumor-specific CD8+ T cells of interest. Pharmaceutical formulations produced by the method, and methods of using the same, are also described.

Abstract: The present disclosure relates to tagged chimeric effector molecules and receptor molecules thereof for genetically engineering a host cell, wherein the recombinant host cell can be identified, isolated, sorted, induced to proliferate, tracked or eliminated. For example, a T cell may be recombinantly modified for use in adoptive immunotherapy.

Abstract: The present disclosure provides methods and compositions for treating cancers using modified immune cells that express a ROR1-specific binding protein according to certain treatment protocols including, for example, dosing regimens, infusion schedules, and patient selection criteria. In certain embodiments, presently disclosed methods and compositions are useful for treating solid cancers and/or hematological malignancies (e.g., triple-negative breast cancer (TBNC), non-small cell lung cancer (NSCLC), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL)), wherein the methods comprise administering modified T cells that target a ROR1 antigen.