Abstract: Provided are methods of identifying peptide epitopes of an antigen recognized by the non-classical major histocompatibility complex (MHC) molecule designated MHC-E. In some embodiments, the antigen is a tumor antigen, autoimmune antigen or pathogenic antigen. Also provided are methods of identifying peptide binding molecules that bind to a peptide in the context of an MHC-E molecule. In some embodiments, the peptide binding molecule is a T cell receptor (TCR) or antibody, including antigen-binding fragments thereof and chimeric antigen receptors (CAR) thereof. Also provided are methods of genetically engineering cells containing such MHC-E-restricted peptide binding molecules, and such genetically engineered cells, including compositions thereof and uses in adoptive cell therapy.

Abstract: Provided herein are binding molecules, such as those that recognize or bind a peptide epitope of a cancer antigen, such as expressed on a cancer cell, including cells infected with human papilloma virus (HPV) or that contain HPV DNA sequences and/or those that recognize or bind a peptide epitope of HPV 16 E6 or E7, in the context of a major histocompatibility complex (MHC) molecule. Among the provided binding molecules are T cell receptors (TCRs) or antibodies, including antigen-binding fragments thereof, that bind or recognize such peptide epitopes. The present disclosure further relates to engineered cells comprising such binding molecules, e.g., TCRs or antibodies (and chimeric antigen receptors containing the antibodies), and uses thereof in adoptive cell therapy.

Abstract: Provided herein are methods, compositions and uses involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and inhibitors of a TEK family kinase, such as BTK or ITK. The provided methods, compositions and uses include those for combination therapies involving the administration or use of one or more such inhibitor in conjunction with another agent, such as an immunotherapeutic agent targeting T cells, such as a therapeutic antibody, e.g., a multispecific (e.g., T cell engaging) antibody, and/or genetically engineered T cells, such as chimeric antigen receptor (CAR)-expressing T cells. Also provided are methods of manufacturing engineered T cells, compositions, methods of administration to subjects, nucleic acids, articles of manufacture and kits for use in the methods.

Abstract: Provided are methods, systems, and kits for cell processing, e.g., for therapeutic use, such as for adoptive cell therapy. The provided methods include transduction methods, in which cells and virus are incubated under conditions that result in transduction of the cells with a viral vector. The incubation in some embodiments is carried out in an internal cavity of a generally rigid centrifugal chamber, such as a cylindrical chamber made of hard plastic, the cavity of which may have a variable volume. The methods include other processing steps, including those carried out in such a chamber, including washing, selection, isolation, culture, and formulation. In particular, the disclosure relates to method providing advantages over available processing methods, such as available methods for large-scale processing. Such advantages include, for example, reduced cost, streamlining, increased efficacy, increased safety, and increased reproducibility among different subjects and conditions.

Abstract: Provided are methods, kits and compositions for ameliorating toxicity, such as cytokine release syndrome or neurotoxicity, suspected or being induced by or associated with, administration of a therapeutic agent, such as a immunotherapeutic agent targeting T cells and/or genetically engineered T cells, e.g. chimeric antigen receptor (CAR)-expressing T cells. The methods involve administering an additional agent, such as an agent having anti-oxidant or anti-inflammatory properties, that modulates immune cells such as by preventing or reducing the production of pro-inflammatory cytokines or stress cytokines and/or promoting differentiation to a neuroprotective phenotype, and/or capable of preventing, blocking or reducing microglial cell activation or function and/or capable of modulating, such as promoting, the activity of NRF2 or a component of an NRF2-regulated pathway, and/or one or more components involved in an antioxidant response element (ARE).

Abstract: Provided herein are methods employing a toxicity and efficacy probability interval (TEPI) design for performing a clinical trial, such as a Phase I dose-finding trial. In some embodiments, the methods can be used in the dosing of subjects administered a therapy, such as adoptive cell therapy or other immunotherapy, where safety and efficacy data for a therapeutic agent can be observed in the same timeframe or period. In some embodiments, one or more of or all of the steps of the method occur at an electronic device containing one or more processors and memory, such as implemented by a computer. Also provided are methods of administering a therapeutic agent to a subject in accord with the dosing decisions.

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 is directed to bioreactor consoles that provide a stable structure with built-in bioreactor component management. The bioreactor consoles disclosed herein can include one or more vertical platforms with notches and/or a recessed platform that can provide the desirable flexibility to easily connect and disconnect various tubes, cables, and components of the bioreactor system as well as organize which tubes and cables connect to which component of a bioreactor on the vertical platforms.

Abstract: Provided are polynucleotides containing a modified PRE having a variant X gene that includes one or more stop codons not present in an unmodified, such as wild-type, hepatitis X gene. Also provided are polynucleotides containing a modified PRE having a variant X gene that includes one or more degradation sequences not present in an unmodified, such as wild-type, hepatitis X gene. The modified PRE can be operably linked to a nucleic acid encoding a recombinant protein. Also provided are expression cassettes, viral vectors and cells containing the polynucleotides, and compositions and methods of use thereof.

Abstract: Provided are binding molecules, such as TCRs or antigen binding fragments thereof and antibodies and antigen-binding fragments thereof, such as those that recognize or bind human papilloma virus (HPV) 16, including HPV 16 E6 and HPV 16 E7. Also provided are engineered cells containing such binding molecules, compositions containing the binding molecules or engineered cells, and methods of treatment, such as administration of the binding molecules, engineered cells, or compositions.

Abstract: The present disclosure is directed to bioreactor bag assemblies that can minimize the amount of additional connections/adaptations made to the bioreactor bag before the bioreactor bag can be used for cell cultivation, thereby reducing the risk of contamination. The bioreactor bag assemblies disclosed herein can include a pre-assembled waste bag connection and pre-assembled tubing arrangements so that the cell media and/or the cell source can be immediately welded to the pre-assembled tubing arrangements.

Abstract: Provided are engineered cells for adoptive therapy, including NK cells and T cells. Also provided are compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to subjects. In some embodiments, the cells contain genetically engineered antigen receptors that specifically bind to antigens, such as chimeric antigen receptors (CARs) and costimulatory receptors. In some embodiments, the cells include receptors targeting multiple antigens. In some embodiments, the cells include repression of one or more gene product, for example, by disruption of a gene encoding the gene product. In some embodiments, a gene encoding an antigen recognized by the engineered antigen receptor is disrupted, reducing the likelihood of targeting of the engineered cells. In some embodiments, the antigen recognized by the engineered antigen receptor is related to a tumor antigen recognized by the engineered antigen receptor.

Abstract: Provided herein are immunomodulatory polypeptides containing first and second submits of a cytokine or a chemokine connected by a joining region containing a targeting moiety that binds to a target molecule. In some aspects, the disclosure further relates to engineered cells and compositions comprising the immunomodulatory polypeptides and methods for their administration to subjects. In some embodiments, the cells engineered to contain the immunomodulatory polypeptide, such as T cells, further contain a genetically engineered antigen receptor that specifically binds to antigens, such as a chimeric antigen receptor (CAR). In some embodiments, features of the polypeptides, engineered cells, and methods provide for improved treatment of diseases or disorders, such as by reducing adverse effects of cytokine or chemokine therapy, or increasing activity, efficacy and/or persistence or decreasing immunogenicity of adoptive cell therapy.

Abstract: Provided herein are methods of assessing or determining the presence or absence of particles, such as bead particles, present in a cell composition. Also provided are articles of manufacture and kits for use in the methods.

Abstract: Provided herein are chimeric receptors, such as chimeric antigen receptors (CARs), comprising BCMA-binding molecules, such as anti-BCMA antibodies and antigen-binding fragments thereof, such as heavy chain variable (VH) regions and single-chain antibody fragments, and encoding polynucleotides. In some embodiments, the anti-BCMA chimeric receptors specifically bind to BCMA. Among the anti-BCMA-binding molecules are human antibodies, including those that compete for binding to BCMA with reference antibodies, such as a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs and uses thereof such as in adoptive cell therapy.

Abstract: Provided are CRIS PR/CAS-related methods, compositions and components for editing a target nucleic acid sequence, or modulating expression of a target nucleic acid sequence, and applications thereof in connection with cancer immunotherapy comprising adoptive transfer of engineered T cells or T cell precursors.

Abstract: Provided are chimeric receptors for engineering cells for adoptive therapy, including T cells, and the genetically engineered cells. In some embodiments, the chimeric receptors, such as chimeric antigen receptors (CARs) are modified in a junction region by one or more amino acid modifications such that peptide fragments of such region exhibit a lower binding affinity for a human leukocyte antigen (HLA) and/or the region exhibits reduced immunogenicity, including following administration to a subject. In some aspects, also provided are methods and compositions for engineering and producing cells expressing such chimeric receptors, compositions containing the cells, and method for their administration to subjects. In some embodiments, features of the chimeric receptors and engineered cells containing the chimeric receptors result in methods that provide for increased or improved activity, efficacy and/or persistence.

Abstract: Provided are cells, e.g., engineered immune cells, expressing recombinant or engineered molecules involved in metabolic pathways, such as those that promote or inhibit one or more metabolic steps, reactions, or pathways, for example, in T cells. Such molecules include those that induce or repress a particular functional outcome or metabolic event, for example, one that promotes differentiation or reprogramming into a particular phenotypic state, such as memory, long-lived, activated or activatable, non-exhausted, phenotype or stem-like phenotype. The cells generally further express an immune receptor, such as an antigen receptor, which may be an engineered receptor, such as a CAR or recombinant TCR, or may be a natural immune receptor. Also provided are cells, such as T cells, expressing such molecules and combinations thereof, compositions comprising such cells, nucleic acids such as vectors encoding the same, and methods of administration to subjects in adoptive cell therapy.

Abstract: Provided are chimeric receptors for engineering cells for adoptive therapy, including T cells, and the genetically engineered cells. In some aspects, also provided are methods and compositions for engineering and producing the cells, compositions containing the cells, and method for their administration to subjects. In some embodiments, the cells, such as T cells, contain genetically engineered antigen receptors that specifically bind to antigens, such as a chimeric antigen receptor (CAR), and which contain an intracellular signaling domain capable of inducing TRAF6-mediated signaling. In some embodiments, features of the cells and methods provide for increased or improved activity, efficacy and/or persistence.

Abstract: Provided are ROR1 binding molecules, including anti-ROR1 antibodies, including antibody fragments such as variable heavy chain (VH) regions, single-chain fragments, and chimeric receptors including the antibodies, such as chimeric antigen receptors (CARs). In some embodiments, the antibodies specifically bind to ROR1. Among the antibodies are human antibodies, including those that compete for binding to ROR1 with reference antibodies, such as a non-human reference antibody. Also provided are genetically engineered cells expressing the chimeric receptors, and uses of the binding molecules and cells adoptive cell therapy.