Compounds, compositions and methods for reducing off-target toxicity of T cells expressing a chimeric antigen receptor (CAR-T cells) and/or providing enhanced control of CAR-T cell activation, and methods of treating a subject and/or modifying CAR-T cell activity in a subject with cancer.

Methods for treating B-cell malignancies such as relapsed and/or refractory B-cell malignancies with a population of genetically engineered T cells expressing a chimeric antigen receptor (CAR) targeting CD19 and having multiple genetic edits, including a disrupted TRAC gene, a disrupted ?2M gene, a disrupted Regnase 1 gene, and/or a disrupted TGFBRII gene.

Provided herein are, among other things, methods for treating a patient suffering from a CD38+ cancer.

The present invention provides novel fusion proteins comprising two cytokines: interleukin-6 (IL-6) and interleukin-1 beta (IL-1?). Methods of using the fusion proteins to activate target cells or treat a disease are also provided.

The present disclosure relates to methods of increasing the efficacy of adoptive cell therapy (ACT) and methods of treating cancer, wherein the methods include administering to a subject with cancer in need thereof a combination therapy comprising a therapeutically effective amount of an ACT (e.g., an immune cell comprising a modified T cell receptor (TCR) against a tumor-associated antigen (TAA), or a chimeric antigen receptor (CAR) against a TAA) and a therapeutically effective amount of a targeted immunocytokine (e.g., a fusion protein comprising an IL2 moiety and an immunoglobulin antigen-binding domain that binds to PD1). The combination therapy demonstrates increased anti-tumor efficacy, increased duration of tumor control and/or increased overall survival, as compared to a subject administered the ACT as monotherapy or the ACT in combination with a non-targeted immunocytokine.

Provided are methods, compositions, uses and articles of manufacture of combination therapies involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and the use of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for treating subjects with disease and conditions such as certain B cell malignancies, and related methods, compositions, uses and articles of manufacture. The cells generally express recombinant receptors such as chimeric antigen receptors (CARs). In some embodiments, the disease or condition is a non-Hodgkin lymphoma (NHL), such as relapsed or refractory NHL or specific NHL subtype.

The disclosure provides a method of preconditioning a subject for chimeric antigen receptor (CAR) T cell therapy. The method comprises administering to the subject a composition comprising a nanoparticle comprising a positively-charged surface and an interior comprising (i) a core and (ii) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between a cationic lipid bilayer, at least one day prior to administering CAR T cell therapy to the subject. The disclosure also provides a method of treating a solid tumor in a subject, the method comprising administering to a subject comprising a surface antigen negative solid tumor a first composition comprising the nanoparticle, wherein the nucleic acid within the nanoparticle encodes the surface antigen, and a second composition comprising a CAR T cell that targets the surface antigen.

The disclosure provides an antibody fusion protein comprising (i) heavy chains comprising variable region sequences comprising the amino acid sequence of SEQ ID NO: 1 and (ii) light chains comprising variable region sequences comprising the amino acid sequence of SEQ ID NO: 8, wherein the light chains are fused at the C-terminus to an A1-A2 domain comprising the amino acid sequence of SEQ ID NO: 11. Nucleic acids encoding all or part of the antibody fusion protein are provided, as well as methods of using the antibody fusion protein in the treatment of, e.g., CD20-positive cancers. The disclosure further provides a mutant A1-A2 domain peptide.

The present invention provides compositions and methods comprising CAR T cells that secrete neuraminidase (e.g., C. perfringens neuraminidase (CpNA)). Compositions and methods of treatment are also provided.

The disclosure provides an antibody fusion protein comprising (i) heavy chains comprising variable region sequences comprising the amino acid sequence of SEQ ID NO: 1 and (ii) light chains comprising variable region sequences comprising the amino acid sequence of SEQ ID NO: 8, wherein the light chains are fused at the C-terminus to an A1-A2 domain comprising the amino acid sequence of SEQ ID NO: 11. Nucleic acids encoding all or part of the antibody fusion protein are provided, as well as methods of using the antibody fusion protein in the treatment of, e.g., CD20-positive cancers.