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.

The present invention is directed toward methods of increasing the immune response to an antigen using TLR1/2 agonist and/or TLR7 agonist in combination with a T cell activating treatment, for example, a vaccine. In some aspects, the present invention provides methods of enhancing an anti-tumor response comprising administering at least one TLR1/2 agonist and/or at least one TLR7 agonist in combination with an immunotherapeutic agent.

Chimeric antigen receptor (CAR) T-cell-rejuvenating conjugates and compositions and methods of use to rejuvenate exhausted CAR T-cells.

CAR cells targeting and antibodies human HLA-G are described as a new method of cancer treatment. It is proposed that HLA-G CAR cells are safe and effective in patients and can be used to treat human tumors expressing the HLA-G.

Provided herein are compositions and methods for the treatment of cancers using modified TILs, wherein the modified TILs include one or more immunomodulatory agents (e.g., cytokines) associated with their cell surface. The immunomodulatory agents associated with the TILs provide a localized immunostimulatory effect that can advantageously enhance TIL survival, proliferation and/or anti-tumor activity in a patient recipient. As such, the compositions and methods disclosed herein provide effective cancer therapies.

Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of the IL-13 alpha 2 (IL13Ra2) receptor, cells containing such CARs, and methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors.

The disclosure provides CARs (CARs) that specifically bind to CD70. The disclosure further relates to engineered immune cells comprising such CARs, CAR-encoding nucleic acids, and methods of making such CARs, engineered immune cells, and nucleic acids. The disclosure further relates to therapeutic methods for use of these CARs and engineered immune cells comprising these CARs for the treatment of a condition associated with malignant cells expressing CD70 (e.g., cancer).

B-cell maturation antigen (BCMA) is expressed on malignant plasma cells. The present invention provides BCMA-specific chimeric antigen receptors and cells expressing such chimeric antigen receptors. In certain embodiments, engineered cells expressing the chimeric antigen receptors of the present invention are capable of inhibiting the growth of tumors expressing BCMA. The engineered cells of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced BCMA-targeted immune response is desired and/or therapeutically beneficial. For example, engineered cells expressing the BCMA-specific chimeric antigen receptors of the invention are useful for the treatment of various cancers, including multiple myeloma.

Provided are compounds that target the lanthionine synthetase C-like protein 2 pathway and cells, such as immune cells, prepared in vitro with the compounds. The compounds and cells can be used to treat a number of conditions, including infectious diseases, hyperproliferative disorders, inborn errors of metabolism, chronic immunometabolic diseases, autoimmune diseases, organ transplant rejection, inflammatory disorders, and chronic pain, among others.

Immune cell engineered to inhibit the endogenous expression of one or more of Blimp-1 and A20 and/or overexpress one or more of exogenous TCF7 and Bach2. Method of treating cancer, comprising administering the cells described herein. Method of increasing one or more of a peak fold proliferation rate, a killing efficiency, or inducing the cellular characteristics associated with nave phenotype of an immune cell, comprising introducing an exogenous construct encoding a CAR or a TCR, and inhibiting the endogenous expression of one or more of Blimp-1 and A20, and/or introducing an exogenous construct encoding one or more of TCF7 and Bach2. Method of generating a modified immune cell, comprising introducing an exogenous construct encoding a CAR or a TCR, and inhibiting the endogenous expression of one or more of Blimp-1 and A20, and/or introducing an exogenous construct encoding one or more of TCF7 and Bach2.