The present invention is directed to the field of immunotherapy. Specifically, the invention provides improved cell compositions and methods for adoptive cell therapy, useful in the treatment of cancer. More specifically, embodiments of the invention employ the use of cell compositions comprising a high proportion of activated cytotoxic CD8.sup.+ cells and in particular CD8.sup.+NKG2D.sup.+granzyme-B.sup.+ cells characterized by enhanced cytotoxicity, to processes for their preparation from peripheral blood mononuclear cells (PBMC), and to their use in cancer management.

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. Embodiments of derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

Disclosed herein are methods and compositions relating to the resistance of adoptive immunotherapy caused by the induction of iNOS in tumor associated macrophage. In one aspect, disclosed herein are methods of methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example large B cell lymphoma) in a subject comprising administering to the subject an adoptive immune cell immunotherapy (including, but not limited to administration of chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, tumor infiltrating lymphocytes (TILs)) and an agent that blocks dysregulation of the citric acid cycle (such as, for example, an agent that inhibits inducible nitric oxide synthase (iNOS) and/or an agent that inhibits immune responsive gene 1 (IRG1)) or administering to the subject an adoptive immune cell immunotherapy (including, but not limited to administration of chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, tumor infiltrating lymphocytes (TILs)) wherein the immune cell has been modified to disrupt expression of IRG1.

The present invention features modified immune cells (e.g., T- or NK-cells) having increased resistance to hypoxia-adenosinergic immunosuppression. Methods for producing and using the same are also provided.

The invention provides, for the first time, cells that express truncated or modified Fc Receptor proteins (e.g. CD16t, CD32t, or CD64t) to evade antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). The cells may be pluripotent cells, including hypoimmune pluripotent cells (HIP) or ABO blood type O Rhesus Factor negative HIP cells (HIPO?), that express a truncated or modified Fc Receptor. The invention encompasses cells derived from the pluripotent cells as well as primary cells. The cells may also be differentiated cells, including chimeric antigen receptor (CAR) cells, T cells, natural killer (NK) cells, endothelial cells, dopaminergic neurons, neuroglial cells, pancreatic islet cells, pancreatic beta cells, thyroid cells, fibroblasts, hepatocytes, cardiomyocytes, or retinal pigment endothelium cells.

Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to Mexpress chimeric antigen receptors as well as genetically edited or otherwise engineered to alter the effectiveness with which another immune cell can target and induce cytotoxic effects on the engineered cells. In several embodiments, the methods and compositions disclosed herein reduce fratricide within a therapeutic cell population, which in some instances comprises mixture of immune cell types. Additionally, the methods and compositions disclosed herein enhance one or more aspects of the efficacy of the immune cells in cellular immunotherapy including cytotoxicity and/or persistence, as well as reduced graft versus host or host versus graft effects.

Described herein are methods for treating and preventing graft versus host disease using ACK inhibitors. The methods include administering to an individual in need thereof an ACK inhibitor such as ibrutinib for treating and preventing graft versus host disease.

This disclosure provides for peptides useful for vaccination and other applications, engineered T cell Receptors (TCRs), cells comprising the peptides and TCRs, and methods of making and using the peptides and TCRs. The current disclosure relates to TCRs that specifically recognize SARS-Cov-2 HLA-A2 restricted peptide from membrane glycol-protein (MGP), MGP-65: FVLAAVYRI (SEQ ID NO:22).

Edited cells, e.g., genomically edited cells, with reduced levels of immune rejection and/or improved persistence are described.

Disclosed are compositions of matter, protocols, and treatment means for inducing an enhanced immunity targeting tumor endothelium in order to prophylactically protect subjects from development of neoplasia. In one embodiment, the invention provides placental endothelial cells that are tissue culture expanded under proliferative conditions to resemble the tumor endothelial driven angiogenesis. The cells are subsequently treated with interferon gamma to increase immunogenicity and utilized as a prophylactic vaccine. Antibody and cell mediated immunity towards tumor endothelial associated antigens is quantified with the aim of establishing protective immunity which inhibits or blocks development of angiogenesis-dependent neoplasia.