The disclosure provides immune cells comprising a first activator receptor specific to CEA, and a second inhibitory receptor, and methods of making and using same for the treatment of cancer.

A fusion protein comprising: a first component comprising an antibody, or a fragment or variant thereof; and a second component comprising a cytokine trap or an adenosine deaminase or a fragment or variant thereof. In certain embodiments, the antibody is an anti-PD-1 antibody. In certain embodiments, the antibody binds to a tumor antigen, for example a MUC16 or MUC1 antigen. In certain embodiments, the cytokine trap is a TGF- trap. A polynucleotide encoding such a fusion protein and a vector comprising such a polynucleotide. A composition comprising the fusion protein. A method of using the composition, including in the treatment of cancer.

Provided are agents comprising a phosphatidylcholine as an active ingredient to serve as a vein-formation promoting agent capable of promoting vein-like morphological change of tumor vessels, a vessel-diameter enlarging agent capable of enlarging the diameter of tumor vessels, a blood vessel-connection promoting agent capable of promoting connection of tumor vessels to each other without mediation of a lysophospholipid receptor, a leukocyte-infiltration promoting agent capable of promoting infiltration of leukocytes throughout a tumor region without mediation of a lysophospholipid receptor, and an antitumor immunostimulatory agent capable of promoting infiltration of leukocytes throughout a tumor region without mediation of a lysophospholipid receptor.

Compounds, compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising a Cbl-b inhibitor and a cancer vaccine, as well as methods for treating cancer using a Cbl-b inhibitor and a cancer vaccine; and pharmaceutical compositions comprising a Cbl-b inhibitor and an oncolytic virus, as well as methods for treating cancer using a Cbl-b inhibitor and an oncolytic virus.

The present invention relates to an isolated cellular targeted delivery system comprising a CD45+ leukocyte cell comprising within said cell a complex of one or more iron binding proteins and/or a label as well as methods for producing such isolated cellular targeted delivery system and uses of such system for therapy diagnosis and in particular for diagnosis of cancer, particularly metastatic cancer, in particular for therapy of cancer.

Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and/or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella, or by modification of the genes so that functional flagella are not produced, and/or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin and/or pagP.sup.. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd.sup., purI.sup., and msbB.sup.. The immunostimulatory bacteria, such as Salmonella species, are modified to encode immunostimulatory proteins that confer anti-tumor activity in the tumor microenvironment, and/or are modified so that the bacteria preferentially infect immune cells in the tumor microenvironment, or tumor-resident immune cells, and/or are modified to induce less cell death in immune cells than in other cells. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the immunostimulatory bacteria.

Therapeutic modalities are provided for targeting adoptive cellular therapies to specific sites of disease, involving the use of specific repertoirs of PRR ligands. In effect, innate immune system signaling is provoked so as to facilitate the homing of adoptive immune cells to sites of disease, for example to the site of a solid tumor.

The present invention provides co-cultures of organoids and immune cells, and methods of using these to identify agents for treating diseases.

Methods of treating a subject with cancer with CD8 T cell-mediated immune therapy are provided. The methods include measuring an amount of CXCR3-positive T cells in a peripheral blood sample or a tumor sample from a subject with cancer following treatment of the subject with at least one dose of the CD8 T cell-mediated therapy and comparing the amount of CXCR3-positive T cells in the sample to a control. Responsiveness of the cancer to the CD8 T cell-mediated therapy is predicted based on whether there is an increase or decrease in the amount of CXCR3-positive T cells in the sample. Methods further including treating the subject with at least one additional dose of the CD8 T cell-mediated immune therapy are also provided.

Provided are therapeutic agent including nucleic acid and CAR-modified immune cell and the use thereof. The therapeutic agent comprises first composition and second composition, the first composition comprises a nucleic acid having a labeling polypeptide coding sequence for being introduced into a tumor cell and/or a cancer cell; the labeling polypeptide has an extracellular antigen determining region, a spacer portion, a transmembrane portion that are operatively linked, which can be expressed to form modification on the surface of the tumor cell and/or cancer cell; the extracellular antigen determining region comprises one or more epitope polypeptides; wherein, amino acid sequences of proteins on cell membrane or secreted proteins of mammal do not comprise the epitope polypeptide amino acid sequence in the natural state; the second composition comprises chimeric antigen receptor modified immune cell which specifically recognize and bind to the extracellular antigen determining region. The therapeutic agent achieves synergistic therapeutic effect.