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.

Immunomodulating polynucleotides are disclosed. The immunomodulating polynucleotides may contain 5-modified uridine, 5-modified cytidine, a total of from 6 to 16 nucleotides, and/or one or more abasic spacers and/or internucleoside phosphotriesters. Also disclosed are conjugates containing a targeting moiety and one or more immunomodulating polynucleotides. The immunomodulating polynucleotides and conjugates may further contain one or more auxiliary moieties. Also disclosed are compositions containing the immunomodulating polynucleotides or the conjugates containing one or more stereochemically enriched internucleoside phosphorothioates. Further disclosed are pharmaceutical compositions containing the immunomodulating polynucleotides or the conjugates and methods of their use.

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.sup. 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.

Disclosed herein are antigenic peptide-MHC complexes, termed comPACT polypeptides and comPACT polynucleotides, and methods of producing such complexes. Also discloses herein are methods of producing libraries of comPACT polynucleotides and polypeptides, and their exemplary use in capturing cancer neoepitope-reactive T cells with high accuracy. Dual particle detection approaches for detection of neoantigen specific T cells with improved sensitivity and specificity are provided. Signal to noise ratio analysis of isolated T cells for detection of neoantigen-specific T cells with improved T cells is also provided.

Provided are genetically modified NK cells expressing a chimeric antigen receptor targeting an EGFR superfamily receptor. The CAR can comprise an intracellular domain of FcRI and further recombinant proteins expressed by the genetically modified NK cells are CD16, autocrine growth stimulating cytokines, and optionally one of IL-12, a TGF-beta trap, or a homing receptor. Also described are methods for treating a patient having or suspected of having a disease that is treatable with NK-92 cells, such as cancer, comprising administering to the patient the genetically modified NK cells.

Disclosed is a method for producing a large amount of natural killer cells and the use of the natural killer cells as an anticancer agent. The method produces fresh NK cells with high purity within a short time, and can also produce cold-preserved NK cells and thawed cryopreserved NK cells having efficacy comparable to the fresh NK cells. NK cells having efficacy comparable to the fresh NK cells can also be produced from cryopreserved CD3-negative cells. The fresh NK cells, cold-preserved NK cells and cryopreserved NK cells exhibit therapeutic effects against various cancers, including colorectal cancer, lung cancer, liver cancer, pancreatic cancer and leukemia, indicating these NK cells are effective as cellular therapeutic agents. Also disclosed are doses and methods of administration that show excellent effects when the fresh NK cells, cold-preserved NK cells and cryopreserved NK cells are used as pharmaceutical compositions for cellular therapy.

A method of treating a cancer, the method comprising: providing a modified macrophage or monocyte that contains an exogenous nucleic acid sequence encoding a Hom- 1 polypeptide or a fragment thereof that contains the Hom-1 homeobox domain, wherein the modified macrophage or monocyte expresses the Hom-1 polypeptide or the fragment thereof; and administering the modified macrophage or monocyte to a subject with a cancer.

The present invention is generally directed to a colorectal (CRC) cell atlas that provides methods of predicting outcomes of cancer patients and therapeutic targets for treating patients in need thereof. The atlas may be used to predict a response to immunotherapy, in particular checkpoint blockade therapy and adoptive cell transfer. Disclosed herein are previously unidentified gene programs in tumors that can be used to predict response and provide for therapeutic targets that can be used to shift a tumor to a responsive phenotype.

The present invention relates to a method for producing natural killer cells using direct reprogramming, natural killer cells produced thereby, a biomarker specific to the natural killer cells, a cell therapeutic agent comprising the natural killer cells, a composition for treatment and prevention of cancer, a cryopreservation cell vial for storing the natural killer cells, and a medium kit for inducing the direct reprogramming. Exhibiting excellent proliferative potential and cancer cell killing potential, the natural killer cells produced by the production method can be effectively utilized for mass production and in a composition for treatment and prevention of cancer.

The present disclosure relates to a method for preparing a cancer-specific T cell based on peripheral blood or a peripheral immune organ for preventing or treating cancer, specifically including steps of: first, isolating an immune cell from peripheral blood or the peripheral immune organ; then, co-incubating with a nanoparticle and/or a microparticle loaded with a tumor whole-cell antigen for a period of time to activate the cancer-specific T cell; then, isolating a cancer-specific T cell activated by the tumor antigen; and, reinfusing the cancer-specific T cell into the body to exert an anti-cancer effect after in vitro expansion. According to the nanoparticle or microparticle prepared by the present disclosure, a tumor antigen component is loaded onto the microparticle and/or the nanoparticle to activate the cancer-specific T cell, and then the cancer-specific T cell is expanded and reinfused into a patient for treating cancer or preventing recurrence or metastasis. The cancer-specific T cell isolated by a sorting method has high specificity, and may prevent or treat cancer by killing cancer cells after expansion.