The present disclosure pertains to methods of modifying an immune cell by delivering a modified messenger RNA (mRNA) encoding a chimeric antigen receptor (CAR) and modified immune cells comprising CARs.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

A novel preparation method for a universal CAR-T cell targeting a T-cell lymphoma cell, the universal CAR-T cell prepared by means of the method and a biological product comprising the universal CAR-T cell. The preparation method for the universal CAR-T cell targeting a T-cell lymphoma cell comprises: obtaining a T cell from a human donor having a healthy lymphatic system, and then disrupting a TRAC genome region and a B2M genome region in the T cell by means of a gene editing technology, so that CAR molecules targeting the T-cell lymphoma cell TCRα/β are stably expressed in the T cell. The universal CAR-T cell targeting a T-cell lymphoma cell prepared by means of the preparation method eliminates the natural TCR expression of a T cell, greatly reduces the graft-versus-host reaction, and meanwhile, also greatly reduces the immunogenicity thereof, and can continuously and efficiently kill the T-cell lymphoma cell.

Disclosed are isolated or purified T cell receptors (TCRs) having antigenic specificity for human p53.sup.R273C or human p53.sup.Y220C. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.

The present disclosure provides compositions and methods for delivering a nucleic acid sequence encoding a chimeric antigen receptor (CAR) to an immune cell using a retroviral vector comprising an optimized Cocal vesiculovirus envelope protein.

Compounds, compositions, and methods for generating T cells with altered phenotype are disclosed. The phenotype-altered T cells have increased persistence, prolonged survival, and increased antitumor activity and are useful for treatment of cancers.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

Provided herein are populations of placental-derived natural killer cells comprising a cleavage resistant CD16. Also provided are methods of treating diseases, disorders or conditions in a human subject comprising administering to the subject an effective amount of a population of placental-derived natural killer cells comprising a cleavage resistant CD16 to the subject so as thereby to provide an effective treatment of the to the subject. The cells, such as CYNK cells, can be placental CD34+ cell-derived natural killer (NK) cells. The diseases, disorders or conditions include cancers such as multiple myeloma and lymphoma. The present invention also provides compositions comprising populations of placental-derived natural killer cells comprising a cleavage resistant CD16 for the treatment of a subject and methods of their use.

Provided herein are gRNA comprising a targeting domain that targets CD6, which may be used, for example, to make modifications in cells. Also provided herein are methods of genetically engineered cell having a modification (e.g., insertion or deletion) in the CD6 gene and methods involving administering such genetically engineered cells to a subject, such as a subject having a hematopoietic malignancy.

Provided is an engineered T cell. The expression of a TCR/CD3 complex on the cell surface is reduced by means of introducing a polypeptide that down-regulates the expression of the TCR/CD3 complex on the cell surface into the cell. The engineered T cell can be used for therapeutic purposes, such as treatment of cancers.