The inventive subject matter relates to methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, provided that said allogeneic donor is not MHC-matched to said subject. The inventive methods can be further enhanced by genetic engineering for targeted immunotherapy.

Described herein are compositions and methods for signaling and antigen-presenting bifunctional receptors (SABRs) comprising one or more antigen presenting domains; and one or more signal transduction domains, wherein the one or more antigen presenting domains comprise a binding fragment of a major histocompatibility complex (MHC) molecule. Various immunological functions of the SABRs are also described.

Methods of treating a subject with a tumor, for example in combination with cancer immunotherapy are provided. In some embodiments, the methods include obtaining one or more samples including tumor cells from the subject and measuring human leukocyte antigen (HLA) and/or 2-microglobulin (B2M) expression level, genotype, and/or copy number in the tumor cells. One or more HLA and/or B2M alleles with reduced expression, function, and/or copy number in the tumor are selected and a nucleic acid encoding the one or more HLA and/or B2M alleles is administered to the subject. One or more cancer immunotherapies are also administered to the subject.

Methods of treating a subject with a tumor, for example in combination with cancer immunotherapy are provided. In some embodiments, the methods include obtaining one or more samples including tumor cells from the subject and measuring human leukocyte antigen (HLA) and/or 2-microglobulin (B2M) expression level, genotype, and/or copy number in the tumor cells. One or more HLA and/or B2M alleles with reduced expression, function, and/or copy number in the tumor are selected and a nucleic acid encoding the one or more HLA and/or B2M alleles is administered to the subject. One or more cancer immunotherapies are also administered to the subject.

The present invention provides methods for treating cancer by T cell therapy comprising the steps of obtaining a biopsy from a subject affected by cancer, identifying mutated amino acids in the tumor and the T cell exposed amino acid motifs which contain the mutated amino acids, identifying a donor with matching alleles, generating an array of alternate peptides in which the T cell exposed motifs are maintained constant, but the other amino acids are substituted, selecting one or more peptides from the array of alternative peptides, each having a desired binding affinity to the MHC allele while maintaining the tumor specific T cell exposed motif, contacting antigen presenting cells with the selected alternative peptides so that the peptide is presented by the MHC of the antigen presenting cells, contacting the antigen presenting cells carrying the selected peptide with T cells harvested from the donor, and infusing the subject with stimulated T cells responding to the peptide of interest presented by the dendritic cell MHC.

A method of treating cancer in a subject is disclosed. The method comprises administering to the subject a therapeutically effective amount of a population of T cells, wherein an alpha chain of a TCR of at least 10% of the T cells of the population has a CDR3 amino acid sequence as set forth in SEQ ID NO: 6, and a beta chain of the CDR has a CDR3 amino acid sequence as set forth in SEQ ID NO: 7.

Immunotherapeutic methods and compositions are contemplated in which neoepitopes and/or tumor associated antigens are delivered to dendritic cells via an adenoviral expression system that targets MHC-I and/or MHC-II presentation systems and that further provides one or more recombinant peptides to stimulate T cell activation and interfere with checkpoint inhibition. Treatment is further supported by transfusion of NK cells, which may be modified to have a high affinity CD 16 receptor and/or a chimeric antigen receptor that binds to one or more neoepitopes and/or tumor associated antigens.

Immunotherapeutic methods and compositions are contemplated in which neoepitopes and/or tumor associated antigens are delivered to dendritic cells via an adenoviral expression system that targets MHC-I and/or MHC-II presentation systems and that further provides one or more recombinant peptides to stimulate T cell activation and interfere with checkpoint inhibition. Treatment is further supported by transfusion of NK cells, which may be modified to have a high affinity CD 16 receptor and/or a chimeric antigen receptor that binds to one or more neoepitopes and/or tumor associated antigens.

Provided are modified immune cells including tumor infiltrating lymphocyte (TIL) or B cells, a composition comprising the immune cells, and a method of treating neoplastic or cancer conditions comprising administering to a subject the immune cells.

The present disclosure includes compounds and methods for treating a subject having a disease such as cancer. A treatment method includes administering to the patient a therapeutically effective amount of one or more peptides corresponding to a tumor neoantigen or administering to the patient a therapeutically effective amount of one or more oligonucleotides each having a nucleic acid sequence that encodes a peptide corresponding to a tumor neoantigen. The tumor neoantigens may be identified from patient-specific tumor mutations in the patient's tumor cells.