MAGE-A4, or Melanoma-Associated Antigen A4, is a cancer-testis antigen (CTA) on the X chromosome. The present disclosure provides MAGE-A4-specific chimeric antigen receptors, cells expressing such chimeric antigen receptors, and MAGE-A4 specific isolated antibodies. In certain embodiments, engineered cells expressing the chimeric antigen receptors of the present disclosure are capable of inhibiting the growth of tumors expressing MAGE-A4. The engineered cells of the present disclosure are useful for the treatment of diseases and disorders in which an upregulated or induced MAGE-A4-targeted immune response is desired and/or therapeutically beneficial. For example, engineered cells expressing the MAGE-A4-specific chimeric antigen receptors of the present disclosure are useful for the treatment of various cancers.

Methods and compositions for treating cancers (e.g., neural cancers) by dendritic cell vaccination are provided herein.

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or b) MAGE-A12 in the context of HLA-Cw7. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention.

The present invention contemplates dendritic cell compositions. The dentritic cell compositions employ MHC class-II targeting signals fused to an antigen or fragment thereof to obtain MHC II presentation of the antigen or fragment thereof. In particular, the invention refers to a dendritic cell vaccine comprising dendritic cells expressing a MHC class-II targeting signal fused to an antigen or fragment thereof. Dendritic cell vaccines for the stimulation of an immune response against melanoma-associated antigen are also described.

The present invention contemplates methods for the generation of human antigen-specific T lymphocytes. The methods employ MHC class-II targeting signals fused to an antigen or fragment thereof to obtain MHC class presentation of RNA coded proteins. Accordingly, the present invention concerns expression vectors comprising MHC class-II targeting signal and at least one antigen or fragment thereof and its use for the in vitro generation of antigen-specific T lymphocytes. T cell clones and T cell receptors (TCRs) specific for tumor antigens or viral antigens are also described.

Disclosed are T-cell receptors (TCRs) binding to tumor-associated antigens (TAAs) for targeting cancer cells, T-cells expressing same, methods for producing same, and methods for treating cancers using same. Disclosed are TCRs and their variants that bind to HLA class I or II molecules with a peptide, such as MAG-003 have the amino acid sequence of KVLEHVVRV (SEQ ID NO:1). The description further relates to peptides, proteins, nucleic acids, cells for use in immunotherapeutic methods, the immunotherapy of cancer, and tmor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T-cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

The present invention relates to the field of immunotherapy, in particular, of cancer, more specifically, to adoptive T cell therapy or T cell receptor (TCR) gene therapy directed to an epitope derived from the cancer-testis antigen MAGEA4 presented on HLA-A*01, in particular, the immunodominant epitope of SEQ ID NO: 1. The invention provides a nucleic acid encoding a TCR alpha chain construct (TRA) and/or a TCR beta chain construct (TRB) of a TCR construct, wherein the TCR construct is capable of specifically binding to said epitope in the context of HLA-A*01. Proteins encoded by said nucleic acids, corresponding host cells and pharmaceutical compositions, e.g., for use in treating cancer such as melanoma, gastric cancer, head and neck, lung, breast, ovarian, bladder, and esophageal cancer, are also objects of the invention. In another aspect, the invention provides specific peptides comprising said epitopes, and pharmaceutical compositions comprising the same, e.g., for use in vaccination.

Embodiments of the present disclosure relate to a polynucleotide encoding a CAR comprising a cytoplasmic domain of CD4, or a CAR comprising SEQ ID NO: 17 in its intracellular domain, and the cytoplasmic domain of CD4 is located between a transmembrane domain of the CAR and a signaling or stimulatory domain, for example, CD3 zeta domain.

The present invention relates to T cell receptors (TCRs) which bind the HLA-A*0201 restricted peptide GVYDGEEHSV (SEQ ID NO: 1) derived from the MAGE-B2 protein. The TCRs of the invention demonstrate excellent specificity profiles for this MAGE epitope. Also provided are nucleic acids encoding the TCRs, cells engineered to present the TCRs, cells harbouring expression vectors encoding the TCRs and pharmaceutical compositions comprising the TCRs, nucleic acids or cells of the invention.

Disclosed are methods of preparing an isolated population of dendritic cells, isolated populations of dendritic cells prepared by the methods, and pharmaceutical compositions comprising the isolated population of dendritic cells. Also disclosed are methods of treating or preventing cancer using the isolated population of dendritic cells or pharmaceutical compositions.