The present disclosure provides processes for genetically engineering T cells, such as primary CD4+ T cells and/or CD8+ T cells, for use in cell therapy that does not involve expanding the cells. In particular aspects, the provided processes successfully generate compositions of engineered T cells, such as containing populations of engineered T cells, that express a chimeric antigen receptor (CAR) within a shortened amount of time as compared to alternative engineering processes, such as processes that involve expanding the cells. In certain aspects, the provided processes successfully generate a composition of engineered T cells suitable for use in cell therapy within 4 days from when the process to stimulate or activate the cells is initiated. In some aspects, the resulting engineered cell compositions are composed of cell population that are less differentiated, less exhausted, and more potent than engineered T cell compositions generated by other means, such as by processes that involve expanding the cells. Also provided are compositions of T cells generated by the provided methods and their uses for treating subjects.

B-cell maturation antigen (BCMA) is expressed on malignant plasma cells. The present invention provides novel bispecific antibodies (bsAbs) that bind to both BCMA and CD3 and activate T cells via the CD3 complex in the presence of BCMA-expressing tumor cells. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing BCMA. The bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced BCMA-targeted immune response is desired and/or therapeutically beneficial. For example, the bispecific antibodies of the invention are useful for the treatment of various cancers, including multiple myeloma.

The present disclosure provides compositions and methods comprising recombinant particles suitable for specifically delivering one or more chimeric antigen receptors to immune effector cells in vivo.

Provided herein is a method of treating a subject who has a cancer. At least one dose of chimeric antigen receptor (CAR)-T cells comprising a CAR comprising a polypeptide is administered to the subject. The peptide comprises an extracellular antigen binding domain with at least two BCMA-binding moieties, a transmembrane domain, and an intracellular signaling domain. The dose of CAR-T cells administered to the subject is from 4.010.sup.5 to 1.010.sup.6 of CAR-T cells per kilogram of the subject's mass. Alternatively, the dose comprises 110.sup.6 to 110.sup.8 of the CAR-T cells.

Provided herein are methods for selecting and stimulating a plurality of cells in a sample of cells using column chromatography, and collecting the cells without using additional steps or reagents to facilitate detachment of the cells from the column. In some aspects, the methods provided herein reduce the time needed to generate a population of selected and stimulated cells useful for genetic engineering, and ultimately, cell therapy, compared to existing methods. Also provided are articles of manufacture and apparatus thereof.

Chimeric antigen receptors containing BCMA antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.

Modified immune cells expressing a heterodimeric gamma-delta T cell receptor (TCR) and a chimeric antigen receptor (CAR) are described. The disclosed modified immune cells enhance expression of CARs. Also disclosed are compositions and methods for making such cells, and use of such cells in treating disease.

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising V.sub.H having the amino acid sequence of SEQ ID NO: 4 and V.sub.L having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. A preferred co-stimulatory domain is CD28 or 41-BB. The humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.

The present disclosure provides methods of treating multiple myeloma in a patient in need thereof comprising administering a gamma secretase and a B-cell maturation antigen (BCMA)-directed therapy to the patient.

The present disclosure provides bispecific chimeric antigen receptors targeting BCMA and CD19. The CAR may comprise an scFv targeting BCMA and an scFv targeting CD19, a hinge region, a transmembrane domain, a co-stimulatory region, and a cytoplasmic signaling domain. The chimeric antigen receptors can be used to treat autoimmune disorders or cancer.