Novel therapeutic immunotherapy compositions comprising at least two vectors, each vector encoding a functional CAR, whereby the combination of vectors results in the expression of two or more non-identical binding domains, wherein each vector encoded binding domain(s) are covalently linked to a transmembrane domain and one or more non-identical intracellular signaling motifs are provided herein as well as are methods of use of same in a patient-specific immunotherapy that can be used to treat cancers and other diseases and conditions.

The present invention provides a cell comprising first and second chimeric antigen receptors (CARs), which bind to different antigens, wherein the first CAR binds to Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). The present invention also provides a cell comprising a tan CAR comprising first and second antigen-binding domains which bind to different antigens, wherein the first antigen binding domain binds the antigen Transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). The present invention further provides corresponding nucleic acid sequences and/or constructs, kits and vectors comprising said nucleic acid sequences and/or constructs, molecules and methods for making such cells. The cells may be used in cellular immunotherapy approaches for treating diseases such as multiple myeloma.

The invention relates to cell preparations comprising dendritic cell (DC) sub-populations, methods of obtaining such cell preparations, and the use of such preparations for improved immune and cancer therapy. More specifically, embodiments of the invention relate to the production and use of substantially pure human DC subpopulations, useful in the preparation of vaccines against inflammatory diseases and cancer, as well as cell preparations for eliciting immuno-tolerance.

The invention relates to cell death inducing chimeric antigen receptors (D-CAR). In particular, the present invention relates to cell death inducing chimeric antigen receptors which comprise at least one death domain in their endodomain, including cell death inducing chimeric antigen receptors comprising within their death domains modifications which attenuate the self-association and/or binding to pro-apoptotic or pro-necrotic adaptor proteins, such as FADD or TRADD. Moreover, the present invention relates to an engineered immune cell expressing at its surface a cell death inducing CAR of the present invention and, optionally, an activating chimeric antigen receptor, wherein the extracellular ligand-binding domains of the cell death inducing CAR and the activating CAR bind to different antigens. The engineered immune cell may furthermore comprise at least one edited (e.g., inactivated) gene selected from TCR genes, immune check point genes, genes involved in drug resistance, and combinations thereof.

The present invention provides a chimeric antigen receptor (CAR) which binds a target antigen having a bulky extracellular domain, wherein the CAR comprises a Fab antigen binding domain. The present invention also provides nucleic acid sequences and constructs encoding such a CAR, cells expressing such a CAR and their therapeutic uses.

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising an antigen-binding domain, a transmembrane domain and an intracellular domain wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22; and wherein the first and/or second CAR is a tunable CAR having an intracellular domain comprising a heterodimenzation domain, which intracellular domain is capable of binding a separate intracellular signalling molecule which comprises a reciprocal heterodimenzation domain and a signalling domain.

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.

Provided herein is a composition comprising, a cell, comprising nucleic acids encoding a chimeric antigen receptor (CAR) and one or more of signaling proteins selected from K13-vFLIP, MC159-vFLIP, cFLIP-L, cFLIP-p22, HTLV1-Tax and HTLV2-Tax, wherein the CAR comprises an a) extracellular antigen specific domain, b)a transmembrane domain and c) an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM); wherein c) is located at the C-terminus of the chimeric receptor. In some embodiments, the CAR further comprises one or more co-stimulatory domains. Also provided herein are methods for treating diseases using the compositions described herein.

An embodiment of the invention provides bicistronic chimeric antigen receptor (CAR) amino acid constructs. Nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the CAR constructs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed. Methods of making the CAR constructs are disclosed.

The present disclosure provides compositions and methods for treating diseases associated with expression of CD19 and/or CD22, e.g., by administering a recombinant T cell or natural killer (NK) cell comprising a CD22 CAR and a CD19 CAR as described herein. The disclosure also relates to CAR molecules specific to CD22 and/or CD19, methods of making a cell comprising the same and vectors encoding the same.