The present invention concerns new engineered immune cells expressing two CARs directed against two different targets, polynucleotides for preparing said immune cells, pharmaceutical compositions comprising said immune cells, and the use of said immune cells in the treatment of cancers.

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.

Chimeric antigen receptors containing CD19/CD22 or CD22/CD19 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.

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 application relates generally to genetically modified arenaviruses that are suitable vaccines against neoplastic diseases, such as cancer. The arenaviruses described herein may be suitable for vaccines and/or treatment of neoplastic diseases and/or for the use in immunotherapies. In particular, provided herein are methods and compositions for treating a neoplastic disease by administering a genetically modified arenavirus in combination with an immune checkpoint inhibitor, wherein the arenavirus has been engineered to include a nucleotide sequence encoding a tumor antigen, tumor associated antigen or antigenic fragment thereof.

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.

Provided herein are immuno-responsive cells expressing a B cell targeting pCAR comprising a 2nd generation chimeric antigen receptor (CAR) and a chimeric co-stimulatory receptor (CCR). Also provided herein are methods of preparing the immuno-responsive cells and methods of directing T cell mediated immune response using the immuno-responsive cells.

Provided is an engineered immune cell comprising on its surface a recognition molecule that comprises a binding moiety specifically binding to a target molecule on the surface of a target cell, wherein the target molecule comprises an extracellular domain, and wherein the immune cell is capable of killing a target cell that comprises on its surface the target molecule. In one aspect, the binding moiety specifically binds to a distal portion of the extracellular domain, and the immune cell is capable of killing a target cell that comprises on its surface both the target molecule and the recognition molecule. In another aspect, the binding moiety specifically binds to a proximal portion of the extracellular domain, and the engineered immune cell has no or reduced capability of killing a target cell comprising on its surface both the target molecule and the recognition molecule.

The present invention provides a method for preconditioning a subject who is about to receive a therapeutic T-cell composition, which comprises the step of administering one or more doses of a checkpoint inhibitor to the subject prior to administration of the therapeutic T-cell composition, wherein the subject does not receive any further doses of the checkpoint inhibitor after administration of the therapeutic T-cell composition.

The present invention provides a virus-like particle (VLP) having a viral envelope which comprises: (i) a membrane protein comprising the extracellular domain of CD86; and (ii) a CD3-binding membrane protein. The VLP may be used to activate T cells prior to viral transduction.