The disclosure relates generally to methods and compositions for performing bone marrow transplants using a non-myeloablative chemotherapeutic agent and chemotherapeutic-resistant cells. Using the methods and compositions described herein, a patient's bone marrow may be reconstituted and the patient avoids adverse side effects, including myeloablation and/or an impaired immune system.

The current invention provides methods to identify ?9?2T-cell receptors (?9?2TCR) that mediate anti-tumour responses. Surprisingly, it was now found that the CDR3 regions of the ?9-T-cell receptor chain and the ?2-T-Cell receptor chain (?2TCR chain) are of importance. Based on these findings, combinatorial-??TCR-chain-exchange (CTE) is proposed as an efficient method for identifying ?9?2TCRs that mediate anti-tumour responses. Using the method of the invention, specific sequences of the respective ?9TCR and ?2TCR chains were identified that mediate anti-tumour responses. Hence, the invention further provides for specific ?9?2TCRs, or fragments thereof, that may be used e.g. in diagnostics or treatment of cancer. The invention further provides for nucleic acid sequences, genetic constructs and retroviral vectors that can be used to express the ?9?2TCRs according to the invention.

The present invention provides a method of carrying out adoptive immunotherapy in a primate subject in need thereof by administering the subject a cytotoxic T lymphocytes (CTL) preparation in a treatment-effective amount. The method comprises administering as the CTL preparation a preparation consisting essentially of an in vitro expanded primate CTL population, the CTL population enriched prior to expansion for central memory T lymphocytes, and depleted prior to expansion of effector memory T lymphocytes. In some embodiments, the method may further comprise concurrently administering Interleukin-15 to the subject in an amount effective to increase the proliferation of the central memory T cells in the subject. Pharmaceutical formulations produced by the method, and methods of using the same, are also described.

Provided herein are T cells expressing a chimeric antigen receptor (CAR) targeted to B cell activating factor receptor (BAFF-R). The CAR targeted to BAFF-R (BAFF-R CAR) described herein includes a domain that binds BAFF-R. Methods of making and using the BAFF-R CAR are also provided.

The present invention relates to a bispecific antibody construct comprising a first binding domain which binds to human DLL3 on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell. Moreover, the invention provides a polynucleotide encoding the antibody construct, a vector comprising said polynucleotide and a host cell transformed or transfected with said polynucleotide or vector. Furthermore, the invention provides a process for the production of the antibody construct of the invention, a medical use of said antibody construct and a kit comprising said antibody construct.

The present invention pertains to novel modulators of resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of immune escape mechanisms and therefore offers a novel approach for treating, or aiding a treatment, of various proliferative diseases such as cancerous diseases, in particular melanoma, pancreatic cancer and colorectal cancer. The invention specifically discloses the receptor Olfactory Receptor, Family 10, Subfamily H, Member 1 (OR10H1)as a checkpoint molecule in tumor resistance against cytotoxic T-cells. Provided is the inhibition of OR10H1 expression and/or function as a strategy for enhancing tumor susceptibility to a patients T-cell mediated immune response. Provided are antigen binding constructs for the detection of the OR10H1 protein, as well as inhibitory compounds, such as siRNA/shRNA molecules targeting OR10H1 and anti-OR10H1 antibodies, forimpairing the immune escape mediated by OR10H1. The invention furthermore provides screening methods for the identification of novel cancer therapeutics based on the modulation OR10H1 expression/function, diagnostic methods for the detection of immune resistance of a tumor to cytotoxic T-cell responses, as well as pharmaceutical compositions and diagnostic kits for performing these methods.

Certain embodiments of the invention are directed to methods for inducing an immunologic response to a tumor in a patient using mature dendritic cells transfected with a nucleic acid composition encoding one or more tumor antigens and loaded with a corresponding tumor antigen composition.

Disclosed herein are antigen-capturing nanoparticles. Specifically, the subject matter contained herein pertains to novel nanoparticles that can capture a multitude of tumor antigens that are released from tumor cells. Also, provided herein are methods for preparing the antigen-capturing nanoparticles and methods for the treatment of disease in a subject comprising administering the antigen-capturing nanoparticles.

Embodiments of the disclosure include methods and compositions that allow for development of efficient chimeric antigen receptors (CARs) by selecting appropriate spacer content and/or length by balancing the effects of tonic signaling with the efficacy of antigen recognition for the spacer. In specific embodiments, the CH3 domain from IgG2 is utilized as a spacer. In specific embodiments, T cell metabolic activity is utilized as a measure of tonic signaling to facilitate determination of suitable CAR constructs. In other embodiments, cells bearing chimeric Fc receptor target molecules are utilized to target Fc gamma receptor (FcR)-bearing for the purpose of their destruction.

Compositions and methods relating to regulatable chimeric antigen receptors (RCARs), where the intracellular signaling or proliferation of the RCAR can be controlled to optimize the use of an RCAR-expressing cell to provide an immune response, are provided. For example, a RCAR can comprise a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain, or costimulatory ECD domain. An RCAR can be engineered to include an appropriate antigen binding domain that is specific to a desired antigen target and used in the treatment of a disease.