The present application provides single-domain antibodies targeting BCMA, and chimeric antigen receptors (such as monovalent CAR, and multivalent CAR including bi-epitope CAR) comprising one or more anti-BCMA single-domain antibodies. Further provided are engineered immune effector cells (such as T cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.

Provided are engineered cells for adoptive therapy, including NK cells and T cells. Also provided are compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to subjects. In some aspects, features of the cells and methods provide specificity and/or efficacy. In some embodiments, the cells contain genetically engineered antigen receptors that specifically bind to antigens, such as chimeric antigen receptors (CARs) and costimulatory receptors. In some embodiments, the cells include receptors targeting multiple antigens. In some embodiments, the cells include repression of one or more gene product, for example, by disruption of a gene encoding the gene product. In some embodiments, a gene encoding an antigen recognized by the engineered antigen receptor is disrupted, reducing the likelihood of targeting of the engineered cells.

Described herein, are the extended and newly discovered novel formulations of FL118 for cancer treatment to preclude, eliminate or reverse cancer phenotypes and treatment resistance.

The present invention provides compositions and methods comprising anti-CD38 chimeric antigen receptors (CARs). Compositions and methods of treatment are also provided.

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the used thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma. In the present invention, the inventors have generated a new antibody against CD38 that could be suitable for producing bispecific antibodies as well as CAR-T cells. In particular, the inventors report the development of Bi38-3, a new bispecific T cell engager that targeted CD38 on MM cells and recruited cytotoxic T cells through the CD3. Bi38-3 lacked the Fc region of natural mAb, which contributes to resistance processes, but triggered T cells to proliferate, release cytokine and lyse CD38 positive MM cells in vitro. Similarly, Bi38-3 induced autologous T cells to eliminate tumor plasma cells isolated from MM patients both at diagnosis and at relapse. The cytotoxicity triggered by Bi38-3 was restricted to cells expressing high levels of CD38 and preserved the integrity of T, B and NK lymphocytes in vitro. Importantly, Bi38-3 rapidly reduced tumor cells in an MM1.S xenograft mouse model of human MM. Taken together, the results show that the antibody of the present invention is an effective reagent to specifically eliminate CD38 positive malignant cells without significantly affecting CD38 lowly expressing cells and represents a promising novel immunotherapeutic tool for the treatment of malignant hematological diseases, and especially multiple myeloma.

The method entails modification of non-malignant cells for transplantation or therapy to avoid recognition and attack by monoclonal antibodies and antibody-derived therapeutics. Many therapies that use monoclonal antibodies or antibody-derived therapeutics not only bind to the intended target epitope on malignant cells, but also to the same target epitope on healthy non-malignant cells that express the target antigen. This phenomenon is termed on-target off-tumor effect. This can cause rejection, immune cell attack or opsonization of non-malignant cells, which in turn can cause severe side effects which often hampers the therapeutic effect. Similarly, cytokines in cytokine therapy can bind to receptors on bystander cells and cause unintended effects. The methods of the present invention change the antigen epitope or the cytokine receptor on non-malignant and bystander cells for adoptive cell therapy, thereby disrupting the binding of the therapeutic agentantibody or cytokineto the target antigen or receptor on non-malignant cells.

The present application provides single-domain antibodies targeting BCMA, and chimeric antigen receptors (such as monovalent CAR, and multivalent CAR including bi-epitope CAR) comprising one or more anti-BCMA single-domain antibodies. Further provided are engineered immune effector cells (such as T cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.

The present invention relates to engineered T-cell(s) and methods for using the same as a therapeutic with a potent and selective ability to target an antigen of choice. Engineered T-cells of the disclosure are useful in the treatment of various cancers, infectious diseases, and immune disorders. Also disclosed are methods for expanding engineered and non-engineered T-cell(s) populations to therapeutically useful quantities. An engineered T-cell of the disclosure can be a universal donor, and can be administered to a subject with any MHC haplotype.

Chimeric antigen receptors containing CD38 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.