The present disclosure arises at least in part from the seminal recognition that a combination treatment regimen including one or more cycles and/or doses of a checkpoint inhibitor and a therapeutic, either sequentially, in either order, or substantially simultaneously, can be more effective in treating cancer in some subjects and/or can initiate, enable, increase, enhance or prolong the activity and/or number of immune cells, or a medically beneficial response by a tumor.

The present invention relates to antibodies, binding polypeptides, and scFvs specific for fibroblast activation protein (FAP) capable of cross reacting with canine, mouse, and human FAP.

Embodiments of the disclosure include methods and compositions related to targeting of antigen-expressing cells with particular engineered antigen receptors expressed by immune cells. In specific embodiments, immune cells specifically engineered to express particular antigen receptor constructs are cultured in the presence of kinase inhibitors and exhibit reduced fratricidal activity compared to immune cells cultured in the absence of kinase inhibitors. In some embodiments, the genetically engineered immune cells having reduced fratricidal activity are used to treat diseases in subjects, and the fratricidal activity of the genetically engineered immune cells is restored in vivo after substantial elimination of the diseased cells, resulting in elimination of the genetically engineered immune cells.

The invention provides compositions including a fusion polypeptide and methods for making a fusion polypeptide that includes a COF1/CRBN-binding polypeptide, COF2/CRBN-binding polypeptide, or COF3/CRBN-binding polypeptide and a heterologous polypeptide of interest.

A chimeric antigen receptor (CAR), containing a BCMA (B cell maturation antigen) binding domain. The BCMA binding domain includes an antibody or an antigen-binding fragment of an antibody that specifically binds to BCMA. The antibody contains a heavy-chain complementarity determining region 3 (HCDR3), a heavy-chain complementarity determining region 2 (HCDR2), and a heavy-chain complementarity determining region 1 (HCDR1). The HCDR3 contains an amino acid sequence as set forth in SEQ ID NO: 25, the HCDR2 contains an amino acid sequence as set forth in SEQ ID NO: 41, and the HCDR1 contains an amino acid sequence as set forth in SEQ ID NO: 21.

An isolated chimeric antigen receptor polypeptide (CAR), wherein the CAR comprises an extracellular antigen-binding domain, comprising an antibody or antibody fragment that binds a B Cell Maturation Antigen (BCMA) polypeptide. The CAR preferably binds an epitope comprising one or more amino acids of residues 13 to 32 of the N-terminus of human BCMA. Also disclosed is a nucleic acid molecule encoding the CAR of the invention, a genetically modified immune cell, preferably a T cell, expressing the CAR of the invention and the use of said cell in the treatment of a medical disorder associated with the presence of pathogenic B cells, such as a disease of plasma cells, memory B cells and/or mature B cells, in particular multiple myeloma, non-Hodgkin's lymphoma or autoantibody-dependent autoimmune diseases.

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

Anaplastic large cell lymphoma (ALCL) is a rare and aggressive peripheral T-cell lymphoma affects lymph nodes and extra-nodal sites with characteristic skin lesions. Approximatively half of the tumors express the NPM1-ALK fusion from the translocation t(2;5)(p23;q32). In the present study, the inventors identify ROR2 as progressively up regulated thought tumorigenesis. Patient samples show a significantly high ROR2 expression (transcriptomic data) as well as a strong ROR2 protein expression (IHC) with some tumors displaying a clear membrane signal. ROR2 mRNA expression level is also positively correlated to NPM-ALK expression level in tumor cells and is not expressed in normal T cells. In addition, ROR2 protein level is significantly increased in resistant cells to the ALK inhibitor, crizotinib, used in clinical trials for children with refractory tumors. This result opens the road to ROR2 specific therapies: ROR2 inhibitors, monoclonal antibodies therapies or even ROR2 specific CAR cells, including for ALCL ALK(+) resistant tumors.

Disclosed is a method for obtaining a population of human Treg cells including the steps of: (a) culturing a population of human monocytes with a medium including an amount of an interleukin-34 (IL-34) polypeptide in order to obtain a population of immunosuppressive macrophages; (b) co-culturing a population of human peripheral blood mononuclear cells (PBMCs) and the population of immunosuppressive macrophages obtained at step (a).

Provided herein, in some embodiments, are methods and compositions (e.g., cell compositions) for the treatment of cancer, such as PTK7.sup.+ malignancies.