The present invention concerns methods and compositions for immunotherapy employing a modified T cell comprising disrupted T cell receptor and/or HLA and comprising a chimeric antigen receptor. In certain embodiments, the compositions are employed allogeneically as universal reagents for “off-the-shelf” treatment of medical conditions such as cancer, autoimmunity, and infection. In particular embodiments, the T cell receptor-negative and/or HLA-negative T cells are generated using zinc finger nucleases, for example.

The present invention provides immunoresponsive cells, including T cells, cytotoxic T cells, regulatory T cells, and Natural Killer (NK) cells, expressing an antigen recognizing receptor and an inhibitory chimeric antigen receptor (iCAR). Methods of using the immunoresponsive cell include those for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.

A genetically modified cytotoxic T cell includes one or more exogenous nucleic acid molecules encoding a transgenic antigen-targeting construct. Estrogen receptor-binding fragment-associated antigen 9 (EBAG9) activity is inhibited in the cells. The antigen-targeting construct can be a chimeric antigen receptor (CAR) or T cell receptor (TCR). The modified T cell can be used in the treatment of a proliferative disease, in particular for the treatment of hematologic malignancies. A pharmaceutical composition includes the modified T cell, a nucleic acid vector encoding the antigen-targeting construct and an inhibitor of EBAG9, such an RNA interference molecule. An in vitro method can increase the cytolytic activity of a cytotoxic T cell.

There is disclosed an improved, safer and commercially efficient process for developing genetically engineered cells. More specifically, there is disclosed a process comprises introducing a donor DNA construct, a guide RNA, and an RNA-guided nuclease with the host cells to be transfected; and introducing the three components into the host cell. There is further disclosed a donor DNA construct designed for inserting a CAR (chimeric antigen receptor) into a defined genomic site of a host cell. Further, the present disclosure provides a host cell transfected with a CAR that lacks viral vectors that can present a safety concern. The disclosure provides for more efficient and more cost-effective process for engineering T cells to express CAR constructs.

CD30-binding moieties, chimeric antigen receptors (CARs) having these CD30-binding moieties, and uses thereof are provided. Polynucleotides encoding the CD30-binding moieties and CARs, compositions comprising CD30-binding moieties and CARs, genetically modified immune cells having a chimeric antigen receptor for use in adoptive cell therapy for treating CD30-expressing cancer or tumor in a subject in need thereof are also provided herein.

The invention provides methods of making immune effector cells (for example, T cells, NK cells) that express a chimeric antigen receptor (CAR), and compositions generated by such methods.

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Described herein is a method of preventing or treating a disease in a mammalian subject, comprising administering to the subject who is in need thereof an effective dosage of a pharmaceutical composition comprising a virus like particle (VLP) comprising: an alphavirus replicon comprising a recombinant polynucleotide, wherein the polynucleotide comprises a sequence encoding both subunits of a human class II major histocompatibility antigen, a retroviral gag protein, and a fusogenic envelope protein, wherein the VLP does not contain an alphavirus structural protein gene.

The present invention relates to combination therapies employing anti-CD20/anti-CD3 bispecific antibodies and 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules, the use of these combination therapies for the treatment of cancer and methods of using the combination therapies.

The present disclosure relates to combinations of antibodies, or antigen-binding fragments thereof, that bind to CD137, and PD-1 antagonists. The disclosure also relates to methods for treating or ameliorating one or more symptoms of a disease, such as cancer, by administering the combination.