Relapse in adoptive cell transfer of CAR-T cells is often the result of CAR-T cells disappearance. Disclosed herein a method for enhancing CAR-T cell therapy in a subject, comprising administering to a subject undergoing adoptive cell transfer of therapeutic CAR-T cells an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells. As a consequence, a subject treated with a combination of CAR-T cells and an Akt inhibitor is less likely to relapse. Therefore, also disclosed herein is a method for treating a subject, comprising adoptively transferring to the subject an effective amount of a composition comprising a CAR-T cell, and administering to the subject an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells.

Provided are anti-TIGIT antibodies that bind to “T cell immunoreceptor with Ig and ITIM domains (TIGIT)”, including multispecific anti-TIGIT antibodies with binding specificity for TIGIT and one or more additional antigen, and methods of using the same. In certain embodiments, the anti-TIGIT antibodies comprises a single domain antibody that binds to TIGIT. In certain embodiments, the one or more additional antigen comprises Programmed cell death ligand 1 (PDL1).

Methods and systems to reduce neurotoxicity associated with the treatment of CD19.sup.+ B-cell hyperproliferative disorders are disclosed. Neurotoxicity is reduced by the use of agents that protect CD19.sup.+ neurovascular pericytes and/or CD19.sup.+ vSMCs from attack by CD19-targeted therapy, and by modification of CD19-targeted therapy to avoid CD19.sup.+ pericytes and/or CD19.sup.+ vSMCs.

The disclosure provides antigen binding domains that bind cluster of differentiation 3 (CD3) protein, comprising the antigen binding domains that bind CD3ε, polynucleotides encoding them, vectors, host cells, methods of making and using them.

The present disclosure provides methods and compositions for genetically modifying lymphocytes, for example T cells and/or NK cells. In some embodiments, the methods include reaction mixtures, and resulting cell formulations, that are created using whole blood, or a component thereof that is not a PBMC, and additionally comprise T cells and recombinant retroviral particles having polynucleotides that encode a CAR. In some embodiments, modified lymphocytes are reintroduced into a subject subcutaneously. In some embodiments, polynucleotides that provide T cells the ability to regulate cell survival and proliferation in response to binding to a CAR, are provided.

An isolated cytotoxic T-lymphocyte (CTL), said CTL being a tolerance inducing cell and substantially depleted of alloreactivity, and wherein said CTL does not comprise a central memory T-lymphocyte (Tcm) phenotype, the CTL being transduced to express a cell surface receptor comprising a T cell receptor signaling module, is disclosed. Methods of generating same and using same are also disclosed.

The present disclosure provides binding proteins, such as antibodies and antigen-binding fragments, which specifically bind to human CD96 receptor protein (hu-CD96) and are capable of decreasing, inhibiting, and/or fully-blocking immune regulatory effects mediated by hu-CD96. The present disclosure also provides methods of using the antibodies (and compositions thereof) to treat diseases and conditions responsive to decreasing, inhibiting and/or blocking immune regulatory function or activity mediated by CD96 binding to CD155, including effects arising from CD96 interactions with CD226 and/or TIGIT.

Provided are methods of treating cancer with non-competitive, agonist anti-OX40 antibodies and antigen-binding fragments thereof that bind to human OX40 (ACT35, CD134, or TNFRSF4), in combination with a PI3K (phosphatidylinositol-4,5-bis-phosphate 3-kinase) delta inhibitor.

Provided herein are antibodies, or antigen-binding portions thereof, that bind to T-cell immunoglobulin and mucin-domain containing-3 (TIM3) protein. Also provided are uses of these antibodies, or antigen-binding portions thereof, in therapeutic applications, such as treatment of cancer. Further provided are cells that produce the antibodies, or antigen-binding portions thereof, polynucleotides encoding the heavy and/or light chain regions of the antibodies, or antigen-binding portions thereof, and vectors comprising the polynucleotides encoding the heavy and/or light chain regions of the antibodies, or antigen-binding portions thereof.

This invention, inter alia, relates to CD19 binding agents and methods of using such CD19 binding agents for treating disease.