Provided herein are multiplexed T cell receptor compositions, combination therapies, and uses thereof.

Provided herein are methods for manufacturing CAR-T cell products with high purity of TSCM subsets (>90%), independent of the variations from incoming leukapheresis. In some embodiments, to isolate the CCR7 and CD45RA double positive T cell subset, the processes described herein deplete CD45RO positive cells from leukapheresis and positively enrich for a CD4 and CD8 T cell population to isolation both TSCM and effector memory T cell (TEMRA) subsets, both of which positively express CD45RA and CCR7.

The invention provides methods and compositions for administration of allogeneic lymphocytes as an exogenous source of CD4+ T cell help for endogenous, tumor-reactive CD8+ T cells. Depletion of CD8+ T cells from the donor lymphocyte infusion reduces the risk of sustained engraftment and graft-versus-host disease. Removal of regulatory T cells from the infused population may augment the ability of non-regulatory T cells to provide help for endogenous effectors of anti-tumor immunity. Allogeneic T cell therapy is typically given in the context of allogeneic stem cell transplantation, in which the patient receives highly immunosuppressive conditioning followed by an infusion of a stem cell graft containing unselected populations of mature T cells. In the treatment described here, the graft is engineered to minimize the possibility of sustained donor cell engraftment, and the anti-tumor effector T cells derive from the host.

Described herein are methods for selecting lymphocytes for adoptive cell therapy based on P-glycoprotein expression and compositions comprising same.

The presently disclosed subject matter provides for methods and compositions for treating cancer (e.g., breast cancer). It relates to mutant PIK3CA-targeted TCRs that specifically target a mutant PIK3CA peptide (e.g., a human mutant PIK3CA peptide), and immunoresponsive cells comprising such TCRs. The presently disclosed mutant PIK3CA peptide-specific TCRs have enhanced immune-activating properties, including anti-tumor activity.

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 use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors or additional cells in combination therapies.

The present disclosure generally relates to compositions and methods for ex vivo expansion of immune cells isolated from a subject, wherein gene expression can be modulated to enhance immune cell activity in the resulting expanded immune cell culture. Modulation of gene expression in an expanded immune cell culture allows for an immune cell therapy contains genetically chemically modified immune cells suitable for the adoptive cell transfer into a subject in need thereof.

The present disclosure relates to expansion and activation of T cells. In an aspect, the present disclosure relates to expansion and activation of T cells that may be used for transgene expression. In another aspect, the disclosure relates to expansion and activation of T cells while depleting - and/or -TCR positive cells. T cell populations comprising expanded T cell and depleted or reduced - and/or -TCR positive cells are also provided for by the instant disclosure. The disclosure further provides for methods of using the disclosed T cell populations.

The invention provides modified an isolated T lymphocytes having reduced or eliminated expression of the T Cell Receptor, due to reduced or eliminated expression of a CD3, T Cell Receptor Alpha Chain, or T Cell Receptor Beta Chain gene relative to a T lymphocyte without modification, where the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal peptide, and UL18.

The invention provides modified an isolated T lymphocytes having reduced or eliminated expression of the T Cell Receptor, due to reduced or eliminated expression of a CD3, T Cell Receptor Alpha Chain, or T Cell Receptor Beta Chain gene relative to a T lymphocyte without modification, where the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal peptide, and UL18.