The present disclosure provides regulatable biocircuit systems. Such systems provide modular and tunable protein expression systems in support of the discovery and development of therapeutic modalities.

Provided herein are constitutively active chimeric cytokine receptors (CACCRs). When present on chimeric antigen receptor (CAR)-bearing immune cells, such CACCRs allow for increased immune cell activation, proliferation, persistence, and/or potency. Also provided are methods of making and using the CACCRs described herein.

Provided are viral particles for activating and transducing immune cells in vitro or in vivo, and compositions and methods for using said viral particles.

The present disclosure provides systems, methods, and compositions for conditionally regulating expression of a target gene. Aspects of the present disclosure utilize intracellular signal transduction pathways to regulate the expression of a gene (e.g., transgene, exogenous gene, endogenous gene).

The invention provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, with increased sialidase activity. The invention also provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, in combination with a sialidase. The invention also provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, pretreated with a sialidase.

The invention provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, with increased sialidase activity. The invention also provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, in combination with a sialidase. The invention also provides compositions and methods for treating a patient with cancer with an immune cell, e.g., a T-cell, e.g., an engineered T-cell, pretreated with a sialidase.

The invention relates to a progenitor T cell comprising an expression cassette that enables controlled expression of a trans gene of interest based on the stage of maturation of said progenitor T cell. The invention also relates to a cell population enriched in progenitor T cells of this kind, to a process for preparing progenitor T cells, and to the use of said cells in a treatment method.

The present disclosure concerns dosages for the treatment of human patients susceptible to or diagnosed with a disease, such as cancer. Provided are methods for administering chimeric antigen receptor (CAR)-T cells. Also provided are compositions and articles of manufacture for use in the methods.

The present disclosure provides a heterodimeric, conditionally active chimeric antigen receptor (CAR), and a nucleic acid comprising a nucleotide sequence encoding the CAR. The present disclosure provides cells genetically modified to produce the CAR. A CAR of the present disclosure can be used in various methods, which are also provided.

Regulatory B cells (tBreg) are disclosed herein. These regulatory B cells express CD25 (CD25.sup.+) a pan B cell marker such as B220 (B220.sup.+), and also express CD19 (CD19.sup.+). These regulatory B cells suppress resting and activated T cells in cell contact-dependent manner. Methods for generating these regulatory B cells are also disclosed herein, as are methods for using these regulatory B cells to produce regulatory T cells (Treg). In some embodiments, methods for treating an immune-mediated disorder, such as an autoimmune disease, transplant rejection, graft-versus-host disease or inflammation, are disclosed. These methods include increasing regulatory B cell number or activity and/or by administering autologous regulatory B cells. Methods for treating cancer are also disclosed herein. These methods include decreasing regulatory B cell activity and/or number.