Compositions and methods described in this document make use of macrophage derived engineered vesicles (MEV) having specificity for delivery to a target environment, for use in modifying macrophage phenotype and/or treating a condition. Further disclosed are MEV derived from a specific phenotype encapsulating a therapeutic agent for targeted therapeutic delivery.

Induced pluripotent stem cells are treated using a combination of compounds that improve competence of the induced pluripotent stem cells in responding to differentiation signals and/or improve the efficiency of differentiation of the treated induced pluripotent stem cells in differentiation towards a desired phenotype. The combination treatment can incorporate two or more of prolongation of early G1 phase, treatment with an interleukin, modulation of DNA methylation, modulation of histone acetylation, and activation of the Wnt pathway. Cells derived from induced pluripotent stem cells so treated can be used in regenerative therapy and production of organoids.

Provided herein are methods of producing TILs via (i) pre-REP stimulation with a combination of interferon gamma (IFN) and an anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody (ii) various concentrations of IL-15 and IL-21, with or without low-concentration IL-2, with or without an AKT inhibitor (AKTi) during REP expansion and/or pre-REP expansion, (iii) low-concentration IL-2 and an AKTi during REP expansion and/or pre-REP expansion, (iv) the combination of (i) and (ii), or (v) the combination of (i) and (iii).

Provided herein are methods of producing TILs via (i) pre-REP stimulation with a combination of interferon gamma (IFN?) and an anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody (ii) various concentrations of IL-15 and IL-21, with or without low-concentration IL-2, with or without an AKT inhibitor (AKTi) during REP expansion and/or pre-REP expansion, (iii) low-concentration IL-2 and an AKTi during REP expansion and/or pre-REP expansion, (iv) the combination of (i) and (ii), or (v) the combination of (i) and (iii).

Provided herein are methods of producing TILs via (i) pre-REP stimulation with a combination of interferon gamma (IFN) and an anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody (ii) various concentrations of IL-15 and IL-21, with or without low-concentration IL-2, with or without an AKT inhibitor (AKTi) during REP expansion and/or pre-REP expansion, (iii) low-concentration IL-2 and an AKTi during REP expansion and/or pre-REP expansion, (iv) the combination of (i) and (ii), or (v) the combination of (i) and (iii).

Compositions and methods described in this document make use of macrophage-derived engineered vesicles (MEV) having specificity for delivery to a target environment, for use in modifying macrophage phenotype and/or treating a condition.