Off-the-shelf third-party HSC-engineered iNKT cells for ameliorating GvHD while preserving GvL effect in the treatment of blood cancers

Target tumor microenvironment by innate T cells

“…The stem cell-derived innate T cells have high yield and purity and can be transferred to more cancer patients. (DLL-1) or 4 (DLL-4), was utilized to generate iPSC-derived iNKT and MAIT cells; the artificial thymic organoid (ATO) culture system, which is based on DLL-1-or DLL-4-overexpressed mouse stromal cell line MS5, was used to develop HSC-engineered iNKT cells; feeder-free, serum-free culture system has also been developed recently to generate iNKT cells with high yield, purity, and safety profile (43,48,50,(127)(128)(129)(130). Overall, in vitro generation of CAR-engineered innate iNKT, MAIT, and gdT cells have the potential to effectively target both tumor cells and immunosuppressive cells, thus highlighting the capacity of innate T cell-based therapy for treatment of solid tumors, especially in the absence of inflammatory signaling, a defect characteristic of TME afflicted "cold" tumors.…”

“…Multiple stem cell sources (e.g., HSCs, ESCs, and iPSCs) and stem cell culture approaches (e.g., OP9-DL, artificial thymic organoid, and Feeder-Free culture) have been employed to generate innate T cells that bear close resemblance to healthy donor PBMC-derived immune cells and maintain their potent tumor targeting capabilities ( Figure 3B ) ( 48 , 50 , 127 , 128 ). For example, the OP9-DL system, which is based on a mouse stromal cell line OP9 overexpressing the Notch ligand, Delta-like ligand 1 (DLL-1) or 4 (DLL-4), was utilized to generate iPSC-derived iNKT and MAIT cells; the artificial thymic organoid (ATO) culture system, which is based on DLL-1- or DLL-4- overexpressed mouse stromal cell line MS5, was used to develop HSC-engineered iNKT cells; feeder-free, serum-free culture system has also been developed recently to generate iNKT cells with high yield, purity, and safety profile ( 43 , 48 , 50 , 127 – 130 ). Overall, in vitro generation of CAR-engineered innate iNKT, MAIT, and γδT cells have the potential to effectively target both tumor cells and immunosuppressive cells, thus highlighting the capacity of innate T cell-based therapy for treatment of solid tumors, especially in the absence of inflammatory signaling, a defect characteristic of TME afflicted “cold” tumors.…”

“…During human stem cell culture, induction of mouse-derived stromal feeder cells (e.g., OP9 and MS5 cells) could potentially increase the risk of mouse cell contamination. The manufacturing process can be improved through replacement with a feeder-free culture system to improve the safety profile of cell products and accelerate the clinical development ( 43 , 57 ). In addition, the highly inflammatory and cytotoxic function of Allo HSC-iNKT cells in conjunction with their rapid in vitro and in vivo cell proliferation may induce cytokine release/storm syndrome (CRS) as a side-effect during massive lysis of tumor cells and TAMs.…”

“…Since their powerful antitumor activity remains independent of antigen priming and MHC restrictions, iNKT cells have become a major focus in the development of novel cell-based immunotherapies. Additionally, implementation of iNKT cells as a strategy for cell-based immunotherapy offers several other advantages, such as eliminating the risk of graft versus host disease (GvHD) from lack of MHC engagement as well as ancillary remediation of the TME through cytotoxic killing of CD1d-expressing TAMs and MDSCs (29,(41)(42)(43). Among macrophages, selective expression of CD1d on TAMs renders iNKT therapy an ideal method for precise disruption of TAM immunosuppression while preserving the pro-inflammatory function of classically activated macrophages (44,45).…”

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

“…A few selected publications from 2022 demonstrate further novel approaches of ACT: (i) adoptive immunotherapy with engineered invariant natural killer T (iNKT) cells to target cancer cells and the suppressive microenvironment [ 137 ]. Off-the-shelf third-party HSC-engineered iNKTcells were demonstrated in xenograft models to ameliorate GvHD while preserving a GvL effect in the treatment of blood cancers [ 138 ]. (ii) use of IL15 in cell-based cancer immunotherapy [ 139 ], (iii) immunotherapy of TAA positive common solid cancers with natural high-avidity TCR-engineered T cells [ 140 ], (iv) improvement of immunotherapeutic efficacy against solid tumors in mice with dual-specific chimeric antigen receptor (CAR) T cells expanded in vitro with TCR reactivity against OV encoded antigens [ 141 ].…”