Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy

Abstract

Key Points GD2-specific CAR renders NKT cells cytotoxic against NB cells and results in potent in vivo antitumor activity without graft-versus-host disease. The 4-1BB-containing CAR constructs induce T helper 1–like polarization in NKT cells.

CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

“…Next, we tested whether the B-8-2 clone was capable of propagating NKTs to clinically sufficient numbers. Figure 6B demonstrates that 1 round of restimulation with B-8-2 produced 272.32 ± 111-fold expansion of NKTs from 4 donors (range from 156 to 424) within 3 weeks, similar to the NKT numbers generated after stimulation with autologous PBMCs (18). However, NKTs expanded with B-8-2 contained significantly higher frequencies of CD62L + cells compared with PBMC-expanded NKTs (P = 0.0089, Figure 6C).…”

“…Conversely, tumor progression is often accompanied by a decrease in NKT number or functional activity (16), or the downregulation of CD1d expression on malignant cells (17). To counteract these tumor escape mechanisms, we developed methods to expand primary human NKTs to clinical scale ex vivo and to redirect their cytotoxicity against tumor cells via transgenic expression of chimeric antigen receptors (CARs) (18). Similar to the observations reported in CAR-T cell clinical trials (19,20), there is a strong correlation between the antitumor efficacy and in vivo persistence of CAR-NKT products in a xenogenic tumor model (18).…”

“…To counteract these tumor escape mechanisms, we developed methods to expand primary human NKTs to clinical scale ex vivo and to redirect their cytotoxicity against tumor cells via transgenic expression of chimeric antigen receptors (CARs) (18). Similar to the observations reported in CAR-T cell clinical trials (19,20), there is a strong correlation between the antitumor efficacy and in vivo persistence of CAR-NKT products in a xenogenic tumor model (18). However, the mechanisms that govern ex vivo expansion and subsequent in vivo persistence of human NKTs remain largely unknown, impeding rational design of NKT-based cancer immunotherapy.…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…More recently, T cell-based immunotherapy has been successfully used to treat many human cancers, such as melanoma, renal cell carcinoma, and lymphoma with varying degrees of tumor regression [5][6][7][8]. Although CD4 + and CD8 + T cells are the major components of T cell-mediated antitumor immunity, natural killer (NK) and NKT cells may also play a role in immunosurveillance against cancer [2,[9][10][11][12].…”

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

“…9 Several groups in the United Kingdom as well as colleagues in Europe are considering direct ACT with NKT cells and/or NKT cells modified with viral vectors encoding chimeric antigen receptors (CARs), based upon their greater efficacy than conventional T-cells in a mouse xenotransplant model. 10 ACT based upon the use of cd T-cells has been largely pioneered in Japan, where ex vivo expansion of cd T-cells using zoledronic acid has been investigated.…”