CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells

A new study has been published in the prestigious nature.com website, completed by a whole range of scientists. I will try summarise the article below, but is a very interesting and promising read and demonstrates the potential that NKT cell therapy will be far superior in the treatment of solid tumours vs CAR-T treatment.

Abstract:
"Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic

Results:
CAR-NKT cells target tumour cells in vitro
"Collectively, these data show that muribe CAR-NKT cells can target tumour cells via CAR expression"
CAR-NKT cells have superior anittumour activity to CAR-T cells in vivo

"Collectively, these data show that CAR-NKT cells control tumour growth more effectively than CAR-T cells in vivo"
CAR-NKT cells reprogram the TME and reduce M2-like macrophages in a CD1d-dependent manner"Overall, these data indicate that CAR-NKT cells mediate superior antitumor functionality compared with CAR-T cells and that this activity is mediated at least in part by the selective CD1d-dependent reduction of M2-like macrophages, while CD1d low-expressing M1-like macrophages are spared"
CAR-NKT cells promote endogenous T Cell responses by activating DCs"Overall, these data demonstrate that PD1 blockade and vaccination further enhance the antitumor efficacy of CAR-NKT cells"

Discussion:
"In summary, our data show that CAR-NKT cells possess the unique ability to target both tumour cells and immunosuppressive M2-like macrophages. In addition, we also demonstrated that CAR-NKT cells can promote endogenous T cell responces to neoantigens in solid tumours by mediating CD1d-dependant activation of DCs. Finally, PD1 blockade and vaccination enhance CAR-NKT antitumor activity. Collectively, our results demonstrate the multimodal action of CAR-NKT cells in solid tumours, further supporting their exploration in clinical studies"


article: https://www.nature.com/articles/s43018-024-00830-0