Utilizing induced neural stem cell‐based delivery of a cytokine cocktail to enhance chimeric antigen receptor‐modified T‐cell therapy for brain cancer

Abstract

Chimeric antigen receptor (CAR)‐modified T‐cell therapy has shown enormous clinical promise against blood cancers, yet efficacy against solid tumors remains a challenge. Here, we investigated the potential of a new combination cell therapy, where tumor‐homing induced neural stem cells (iNSCs) are used to enhance CAR‐T‐cell therapy and achieve efficacious suppression of brain tumors. Using in vitro and in vivo migration assays, we found iNSC‐secreted RANTES/IL‐15 increased CAR‐T‐cell migration sixfold and expansion threefold, resulting in greater antitumor activity in a glioblastoma (GBM) tumor model. Furthermore, multimodal imaging showed iNSC delivery of RANTES/IL‐15 in combination with intravenous administration of CAR‐T cells reduced established orthotopic GBM xenografts 2538‐fold within the first week, followed by durable tumor remission through 60 days post‐treatment. By contrast, CAR‐T‐cell therapy alone only partially controlled tumor growth, with a median survival of only 19 days. Together, these studies demonstrate the potential of combined cell therapy platforms to improve the efficacy of CAR‐T‐cell therapy for brain tumors.

Combination of Oncolytic Virotherapy with Different Antitumor Approaches against Glioblastoma

“…Immunoactivating cytokines, like interleukines, are also able to modulate the TME. However, they trigger serious side effects when administered systemically [91]. In particular, the construction of OVs carrying genes for immunostimulating molecules (e.g., IL-12, IL-15, IL-21, GM-CSF) is common.…”

“…The NSC-CRAd-S-pk7 study noted adverse events, but all of them were related to adjuvant chemo-and radiotherapy [49]. Moreover, interleukins, which are useful in inducing immune responses in patients with glioblastoma, are known to facilitate severe toxicity when administered systemically [91]. At the same time, OVs with insertions of interleukin genes make it possible to bypass this limitation and deliver the necessary immunostimulating molecules directly to the tumor without causing undesirable inflammation.…”