Convection-enhanced delivery of nanoencapsulated gene locoregionally yielding ErbB2/Her2-specific CAR-macrophages for brainstem glioma immunotherapy

Abstract

Locoregional delivery of chimeric antigen receptor (CAR)-modified T (CAR-T) cells has emerged as a promising strategy for brain tumors. However, the complicated ex vivo cell manufacturing procedures and the rapid progression of the disease have limited its broader applications. Macrophages (MΦs) exhibit unique effector functions and a high degree of infiltration within the solid tumor microenvironment (TME), especially in the brain, where MΦs function as structural support, and the main immune effector cells of the CNS represent 5–12% of brain cells. Here, we report a synthetic universal DNA nanocarrier for in situ genetic editing of intratumoral MΦs with an ErbB2-specific CAR to direct their phagocytic activity towards tumors and subsequently initiate a locoregional antitumor immune response. Specifically, we demonstrated that when delivered locoregionally, the RP-182 peptide, located in the shell of a nanoparticle, targeted MΦs and reprogrammed M2-like tumor-associated macrophages (TAMs) to an antitumor M1-like phenotype. Subsequently, the CAR gene-laden DNA nanocomplex can be used to introduce ErbB2-targeted CAR, and the generated CAR-MΦs then act as “living” cures, thereby serially clearing the invasive tumor cells. Our work demonstrates a practical antitumor immunotherapy for brainstem gliomas (BSGs) that may be broadly applicable for patients suffering from other ErbB2-positive solid malignancies.

In Situ Reprogramming of Immune Cells Using Synthetic Nanomaterials

“…Later, following the same design principle, the research group successfully reprogrammed tumor-associated macrophages to CAR-M against ErbB2, or mucin 1 tumor antigens. [74,75] Most recently, the same group reported a unique implant nanoparticle that locoregionally yielded CAR-M targeting Staphylococcus aureus to prevent periprosthetic joint infection. [76]…”

CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy

“…Macrophages can also be induced from hematopoietic stem and progenitor cells (172)(173)(174)(175)(176), human pluripotent stem cells (177), and iPSCs (175,(178)(179)(180). In addition, there is interest in the in-situ generation of CAR macrophages using nanoparticles as well (181)(182)(183)(184). These nanoparticles can induce CAR expression, direct phagocytic activity towards tumor cells, and prompt a shift from M2-like TAMs to M1-like macrophages.…”

“…These engineered macrophages exhibit dual capabilities of phagocytosis and immunomodulation. Notably, HER2-specific CAR macrophages targeting various tumor models have attracted significant attention (166,170,172,173,182). Dong et al developed HER2-CAR macrophages for gastric cancers, utilizing human peritoneal macrophages (166).…”

Good CARMA: Turning bad tumor‐resident myeloid cells good with chimeric antigen receptor macrophages

“…The advent and recent widespread adoption of nanoparticle‐based technologies allow the possibility of delivering small molecules or mRNA to immune cells (particularly phagocytic cells) directly in vivo. This has been done using nanoparticle delivery of mRNA or DNA encoding the anti‐HER2 antibody trastuzumab, the anti‐HER2 CAR construct, or the secretable bispecific engager, or of the pro‐inflammatory transcription factor IRF5 directly in vivo 120–123 …”

“…This has been done using nanoparticle delivery of mRNA or DNA encoding the anti-HER2 antibody trastuzumab, the anti-HER2 CAR construct, or the secretable bispecific engager, or of the proinflammatory transcription factor IRF5 directly in vivo. [120][121][122][123]…”