Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases

Jiang, Ting; Zhang, Hongji; Li, Yiming; Preethi, Jayakumar; Liao, Hong; Huang, Hai; Billiar, Timothy R.; Deng, Meihong

doi:10.1172/jci.insight.160063

Cited by 3 publications

(2 citation statements)

References 36 publications

(94 reference statements)

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“…Optimal treatment schedules are lacking and are hampered by the heterogeneity of evidence. Intraperitoneal immunotherapy, such as checkpoint inhibitors or tumor-specific antibodies, might be a promising route for in the future, but current evidence is confined to animal-studies only [62,63]. To generalize the use of intraperitoneal chemotherapy and to determine the optimal drug combination, studies directly comparing different regimens are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…These novel methods might enhance intraperitoneal drug delivery by prolonging its local exposure, but no clinical or pharmacokinetic studies in patients with unresectable peritoneal disease have been performed so far. Intraperitoneal immunotherapy (anti-PD-1 therapy) has been studied in vivo for intraperitoneal use [62,63]. A cellular immune response has been shown in mouse models and might therefore have potential as an intraperitoneal drug, but as yet, no pharmacokinetic or clinical data are available demonstrating this rationale.…”

Section: Novel Intraperitoneal Agentsmentioning

confidence: 99%

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Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Guchelaar

Noordman

Koolen

et al. 2023

Drugs

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Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-022-01828-7.

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Section: Discussionmentioning

confidence: 99%

Section: Novel Intraperitoneal Agentsmentioning

confidence: 99%

Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Guchelaar

Noordman

Koolen

et al. 2023

Drugs

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Activation of TLR9 signaling suppresses the immunomodulating functions of CD55lo fibroblastic reticular cells during bacterial peritonitis

Jiang,

Li,

Huang

et al. 2024

Front. Immunol.

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Fibroblastic reticular cells (FRCs) are a subpopulation of stromal cells modulating the immune environments in health and disease. We have previously shown that activation of TLR9 signaling in FRC in fat-associated lymphoid clusters (FALC) regulate peritoneal immunity via suppressing immune cell recruitment and peritoneal resident macrophage (PRM) retention. However, FRCs are heterogeneous across tissues and organs. The functions of each FRC subset and the regulation of TLR9 in distinct FRC subsets are unknown. Here, we confirmed that specific deletion of TLR9 in FRC improved bacterial clearance and survival during peritoneal infection. Furthermore, using single-cell RNA sequencing, we found two subsets of FRCs (CD55hi and CD55lo) in the mesenteric FALC. The CD55hi FRCs were enriched in gene expression related to extracellular matrix formation. The CD55lo FRCs were enriched in gene expression related to immune response. Interestingly, we found that TLR9 is dominantly expressed in the CD55lo subset. Activation of TLR9 signaling suppressed proliferation, cytokine production, and retinoid metabolism in the CD55lo FRC, but not CD55hi FRC. Notably, we found that adoptive transfer of Tlr9-/–CD55lo FRC from mesenteric FALC more effectively improved the survival during peritonitis compared with WT-FRC or Tlr9-/–CD55hi FRC. Furthermore, we identified CD55hi and CD55lo subsets in human adipose tissue-derived FRC and confirmed the suppressive effect of TLR9 on the proliferation and cytokine production in the CD55lo subset. Therefore, inhibition of TLR9 in the CD55lo FRCs from adipose tissue could be a useful strategy to improve the therapeutic efficacy of FRC-based therapy for peritonitis.

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Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer

Xia,

Geng,

2023

Cancers

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Peritoneal metastasis (PM) is a common mode of distant metastasis in colorectal cancer (CRC) and has a poorer prognosis compared to other metastatic sites. The formation of PM foci depends on the synergistic effect of multiple molecules and the modulation of various components of the tumor microenvironment. The current treatment of CRC-PM is based on systemic chemotherapy. However, recent developments in local therapeutic modalities, such as cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC), have improved the survival of these patients. This article reviews the research progress on the mechanism, characteristics, diagnosis, and treatment strategies of CRC-PM, and discusses the current challenges, so as to deepen the understanding of CRC-PM among clinicians.

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Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases

Cited by 3 publications

References 36 publications

Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Activation of TLR9 signaling suppresses the immunomodulating functions of CD55lo fibroblastic reticular cells during bacterial peritonitis

Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer

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