Intraperitoneal CAR T-cell therapy for peritoneal carcinomatosis from gastroesophageal cancer: Preclinical investigations to a phase I clinical trial (NCT06623396) Journal Article

   

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Authors:	Restle, D.; Amador-Molina, A.; Misawa, K.; Banerjee, S.; Ku, G.; Adusumilli, P. S.
Article Title:	Intraperitoneal CAR T-cell therapy for peritoneal carcinomatosis from gastroesophageal cancer: Preclinical investigations to a phase I clinical trial (NCT06623396)
Abstract:	<p>Peritoneal carcinomatosis is a frequent metastatic condition in gastroesophageal cancer and is associated with poor prognosis and limited therapeutic options. Here, we establish clinically relevant mouse models of peritoneal carcinomatosis to evaluate the efficacy of a second-generation mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Our model recapitulates key clinical features, including ascites, bowel obstruction, and an immunosuppressive tumor microenvironment characterized by tumor-cell programmed death-ligand 1 expression and elevated TGF-beta levels in ascites. To overcome T-cell exhaustion, we engineered a CAR T-cell construct (M28z1XXPD1DNR) that incorporates a programmed cell death protein-1 decoy receptor lacking the intracellular signaling domain, which enhances functional persistence. We demonstrate that intraperitoneal (regional) administration of CAR T cells at low doses achieves superior antitumor efficacy, longer survival, and sustained functional persistence, compared with intravenous (systemic) administration. Of note, intraperitoneal treatment also exhibits potency against distant disease sites. These findings provide a strong rationale for clinical translation; we are now conducting a clinical trial (NCT06623396) to evaluate intraperitoneal administration of M28z1XXPD1DNR CAR T cells in patients with gastroesophageal cancer peritoneal carcinomatosis.</p>
Keywords:	esophageal cancer; t cell; adoptive cell therapy - act; chimeric antigen receptor - car
Journal Title:	Journal for ImmunoTherapy of Cancer
Volume:	13
Issue:	9
ISSN:	2051-1426
Publisher:	Biomed Central Ltd
Date Published:	2025-09-15
Start Page:	e012292
Language:	English
ACCESSION:	WOS:001571443400001
DOI:	10.1136/jitc-2025-012292
PROVIDER:	wos
PMCID:	PMC12439142
PUBMED:	40954076
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Prasad Adusumilli -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/229014