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Preprint WatchModerateSeptember 26th, 2026

Immune-Depleted Features of HER2-Expressing Gastric Cancer and Immune Remodeling After Trastuzumab-Containing Therapy

Harima T, Hu Q, Ando K, Kawazoe T, Nambara S, Tsuda Y, Nakanoko T, Oki E, Yoshizumi T.

HER2-expressing gastric cancer is immune depleted at baseline, with lower CD8 infiltration, lower PD-L1 CPS and lower cytolytic activity, and trastuzumab-containing preoperative therapy remodels that microenvironment.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that HER2-expressing gastric cancers are immune depleted at baseline and that trastuzumab-containing therapy remodels the microenvironment, which is an argument for combining anti-HER2 agents with immune activation. Claidex holds two prior ERBB2 failures. In poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch, potent preclinical activity against HER2 exon 20 insertions did not carry into durable clinical benefit. In xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation, a HER2-directed STING agonist antibody drug conjugate built on exactly this immune-remodeling premise was discontinued in Phase 1. The second is the direct precedent, since it tested the therapeutic version of the hypothesis this preprint advances. Severity is MODERATE on the count rule, and the specific warning is that immune remodeling after anti-HER2 therapy has already been observed and has not yet converted into a successful combination program.

Abstract excerpt

Purpose Immune checkpoint inhibitors (ICIs) have become integral to the treatment of gastric cancer, and pembrolizumab combined with trastuzumab and chemotherapy has improved outcomes in HER2-positive advanced disease. However, the baseline immune phenotype of HER2-expressing gastric cancer and the changes induced by anti-HER2 therapy remain incompletely defined. We investigated the local immune microenvironment associated with HER2 expression and explored immune changes after trastuzumab-containing preoperative therapy. Methods Three complementary analyses were performed. First, HER2 expression, CD8 + T-cell infiltration, and PD-L1 combined positive score (CPS) were assessed by immunohistochemistry in 64 gastrectomy specimens without preoperative therapy. Second, The Cancer Genome Atlas gastric cancer dataset was used to examine ERBB2 amplification in relation to somatic mutation count, cytolytic activity (CYT) score, and CIBERSORT-estimated immune-cell fractions. Third, paired pretreatment biopsy and post-treatment resection specimens from six patients with HER2-positive gastric cancer who received trastuzumab-containing preoperative therapy were analyzed for CD8, PD-L1, PD-L2, SIRPα, and CD80. Results The IHC 2+/3 + group showed significantly lower CD8 + T-cell infiltration and lower PD-L1 CPS than the IHC 0/1 + group (P = 0.04 and P = 0.03, respectively). In TCGA, ERBB2-amp

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.