Study on the Mechanism of ADC Drug Evaluation Based on Immune Co-culture of Lung Cancer Organoids

Summary

A case-control study was conducted to evaluate the efficacy and mechanism of action of antibody-drug conjugates (ADCs) in lung cancer, utilizing patient-derived organoid (PDO)-immune co-cultures. Focusing on HER2-positive and TROP2-positive non-small cell lung cancer (NSCLC) cases, ADC candidates were screened for in vitro activity based on organoid-immune interaction models. Key assessments included: Tumor killing efficiency, assessed by dose-response relationships; Drug internalization (cellular uptake), as a measure of penetration into cancer cells; Antibody-dependent cellular cytotoxicity (ADCC) and bystander effect, with negative control targets employed to delineate specificity; Single-cell RNA sequencing, to profile transcriptional alterations at single-cell resolution. Data demonstrated distinct ADC responses correlating with target expression and immune microenvironment features. The integrated approach provided cell-based evidence of ADC potency and revealed mechanistic insights-including immune-mediated cytotoxicity pathways and intracellular trafficking-supporting the rational design of clinical trials. These findings established a foundation for precision immunotherapy strategies and offered a mechanistic rationale for patient selection in HER2/TROP2-positive lung cancer.

Eligibility

Inclusion Criteria:

* Age ≥ 18 years.
* Availability of patient-derived organoids (PDOs) with matched autologous tumor-infiltrating lymphocytes (TILs) or peripheral blood mononuclear cells (PBMCs) from non-small cell lung cancer (NSCLC) cases.
* Patients currently undergoing or scheduled to receive Trastuzumab deruxtecan (T-DXd) therapy who meet clinical eligibility criteria.
* Provision of written informed consent.
* PDOs exhibiting strong positive HER2 and TROP2 expression by immunohistochemistry (IHC) assigned to the experimental group.
* PDOs exhibiting weak positive HER2 and TROP2 expression by IHC assigned to the negative control group.

Exclusion Criteria:

* PDOs derived from patients with pathologically confirmed small cell lung cancer (SCLC).
* Unavailability of matched autologous PDOs, TILs, or PBMCs.
* Presence of any contraindications to T-DXd treatment.
* Presence of other serious comorbidities resulting in an estimated survival of \<3 months.
* Pregnant or breastfeeding women.

Conditions3

Interventions1

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