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

25 mei 2026 bijgewerkt door: Zhou Chengzhi, Guangzhou Institute of Respiratory Disease

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.

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

A case-control study was conducted to systematically evaluate the therapeutic efficacy and underlying mechanisms of antibody-drug conjugates (ADCs) in non-small cell lung cancer (NSCLC), utilizing an integrated patient-derived organoid (PDO)-immune cell co-culture platform. Focusing on HER2-positive and TROP2-positive NSCLC cases, a comprehensive research pipeline was established, comprising three core components: the construction of a PDO-immune co-culture model, multidimensional tumor killing assessment, and mechanistic dissection of cellular internalization.

Clinically resected tumor tissues and malignant pleural effusion specimens were harvested to generate PDOs, which were rigorously validated for histological fidelity and phenotypic stability via H&E staining and TTF-1 immunohistochemistry; cases were subsequently stratified based on HER2/TROP2 expression intensity. The functional integrity of the co-culture system was confirmed through flow cytometric analysis of immune cell purity and activation status, coupled with ELISA quantification of cytokines to verify effective immune-tumor crosstalk.

Pharmacodynamic evaluations were performed using ATP-based viability assays, PDO viability imaging, and Caspase-3/7 apoptosis detection. These assays simulated clinically relevant peak plasma concentrations (C max) to directly reflect in vivo drug exposure, while also assessing the synergistic potential of "ADC + Immuno-oncology" combination strategies to optimize clinical dosing regimens. Mechanistically, pHrodo dye tracking was employed to visualize and quantify cellular internalization and phagocytosis, complemented by single-cell RNA sequencing to delineate transcriptional profiles and identify specific subpopulations sensitive to ADC therapy. Furthermore, high-sensitivity Olink proteomics and multiplex fluorescence immunohistochemistry provided "cellular-molecular-spatial" evidence of immune activation and intracellular trafficking dynamics.

Collectively, the data revealed that distinct ADC responses correlated with target expression and the immune microenvironment, precisely characterizing the molecular signatures of sensitive cell subpopulations and their enhanced endocytic activity. These findings provide critical molecular targets and a theoretical basis for patient selection and the rational design of next-generation ADC therapies in HER2/TROP2-positive lung cancer.

Studietype

Observationeel

Inschrijving (Geschat)

10

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Studie Locaties

  • China
    • Guangdong
      • Guangzhou, Guangdong, China
        • Werving
        • The First Affiliated Hospital of Guangzhou Medical University
        • Contact:
        • Contact:
        • Hoofdonderzoeker:
          • Chengzhi Zhou, PhD

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Bemonsteringsmethode

Niet-waarschijnlijkheidssteekproef

Studie Bevolking

Patients with a pathological diagnosis of non-small cell lung cancer (NSCLC), whose tumor patient-derived organoids (PDOs) exhibited strong or weak positive expression of the HER2 or TROP2 targets as determined by immunohistochemistry.

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / Cohort
Interventie / Behandeling
HER2 Positive OrTROP2 Positive non-small cell lung cancer
The abundance of HER2 or TROP2 target expression was determined by immunohistochemistry and categorized into strongly positive and weakly positive groups, representing the experimental group and negative control group, respectively. Using an immunococulture system based on patient-derived organoids, the in vitro activity of antibody-drug conjugates (ADCs)-including trastuzumab emtansine (an approved ADC administered intravenously)-that are either approved or currently in clinical trials was evaluated. In parallel, clinical patients provided ex vivo cytological assay results indicating their sensitivity to ADC therapy.
Geneesmiddel: Antibody-drug conjugate (ADC) combination therapy

In a co-culture system of tumor patient-derived organoids (PDOs) and autologous immune cells, at least ten drug combinations comprising antibody-drug conjugates (ADCs) plus tyrosine kinase inhibitors (TKIs) or immune checkpoint blockers (ICBs) were employed to screen for ADCs with sensitivity against the tumor PDOs. The ADCs selected for evaluation included:

Trastuzumab deruxtecan for injection (intravenous) Trastuzumab emtansine for injection (intravenous) Sacituzumab govitecan for injection (intravenous)

Andere namen:
  • ADC + TKI/ICB + Cellular Therapy DS-8201
  • ADC + TKI/ICB + Cellular Therapy T-DM1
  • ADC + TKI/ICB + Cellular Therapy SG

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Changes in ATP assay of tumor patient-derived organoids (PDOs) under treatment with ADCs and various drug combinations
Tijdsspanne: Tumor viability assessed by luminescence measurement at 72 hours after co-culture with immune cells
The single high-concentration ADC design was formulated to mimic the peak plasma concentration achieved after clinical administration, thereby directly reflecting the cytotoxic potency of the drug at effective concentrations. The combination therapy assessment focuses on the current trend of "ADC + immuno" strategies in oncology, providing ex vivo data to support optimization of clinical dosing regimens.
Tumor viability assessed by luminescence measurement at 72 hours after co-culture with immune cells
Real-time high-content imaging reveals efficient internalization of pHrodo-conjugated ADCs
Tijdsspanne: 24hours
Kinetic analysis of ADC internalization was performed using a high-content imaging system. Briefly, cells were incubated with pHrodo-conjugated ADCs at 37°C. Real-time fluorescence imaging was conducted at 15-minute intervals for 24 hours to track the internalization efficiency. Quantitative data regarding cellular uptake were analyzed using the integrated high-content analysis software."
24hours
Integrated analysis of ADC IC50 determination and scRNA-seq data post co-culture
Tijdsspanne: 96hours
We observed a wide range of sensitivities to ADC treatment across different PDO models, as reflected by varying IC50 values (ranging from X nM to Y nM). To uncover the mechanistic basis for this heterogeneity, we performed scRNA-seq on tumor cells following the co-culture and ADC treatment. Unsupervised clustering revealed distinct tumor cell subpopulations, including a cluster characterized by high proliferative signature and another marked by stress-response pathways.
96hours
Multiplex immunofluorescence (mIF) and high-sensitivity Olink proteomics for inflammatory cytokines.
Tijdsspanne: 96hours
To characterize the immune landscape, we performed multiplex immunofluorescence (mIF) staining on tissue sections to analyze the spatial distribution of immune cells. Additionally, high-sensitivity Olink proteomics was utilized to quantify a panel of inflammatory cytokines in the culture supernatant.
96hours

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Fluorescence imaging of PDO viability and apoptosis assessment via caspase-3/7 activity in pharmaco-sensitivity and PDO-immune co-culture assays.
Tijdsspanne: 96hours
We utilized fluorescent viability dyes to visualize the cytotoxic effects of ADCs in co-culture. Concurrently, caspase-3/7 cleavage was detected as a marker of intrinsic apoptosis induced by the drug payload.
96hours
Cytokine secretion profiles (IL-6, TNF-α, IFN-γ) in co-culture supernatants measured by ELISA
Tijdsspanne: 96hours
The levels of key effector cytokines, including IL-6, TNF-α, and IFN-γ, were quantified in the supernatant of the PDO-immune co-culture system using ELISA kits。
96hours
Flow cytometric analysis of T cell activation and exhaustion markers in co-culture assays
Tijdsspanne: 96hours
Cells harvested from co-cultures were stained with fluorophore-conjugated antibodies against surface markers. T cell activation was defined by the upregulation of CD69 and CD25, while T cell dysfunction was characterized by the expression of inhibitory receptors such as PD-1 and TIM-3.
96hours

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Guangzhou Institute of Respiratory Disease

Onderzoekers

  • Hoofdonderzoeker: Chengzhi Zhou, PhD, The First Affiliated Hospital of Guangzhou Medical University

Publicaties en nuttige links

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Algemene publicaties

Nuttige links

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

28 december 2025

Primaire voltooiing (Geschat)

1 oktober 2027

Studie voltooiing (Geschat)

1 oktober 2027

Studieregistratiedata

Eerst ingediend

12 mei 2026

Eerst ingediend dat voldeed aan de QC-criteria

25 mei 2026

Eerst geplaatst (Werkelijk)

28 mei 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

28 mei 2026

Laatste update ingediend die voldeed aan QC-criteria

25 mei 2026

Laatst geverifieerd

1 mei 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • ADC-2025-10-1

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

product vervaardigd in en geëxporteerd uit de V.S.

Ja

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