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

2026년 5월 25일 업데이트: 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.

연구 개요

상태

모병

정황

개입 / 치료

상세 설명

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.

연구 유형

관찰

등록 (추정된)

10

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 연락처

  • 이름: chengzhi Professor Zhou, PhD
  • 전화번호: 13560351186
  • 이메일: 13560351186@163.com

연구 연락처 백업

연구 장소

  • 중국
    • Guangdong
      • Guangzhou, Guangdong, 중국
        • 모병
        • The First Affiliated Hospital of Guangzhou Medical University
        • 연락하다:
        • 연락하다:
        • 수석 연구원:
          • Chengzhi Zhou, PhD

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

  • 성인
  • 고령자

건강한 자원 봉사자를 받아들입니다

아니

샘플링 방법

비확률 샘플

연구 인구

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.

설명

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.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

코호트 및 개입

그룹/코호트
개입 / 치료
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.
의약품: 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)

다른 이름들:
  • ADC + TKI/ICB + Cellular Therapy DS-8201
  • ADC + TKI/ICB + Cellular Therapy T-DM1
  • ADC + TKI/ICB + Cellular Therapy SG

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
Changes in ATP assay of tumor patient-derived organoids (PDOs) under treatment with ADCs and various drug combinations
기간: 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
기간: 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
기간: 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.
기간: 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

2차 결과 측정

결과 측정
측정값 설명
기간
Fluorescence imaging of PDO viability and apoptosis assessment via caspase-3/7 activity in pharmaco-sensitivity and PDO-immune co-culture assays.
기간: 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
기간: 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
기간: 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

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

Guangzhou Institute of Respiratory Disease

수사관

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

간행물 및 유용한 링크

연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.

일반 간행물

유용한 링크

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작 (실제)

2025년 12월 28일

기본 완료 (추정된)

2027년 10월 1일

연구 완료 (추정된)

2027년 10월 1일

연구 등록 날짜

최초 제출

2026년 5월 12일

QC 기준을 충족하는 최초 제출

2026년 5월 25일

처음 게시됨 (실제)

2026년 5월 28일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2026년 5월 28일

QC 기준을 충족하는 마지막 업데이트 제출

2026년 5월 25일

마지막으로 확인됨

2026년 5월 1일

추가 정보

이 연구와 관련된 용어

키워드

추가 관련 MeSH 약관

기타 연구 ID 번호

  • ADC-2025-10-1

개별 참가자 데이터(IPD) 계획

개별 참가자 데이터(IPD)를 공유할 계획입니까?

아니요

약물 및 장치 정보, 연구 문서

미국 FDA 규제 의약품 연구

아니

미국 FDA 규제 기기 제품 연구

아니

미국에서 제조되어 미국에서 수출되는 제품

예

이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .

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