Personalized Lung Tumor Chips Assess PD-1 Therapy Response

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Personalized Lung Tumor Chips Assess PD-1 Therapy Response

Personalized Lung Tumor Chips Assess PD-1 Therapy Response

Patients’ derived tumor chips used to assess lung cancer patients’ response to PD-1 therapy.

The lack of sufficient model systems is a key barrier to developing and deploying new effective cancer treatments. The currently widely used traditional cell culture or animal models cannot accurately predict human responses to cancer treatments because they cannot accurately simulate human pathophysiology, especially the immune system.

Over the past decade, a new concept has emerged: using microphysiological systems to achieve a rational simplification of the human body, leading to the emergence of a new research field—organ-on-chip and tumor-on-chip (ToC). Specifically, tumor chip technology uses microfabrication and microfluidic techniques to generate co-cultures of cells embedded in 3D hydrogels, simulating the extracellular matrix, and reproducing the immune and matrix characteristics of the tumor ecosystem. While research in the field of tumor chips is growing exponentially, current efforts mainly rely on established, mostly immortalized cell lines. It is time to move towards clinically relevant cell models (e.g., primary autologous cells) and lay the foundation for the translational application of personalized medicine.

On May 3, 2024, researchers at the Paris Sciences et Lettres University published a study titled “Assessing personalized responses to anti-PD-1 treatment using patient-derived lung tumor-on-chip” in the journal Cell Reports Medicine.

Personalized Lung Tumor Chips Assess PD-1 Therapy Response

The study used primary autologous tumor cells derived from non-small cell lung cancer (NSCLC) patients to construct personalized lung tumor chips and used them to evaluate patients’ responses to anti-PD-1 therapy. They also found that adding FAP+ cancer-associated fibroblasts to the tumor chips impaired the response to anti-PD-1 therapy.

The emergence of novel immunotherapeutic drugs, especially immune checkpoint inhibitors (ICI), is driving a therapeutic revolution in clinical oncology. Cancers such as melanoma, lung cancer, head and neck cancer, and bladder cancer benefit most from these immunotherapies, and many clinical trials are still ongoing to demonstrate the survival improvements of these immunotherapies for other common cancers. New concepts and methods are urgently needed to develop and test cancer immunotherapeutic drugs, among which the tumor-on-chip (ToC) platform has tremendous potential.

In this work, the research team aimed to generate a tumor-on-chip (ToC) platform as an in vitro experimental paradigm for preclinical studies of immune checkpoint inhibitor (ICI) responses, paving the way for addressing immunooncology questions in fully human, controllable, and directly observable tumor 3D ecosystems.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most common type, accounting for over 80% of lung cancer cases. Although immune checkpoint inhibitors (ICI) have greatly improved the treatment of NSCLC, only 20%-40% of NSCLC patients benefit from ICI drugs, and the reasons for the lack of response and resistance to ICI in non-responding patients are still unclear.

The research team inferred that the use of autologous cytotoxic T lymphocytes (CTL) is necessary when studying cancer-immune interactions and their response to immune checkpoint inhibitors (ICI) to avoid any allogeneic reactions. The team first used an established pair of NSCLC cell lines (IGR-Heu) and autologous CTL (H5B) to achieve a robust method to quantitatively measure T cell-mediated anti-tumor activity and performed immunotherapy using the tumor-on-chip (ToC) platform. Next, the team turned to freshly isolated primary cells from NSCLC samples to assess the feasibility of using patient-derived tumor chips (ToC) for personalized immune therapy response spectrum analysis within a few days, consistent with the clinical decision-making process.

Importantly, the study strategy involved continuous live imaging of autologous 3D tumor chip (ToC) co-cultures for two days, rather than just endpoint detection, to quantify the dynamics of key cellular processes in the tumor ecosystem, such as cancer cell apoptosis and cancer-immune interactions.

The original combination of 3D co-culture of tumor chips (ToC), patient-derived autologous cell models, and advanced image analysis computational methods enabled the research team to develop and validate a protocol to measure the in vitro effects of immune therapy on T cell-mediated anti-tumor activity, paving the way for basic and translational research in immuno-oncology.

In summary, the study proposed a lung tumor chip (ToC) platform for the rapid and precise measurement of in vitro immune checkpoint inhibitor (ICI) effects on T cell-mediated tumor cell killing using live imaging and advanced image analysis algorithms. Integrating autologous immunosuppressive FAP+ cancer-associated fibroblasts into the tumor chip reduces the response to anti-PD-1 therapy, indicating the tumor chip’s ability to reproduce stroma-dependent mechanisms associated with immunotherapy resistance. For a small subset of NSCLC patients, the use of personalized tumor chips generated from fresh tumor samples has been shown to measure responses to anti-PD-1 therapy. These results support the potential of tumor chip technology in immuno-oncology research and pave the way for future clinical validation.