Enhancing Immunotherapy with MET Inhibitors Against Aggressive Lung Cancer

MET Inhibitor Shows Promise in Aggressive Lung Cancer Treatment

A new study from the Hospital del Mar Research Institute in barcelona suggests adding a MET inhibitor to chemotherapy and immunotherapy could significantly improve outcomes for patients with small cell lung cancer, one of the most aggressive forms of the disease. The findings, published in Cell Reports Medicine, highlight the role of Hepatocyte Growth Factor (HGF) – linked to cell multiplication and survival – in treatment resistance and poor prognosis.

Despite representing only 15% of all lung tumors, small cell lung cancer has a grim three-year survival rate of just 15%, often progressing rapidly and being diagnosed late, hindering surgical intervention. Current treatment involves a combination of chemotherapy and immunotherapy, but the cancer’s ability to develop resistance and spread remains a major challenge.

The ten-year-plus research utilized mouse models to test various treatment combinations: a control group receiving no treatment, chemotherapy alone, chemotherapy plus immunotherapy with an anti-PD-L1 antibody, and chemotherapy, immunotherapy, and a MET inhibitor. Results demonstrated significantly improved tumor progression and survival rates in the group receiving the triple combination, with complete responses observed in six out of nine tumors.

Researchers discovered the MET inhibitor boosts the efficacy of immunotherapy by altering the tumor microenvironment. Dr. Edurne Arriola, lead author of the study, explained that the inhibitor disrupts the effect of the MET gene, facilitating greater activity of immune system T cells activated by immunotherapy. In essence,the inhibitor doesn’t directly attack the tumor but optimizes the immune response for more effective targeting.

What specific mechanisms link MET pathway activation to the recruitment of immunosuppressive cells within the tumor microenvironment?

understanding the Challenge: Aggressive Lung Cancer & Immunotherapy Resistance

Aggressive forms of lung cancer, notably non-small cell lung cancer (NSCLC), often present a significant challenge in treatment.While immunotherapy has revolutionized cancer care – as defined by institutions like the Deutsches Zentrum Immuntherapie https://www.dzi.uk-erlangen.de/en/immunotherapy/ – not all patients respond. A key reason for this is immunotherapy resistance. The tumor microenvironment can actively suppress the immune system, preventing immune cells from effectively attacking cancer cells. This suppression often involves pathways like the MET pathway.

The Role of MET in Lung Cancer Progression

MET (Mesenchymal-Epithelial Transition factor) is a receptor tyrosine kinase involved in several cellular processes crucial for cancer development,including:

Cell growth and proliferation: MET signaling promotes uncontrolled cell division.

Angiogenesis: It stimulates the formation of new blood vessels, feeding the tumor.

Metastasis: MET contributes to the spread of cancer cells to other parts of the body.

Immune suppression: Increasingly, MET activation is linked to the recruitment of immunosuppressive cells within the tumor microenvironment.

High MET expression is observed in a substantial proportion of NSCLC patients, and its amplification or activation is frequently enough associated with poorer prognosis and resistance to standard therapies, including PD-1/PD-L1 inhibitors – a common form of immunotherapy.

How MET Inhibitors can Boost Immunotherapy Efficacy

MET inhibitors are drugs designed to block the activity of the MET protein. Combining these inhibitors with immunotherapy offers a promising strategy to overcome resistance and enhance treatment outcomes. Hear’s how:

1. Reversing Immune Suppression: by inhibiting MET, we can reduce the recruitment of immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). This allows immune cells, such as T cells, to infiltrate the tumor more effectively.
2. Enhancing T cell Activity: MET inhibition can directly improve T cell function, making them more capable of recognizing and destroying cancer cells. studies suggest MET signaling can suppress T cell activation; blocking it restores this crucial immune response.
3. Improving Antigen Presentation: MET inhibition can upregulate the expression of MHC class I molecules on tumor cells. MHC molecules are essential for presenting tumor antigens to T cells, triggering an immune attack.
4. Reducing Tumor Vascularity: By inhibiting angiogenesis,MET inhibitors can normalize tumor blood vessels,improving drug delivery and immune cell infiltration.

Clinical Evidence: MET Inhibitors & Immunotherapy Combinations

Several clinical trials are investigating the efficacy of combining MET inhibitors (like capmatinib and tepotinib) with immunotherapy in NSCLC. Early results are encouraging:

Capmatinib + Pembrolizumab: Studies have shown improved objective response rates and progression-free survival in patients with MET exon 14 skipping mutations when treated with this combination compared to pembrolizumab alone.

Tepotinib + Nivolumab: Preliminary data suggests a synergistic effect, with increased anti-tumor activity observed in patients receiving both drugs.

Ongoing Trials: Numerous phase II and phase III trials are currently underway, exploring different MET inhibitor/immunotherapy combinations and patient populations. These trials are crucial for establishing definitive treatment guidelines.

Identifying Patients Most Likely to Benefit

Not all patients with lung cancer will respond to this combination therapy. Biomarker analysis is key to identifying those most likely to benefit. Significant biomarkers include:

MET amplification or exon 14 skipping mutations: These genetic alterations indicate MET pathway activation.

PD-L1 expression: While not definitive, PD-L1 expression levels can help predict response to immunotherapy.

Tumor Mutational Burden (TMB): Higher TMB often correlates with better immunotherapy response.

Immune cell infiltration: Assessing the presence and activity of immune cells within the tumor microenvironment can provide valuable insights.

Potential Side Effects & Management

Combining MET inhibitors with immunotherapy can lead to side effects associated with both drug classes. Common side effects include:

MET inhibitor-related: Diarrhea, nausea, fatigue, peripheral edema, and hypertension.

Immunotherapy-related: Immune-related adverse events (irAEs) affecting various organs, such as the lungs, liver, and endocrine system.

Careful monitoring and prompt management of side effects are crucial. Immunosuppressive medications (like corticosteroids) might potentially be necesary to control irAEs.

Future Directions in MET & Immunotherapy Research

Research is ongoing to further optimize this therapeutic approach:

Novel MET inhibitors: Developing more selective and potent MET inhibitors.

Biomarker finding: identifying new biomarkers to predict response and personalize treatment.

Combination strategies: Exploring combinations with other targeted therapies and chemotherapy.

* Understanding resistance mechanisms: investigating how tumors develop resistance to MET inhibitor/immunotherapy combinations.

Keywords: Lung Cancer, Immunotherapy, MET Inhibitors, NSCLC, MET pathway, PD-1 inhibitors, PD-L1 inhibitors, Capmat