A novel combination strategy of anti-CD70 immunotherapy and chemotherapy in non-small cell lung cancer

Ondertitel:the right partners in crime?

This PhD dissertation focused on the immune checkpoint protein CD70, as an attractive immunotherapeutic target to exploit in non-small cell lung cancer (NSCLC). First, we evaluated CD70 expression using one validated method, which showed that anti-CD70 therapy could be explored in a broad range of tumor types, including NSCLC. When CD70 binds to its unique receptor CD27 (present on tumor-infiltrating lymphocytes), the soluble form of CD27 (sCD27) is released and can be found in body fluids. In line with this notion, we evaluated the potential use of sCD27 as a blood-based surrogate marker for CD70 expression on the tumor cells, which would provide a less invasive method to decide upon anti-CD70 therapy. Here, we did not find a correlation between patient-matched sCD27 serum levels and CD70 expression on tumor specimens in the NSCLC patient population. In addition, we found that 31% of the NSCLC specimens were CD70 positive, pointing out the potential of anti-CD70 therapy in a considerable subset of NSCLC patients. To further improve the treatment efficacy, we further assessed a combination strategy of anti-CD70 therapy and chemotherapy. Different clinically relevant chemotherapies were evaluated for their ability to induce immunogenic cell death (ICD), a type of cell death that can enhance the anti-tumor immune response. Here, we observed that the chemotherapeutic regimen of docetaxel and cisplatin was the most ideal partner for anti-CD70 therapy in terms of its ability to induce ICD. Moreover, we observed increased CD70 expression on the tumor cells after treatment with this chemotherapeutic regimen, suggesting this combination could be used to broaden the therapeutic window of anti-CD70 as well. Finally, the effects of anti-CD70 therapy as single agent or in combination with chemotherapy on NSCLC killing and the anti-tumor immune response were evaluated. We observed that the sequential treatment schedule of chemotherapy and anti-CD70 therapy resulted in significantly improved overall survival and a delay in tumor growth in Lewis lung carcinoma-bearing mice. Chemotherapy increased the numbers of dendritic cells in the tumor-draining lymph nodes, suggesting its ability to enable responsiveness to anti-CD70 therapy. Furthermore, the sequential treatment schedule showed increased intratumoral T and NK cell numbers, and increased ratios of CD8+ T cells over regulatory T cells, which could explain the enhanced anti-tumor effects after sequential therapy in this in vivo NSCLC model. The superior effect of the sequential combination therapy on improved survival was further validated in a more humanized in vivo model.

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open