Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide and a marginally improving 5-year overall survival rate which remains below 20%. Successful therapeutic advances have emerged, but these treatment options are limited to only a small subset of NSCLC patients. Therefore, new treatment strategies are needed that will result in durable responses for the majority of NSCLC patients. In this regard, combining an immune modulatory chemotherapeutic agent with immunotherapy would be a suitable and promising approach. On the one hand, it has been shown that certain chemotherapeutics can induce immunogenic cell death, thereby releasing neoantigens and enabling tumor-specific cytotoxic T cell responses. On the other hand, CD70 has emerged as a promising target to be blocked in various hematological and solid malignancies. Its overexpression on tumor cells is associated with immune suppression in the tumor microenvironment. CD70 overexpression on NSCLC cells was detected by us in a subset of patients (16%). More importantly, preliminary findings from our group demonstrated the ability of certain chemotherapeutics to induce CD70 overexpression on NSCLC cells, which broadens the therapeutic window of anti-CD70 immunotherapy. Built on these preliminary findings, the primary aim of this study is to identify the ideal chemotherapeutic agent to combine with anti-CD70 immunotherapy by thoroughly evaluating several chemotherapeutics for their capacity to induce immunogenic cell death and stimulate CD70 overexpression on NSCLC cells. The second aim is to investigate the anti-tumor capacity of this treatment strategy together with the recently approved immune checkpoint inhibitor anti-programmed death (PD)-1, in order to develop an innovative approach that tackles the immunosuppressive factors of the tumor from different angles. Experiments will be performed in vitro in normoxic and hypoxic conditions and in vivo in a syngeneic mouse model. This project has the exciting potential to unravel a novel combination strategy for NSCLC patients that enables specific targeting of the tumor cells and realizes durable responses by stimulating the anti-tumor immune response. In addition, these study results might also pave the way for improved treatment options in other tumor types.
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