Non-small cell lung cancer (NSCLC) constitutes ~80% of all lung cancer cases and has a 5-year survival rate of only 15-20%. Over the past decade, targeted therapies have shown some efficacy in NSCLC patients who present drug sensitive mutations. However, acquired drug resistance has been a major obstacle to achieving durable responses. Novel and more effective combinatorial treatments are urgently needed in the clinic to improve the dismal prognosis of NSCLC patients. Recently, immune checkpoint inhibitors have led to durable response rates in NSCLC patients of up to 25%, but a large portion of patients continue to show minimal or no response. Notably, the mechanisms responsible for regulating the tumor's response to immune checkpoint inhibitors have not been elucidated. There is increasing evidence that oncogenes modulate expression of immune regulatory genes, leading to the notion that therapies that target specific oncogene pathways may influence diverse aspects of the immune response. To this end, we have focused on mouse models of NSCLC carrying mutations in the KRAS or EGFR oncogenes or the EML4-ALK translocation. These mutations were chosen because 1) together they account for >40% of the NSCLC patients and 2) FDA approved targeted therapies are available for EML4-ALK and EGFR mutants. We have performed comprehensive immunophenotyping in each of these models and observed mutation-specific distribution and abundance of specific immune subsets, suggesting diverse mechanisms and varying degrees of immune invasion/exclusion. These findings have predictive value in determining which tumor has the most likelihood of responding to specific immune checkpoint inhibitors (anti-PD-1, anti-PD-L1 or anti-CTLA4). We will discuss the implication of this approach in improving response rates to other standard of care treatments such as targeted therapies, radiation and/or chemotherapy in combination with the checkpoint inhibitors. Overall, this work has the potential to provide a mechanism-based rationale for combining standard of care treatments and immunotherapies for the treatment of NSCLC.
Citation Format: Lauren S. Havel, Dingcheng Gao, Nasser Altorki, Vivek Mittal. Oncogene-mediated immune microenvironments in lung cancer provide a rationale for combination therapies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B172.
- ©2016 American Association for Cancer Research.