Abstract
Immune checkpoint inhibitors have transformed the treatment of metastatic non-small-cell lung cancer, yielding marked improvements in survival and the potential for durable clinical responses. Primary and acquired resistance to current immune checkpoint inhibitors constitute a key challenge despite the remarkable responses observed in a subset of patients. Multiple novel combination immunotherapy and adoptive cell therapy strategies are presently being developed to address treatment resistance. The success of these strategies hinges upon rational clinical trial design as well as careful consideration of the immunologic mechanisms within the variable tumor immune microenvironment (TIME) which underpin resistance to immunotherapy. Further research is needed to facilitate a deeper understanding of these complex mechanisms within the TIME, which may ultimately provide the key to restoring and enhancing an effective anti-tumor immune response. This review aims to provide an introduction to some of the recent and notable combination immunotherapy and cell therapy strategies used in advanced non-small-cell lung cancer (NSCLC), and the rationale for their use based on current understanding of the anti-tumor immune response and mechanisms of resistance within the TIME.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide
This review will utilize our current understanding of the tumor immune microenvironment (TIME) and the mechanisms involved in the induction of an effective anti-tumor immune response as a framework to understand the rationale as well as potential of novel combination immunotherapeutic and cell therapy strategies in metastatic non-small-cell lung cancer (mNSCLC)
These findings provide a compelling rationale for the efficacy of PD-1 inhibitors in mNSCLC with an inflamed TIME as well as the use of PD-1 inhibitors as a backbone for the development of novel immunotherapy combinations
Summary
Lung cancer is the leading cause of cancer-related death worldwide. Immune checkpoint inhibitors have revolutionized the treatment of metastatic non-small-cell lung cancer (mNSCLC), with marked improvement in overall survival and the potential for durable clinical benefit. These latter two tumor environments are poorly responsive to checkpoint inhibition alone and new combination therapies are being investigated. Immune-excluded tumors often contain an active immune infiltrate which is displaced and unable to penetrate into the TIME likely secondary to immuno-modulatory stromal populations and secreted factors (e.g., TGF-β) Each of these immune categories should be considered a distinct entity produced by complex and varied immunologic mechanisms [5]. PD-1 inhibitors are thought to be less effective in mNSCLC patients with a non-inflamed TIME likely secondary to the absence of an immune infiltrate capable of recognizing and eliminating tumor cells in response to downregulation of co-inhibitory signaling through PD-1 [8]. PD-1/PD-L1 inhibitor therapy hinges upon understanding these immunologic states, the mechanisms that underpin them, and the appropriate targets that can unleash a potent anti-tumor immune response in these specific immunologic contexts
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