Advancing non-small cell lung cancer treatment: the power of combination immunotherapies

Abstract

Non-small cell lung cancer (NSCLC) remains an unsolved challenge in oncology, signifying a substantial global health burden. While considerable progress has been made in recent years through the emergence of immunotherapy modalities, such as immune checkpoint inhibitors (ICIs), monotherapies often yield limited clinical outcomes. The rationale behind combining various immunotherapeutic or other anticancer agents, the mechanistic underpinnings, and the clinical evidence supporting their utilization is crucial in NSCLC therapy. Regarding the synergistic potential of combination immunotherapies, this study aims to provide insights to help the landscape of NSCLC treatment and improve clinical outcomes. In addition, this review article discusses the challenges and considerations of combination regimens, including toxicity management and patient selection.

Keywords: cancer vaccines; combination therapy; immunotherapy; non-small cell lung cancer; tumor microenvironment.

Figure 1

Tumor microenvironment in NSCLC. The inhibitory TME encompasses diverse immune system cells, including inhibitory cells and those with antitumor activity. MDSCs, Tregs, and M2 macrophages are notable among the inhibitory and tumor-associated cells. In contrast, antitumor cells such as NK and CD8⁺ cytotoxic T lymphocytes (CTLs) are specifically responsible for targeting and eliminating tumor cells. Conditions such as reduced oxygen concentration and heightened acidity prevail within the TME. Furthermore, tumor cells express inhibitory molecules like PD-1, which interact with PD-L1 on the surface of CTLs, diminishing the antitumor activity of these cells, which is the base of ICI therapy. However, it is noteworthy that monotherapy and conventional therapies such as surgery, chemotherapy, targeted therapies, radiotherapy, or immunotherapeutic methods exhibit limited effectiveness. Based on the available evidence, a more favorable strategy is combination therapy. This approach seeks to synergize various treatment modalities, enhancing their collective impact and providing a more comprehensive and effective response to the complexities of the TME. NSCLC, non-small cell lung cancer; TME, tumor microenvironment; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; NK, natural killer; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; ICI, immune checkpoint inhibitor.

Figure 2

Monotherapies and combination therapies using ICIs and other anticancer approaches. In the TME, the expression of inhibitory molecules on the surface of immune and tumor cells can lead to tumor development and growth by exhausting CD8⁺ T cells and inhibiting the antitumor responses of the immune system. However, according to the studies conducted in this field, the use of ICIs alone cannot have a significant effect in the treatment of cancer, but by combining these inhibitors with other anticancer agents, such as chemotherapy, radiotherapy, TKIs, and cytokines, the effectiveness of the treatment can be increased. ICIs, immune checkpoint inhibitors; TME, tumor microenvironment; TKIs, tyrosine kinase inhibitors.