High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study

Abstract

Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Neutrophils in the era of immune checkpoint blockade

“… 84 While diminution of the ANC during treatment is associated with a better patient response to ICI in lung cancer, 85 86 high baseline ALC associates with better response to ICI in HNC 87 and patients with NSCLC. 88 Hence, the NLR prognostic value comes from the cointegration of the ANC and ALC, which it is determined by biogenesis as well as survival of both neutrophils and lymphocytes ( figure 3 ).…”

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…For example, chromomycin A5 (CA5) can serve as a bona fide ICD inducer, since it enhances the activation of APCs and T-cells in syngeneic mouse models vaccinated with metastatic melanoma B16-F10 cells ( Florêncio et al, 2022 ). Additionally, pemetrexed is a multi-targeting antifolate antagonist established as the first-line chemotherapeutic drug for advanced lung adenocarcinoma, and mesothelioma which increases immune-regulatory genes and induces ICD ( Mathew et al, 2018 ; Sumiyoshi et al, 2021 ).…”

From targeted therapy to a novel way: Immunogenic cell death in lung cancer

“…But the research by Fileswasser et al has shown that oxaliplatin does not induce ICD in NSCLC cells (4). Pemetrexed, a multi-targeting antifolate antagonist which is established as the main chemotherapy drug for the first-line treatment of advanced non-squamous NSCLC (NSq-NSCLC) and mesothelioma, has also been shown to induce ICD and to increase of immune-regulatory genes (177,178). Liu et al found that crizotinib, a kind of drugs used to treat NSCLC patients which carries activated ALK/ROS1, is an efficient ICD stimulator via off-target effects (162).…”

“…The antitumor effect of ICIs works by interfering with immune tolerance (178). The most clinically common immune checkpoints include: PD-1/PD-L1, cytotoxic T lymphocyteassociated antigen-4 (CTLA-4), indoleamine 2.3-dioxygenase (IDO), and CD47 (197,198).…”

“…In clinical application, the combination of ICIs and chemotherapy can improve the efficacy of anti-tumor therapy, this may be because chemotherapy drugs increase tumor sensitivity to ICIs (208). Pemetrexed and ICIs targeting PD-1/PD-L1 are applied widely for the treatment of advanced NSq-NSCLC (178). Moreover, lurbinectedin is a kind of DNA-binding inhibitors of transcription, which is efficient at inducing ICD (209).…”