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Adaptive immunity plays a major role in the prevention of tumor growth and development.
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Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death, increasing tumor neo-antigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
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Antibodies targeting the PD-1 receptor-ligand interaction, which tumor cells exploit to evade immune detection, enhance the antitumor immune response.
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Based on preclinical studies, there is
Combining Immunotherapy and Chemotherapy for Non–Small Cell Lung Cancer
Section snippets
Key points
Introduction: overview of advanced non–small cell lung cancer treatment
Lung cancer remains the leading cause of cancer-related deaths worldwide.1 In the United States, there were an estimated 234,030 new lung cancer cases and 154,050 lung cancer–related deaths in 2018, with higher incidence and mortality in men compared with women. Non–small cell lung cancer (NSCLC) is the most common histologic subtype, accounting for approximately 85% of all lung cancer cases.2 Unfortunately, most patients with lung cancer are deemed incurable, with advanced disease at
Non–small cell lung cancer immunology and the use of checkpoint inhibition
Cancer is associated with a state of chronic inflammation, as well as severe systemic immune suppression.14 Cancer develops by accumulating genetic alterations and the loss of normal cellular regulation. These events lead to the expression of neo-antigens, a peptide bound to major histocompatibility class I (MHC-I) molecules, on the cancer cell surface, which differentiates them from normal cells.15 It is well established that evasion of immune surveillance is one of the hallmarks of cancer.16
Platinum-based chemotherapy immunomodulation and synergy with immunotherapy
Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death (ICD), increasing tumor neo-antigen expression and also by disturbing the immunosuppressive tumor microenvironment that prevents immune detection.6 ICD involves changes on the cell membrane that signal DCs to remove the dying cell followed by release of factors, which stimulates DC activation and maturation. Subsequently, DCs present tumor antigens to T cells creating tumor-specific effector cells.6
Clinical data combining chemotherapy with immunotherapy in nonsquamous non–small cell lung cancer
In patients with metastatic nonsquamous NSCLC, 3 trials, KEYNOTE-189, IMpower150, and IMpower130, have demonstrated improved overall survival (OS) with the addition of an anti-PD-1/PD-L1 antibody to standard chemotherapy (Table 1).
KEYNOTE-189 was a phase III trial of treatment-naïve patients with nonsquamous NSCLC without sensitizing epidermal growth factor receptor (EGFR) or anaplastic large-cell lymphoma kinase (ALK) mutations, who were randomized to receive a platinum and pemetrexed doublet
Role of immunotherapy in epidermal growth factor receptor and anaplastic large-cell lymphoma kinase mutated non–small cell lung cancer tumors
Earlier randomized trials in patients with EGFR or ALK sensitizing alterations, previously treated with a TKI, indicated that immunotherapy was less effective in the second line compared with patients with WT tumors.24, 25, 26 In fact, in patients with tumors harboring EGFR or ALK alterations, inferior outcomes were observed in those treated with immunotherapy compared with chemotherapy, as first line or after progression on a TKI, regardless of their PD-L1 expression.27,28 However, in the more
Trial data combining chemotherapy with immunotherapy in squamous non–small cell lung cancer
In patients with metastatic squamous NSCLC, the KEYNOTE-407 trial demonstrated improved survival in patients treated with the combination of pembrolizumab and a standard platinum doublet (see Table 1).13 This was a phase III trial in treatment-naïve patients randomized to receive carboplatin and the physician’s choice of either paclitaxel or nab-paclitaxel in addition to pembrolizumab or placebo for 4 cycles, followed by pembrolizumab or placebo maintenance. There was improvement in the
Outline of active treatment protocols
Currently, per National Comprehensive Cancer Network guidelines, platinum-based chemotherapy combined with immunotherapy is considered the preferred, category 1, treatment for most cases of advanced or metastatic NSCLC.30 Patients with metastatic adenocarcinoma, not harboring a driver mutation in EGFR, ALK, ROS1, or BRAF V600 E, and with PDL1 TPS <50%, should receive systemic triplet therapy with carboplatin or cisplatin and pemetrexed combined with pembrolizumab or quadruple therapy with
Summary
During the past decade, there has been significant advancement in the treatment of lung cancer, including the identification of targetable oncogenic driver mutations and more recently with the development of immunotherapeutic agents. It is well established that adaptive immunity plays a major role in the prevention of tumor growth. However, tumor cells exploit mechanisms of self-tolerance, including the PD1/PD-L1 interaction, causing immunosuppression. Antibodies targeting PD-1 and PD-L1 have
Disclosure
J. Judd has nothing to disclose. H. Borghaei has research support from Millennium, Merck/Celgene, and BMS/Lilly; Advisory Board role/Consultant for BMS, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, Astra Zeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio; and Data and Safety Monitoring Board role with University of Pennsylvania CAR T Program and Takeda.
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Cited by (31)
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Lymph node micrometastasis in non–small cell lung cancer
2022, Biomedicine and PharmacotherapyCitation Excerpt :Current guidelines do not include adjunctive treatment methods for stage I patients with occult metastasis. Considering that even stage I patients may have early micrometastasis, Judd et al. [51] suggested that all patients who have undergone radical surgery for NSCLC should be treated with adjuvant chemotherapy combined with immunotherapy. Coincidentally, the results of Yamaguchi et al. [52] also showed that adjuvant treatment of patients with positive lymph node micrometastasis can be beneficial and that postoperative radiotherapy and chemotherapy improve survival rates.
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First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial
2021, The Lancet OncologyCitation Excerpt :However, as reported in other NSCLC trials that assessed first-line single-agent or dual immunotherapy,4,7,15,16 there remains a need, in a subset of patients, for disease control during the first few weeks of immunotherapy to enhance clinical benefit. Previous studies have shown that chemotherapy elicits anti-tumour effects through the immune system, which might result in increased immunotherapy activity,17,18 although whether this effect is additive or synergistic with immunotherapy, or potentially due to interpatient variability, is not known.19–21 We hypothesised that dual immunotherapy combined with two cycles of chemotherapy would provide early disease control while building on the durable survival benefit provided by nivolumab and ipilimumab, and minimise the side-effects that are associated with a full course of chemotherapy.
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Experience of patients considering or using checkpoint inhibitors in cancer treatment: A systematic review of qualitative research
2024, Journal for ImmunoTherapy of Cancer -
Multifunctional Probe Based on “Chemical Antibody-Aptamer” for Noninvasive Detection of PD-L1 Expression in Cancer
2024, Molecular Pharmaceutics -
Immunotherapeutics in lung cancers: from mechanistic insight to clinical implications and synergistic perspectives
2023, Molecular Biology Reports