Checkpoint Inhibitors In Lung Cancer Research Articles

Peripheral Blood TCRβ Repertoire, IL15, IL2 and Soluble Ligands for NKG2D Activating Receptor Predict Efficacy of Immune Checkpoint Inhibitors in Lung Cancer.

The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs.

212 Incidence and Outcomes of MRI-confirmed Myocarditis in Patients Receiving Immune Checkpoint Inhibitors for Lung Cancer - A Single Tertiary Centre Experience

212 Incidence and Outcomes of MRI-confirmed Myocarditis in Patients Receiving Immune Checkpoint Inhibitors for Lung Cancer - A Single Tertiary Centre Experience

User-experience testing of an evidence-to-decision framework for selecting essential medicines.

Essential medicine lists (EMLs) are important medicine prioritization tools used by the World Health Organization (WHO) EML and over 130 countries. The criteria used by WHO's Expert Committee on the Selection and Use of Essential Medicines has parallels to the GRADE Evidence-to-Decision (EtD) frameworks. In this study, we explored the EtD frameworks and a visual abstract as adjunctive tools to strengthen the integrate evidence and improve the transparency of decisions of EML applications. We conducted user-experience testing interviews of key EML stakeholders using Morville's honeycomb model. Interviews explored multifaceted dimensions (e.g., usability) on two EML applications for the 2021 WHO EML-long-acting insulin analogues for diabetes and immune checkpoint inhibitors for lung cancer. Using a pre-determined coding framework and thematic analysis we iteratively improved both the EtD framework and the visual abstract. We coded the transcripts of 17 interviews with 13 respondents in 103 locations of the interview texts across all dimensions of the user-experience honeycomb. Respondents felt the EtD framework and visual abstract presented complementary useful and findable adjuncts to the traditional EML application. They felt this would increase transparency and efficiency in evidence assessed by EML committees. As EtD frameworks are also used in health practice guidelines, including those by the WHO, respondents articulated that the adoption of the EtD by EML applications represents a tangible mechanism to align EMLs and guidelines, decrease duplication of work and improve coordination. Improvements were made to clarify instructions for the EtD and visual abstract, and to refine the design and content included. 'Availability' was added as an additional criterion for EML applications to highlight this criterion in alignment with WHO EML criteria. EtD frameworks and visual abstracts present additional important tools to communicate evidence and support decision-criteria in EML applications, which have global health impact. Access to essential medicines is important for achieving universal health coverage, and the development of essential medicine lists should be as evidence-based and trustworthy as possible.

The Weighted Toxicity Score: Confirmation of a Simple Metric to Communicate Toxicity in Randomized Trials of Systemic Cancer Therapy.

FDA's Project Optimus was developed in part to better identify appropriate dose and schedule of cancer therapeutics. The tabular method to summarize patients' maximum toxicity in a clinical trial does not allow for ready comparison to the treatment's benefit. In this manuscript, we apply a simple tool, the weighted toxicity score (WTS), to trials involving lung cancer immunotherapy and chemotherapy, as well as those cited in a recent publication as examples of trials that represent successful reduction of the appropriate dose of anti-cancer agents. PubMed was queried for randomized controlled trials of therapy involving immune checkpoint inhibitors in lung cancer. Trial data from studies highlighting initial success with dose adjustments after FDA approval also were assembled and analyzed according to the WTS procedure described previously, compared to clinical outcomes data. The WTS provided, with the clinical outcome(s), a data pair that leads to easy interpretation of the expected benefit versus relative toxicity of studies involving immunotherapy or chemoimmunotherapy in lung cancers. The WTS was consistent with the conclusions of the primary studies, helping to quantitate the toxicity difference between treatments in a previously unavailable way. The WTS provides a tool to show the cost in toxicity of therapy in a randomized clinical trial, with applicability to studies involving chemotherapy, immunotherapy, or kinase-directed therapy. Inclusion of a running tally of WTS during conduct of a trial could serve as one means to adjust dosing or to provide feedback during data safety monitoring of a clinical trial.

Predicting response and toxicity to immune checkpoint inhibitors in lung cancer using antibodies to frameshift neoantigens

PurposeTo evaluate a new class of blood-based biomarkers, anti-frameshift peptide antibodies, for predicting both tumor responses and adverse immune events to immune checkpoint inhibitor (ICI) therapies in advanced lung cancer patients.Experimental designSerum samples were obtained from 74 lung cancer patients prior to palliative PD-(L)1 therapies with subsequently recorded tumor responses and immune adverse events (irAEs). Pretreatment samples were assayed on microarrays of frameshift peptides (FSPs), representing ~ 375,000 variant peptides that tumor cells can be informatically predicted to produce from translated mRNA processing errors. Serum-antibodies specifically recognizing these ligands were measured. Binding activities preferentially associated with best-response and adverse-event outcomes were determined. These antibody bound FSPs were used in iterative resampling analyses to develop predictive models of tumor response and immune toxicity.ResultsLung cancer serum samples were classified based on predictive models of ICI treatment outcomes. Disease progression was predicted pretreatment with ~ 98% accuracy in the full cohort of all response categories, though ~ 30% of the samples were indeterminate. This model was built with a heterogeneous sample cohort from patients that (i) would show either clear response or stable outcomes, (ii) would be administered either single or combination therapies and (iii) were diagnosed with different lung cancer subtypes. Removing the stable disease, combination therapy or SCLC groups from model building increased the proportion of samples classified while performance remained high. Informatic analyses showed that several of the FSPs in the all-response model mapped to translations of variant mRNAs from the same genes. In the predictive model for treatment toxicities, binding to irAE-associated FSPs provided 90% accuracy pretreatment, with no indeterminates. Several of the classifying FSPs displayed sequence similarity to self-proteins.ConclusionsAnti-FSP antibodies may serve as biomarkers for predicting ICI outcomes when tested against ligands corresponding to mRNA-error derived FSPs. Model performances suggest this approach might provide a single test to predict treatment response to ICI and identify patients at high risk for immunotherapy toxicities.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

A Subset of PD-1-Expressing CD56bright NK Cells Identifies Patients with Good Response to Immune Checkpoint Inhibitors in Lung Cancer.

(1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3-CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3-CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3-CD16-PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size.

Quality of life after treatment with immune checkpoint inhibitors for lung cancer; the impact of age

IntroductionImmune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment. However, it remains unclear as to whether changes in Health-Related Quality-of-Life (HRQoL) are associated with the age of lung cancer patients treated using ICIs. This study aimed to evaluate this possible association and to compare ICI-treated patients’ HRQoL scores with normative data of an age-matched non-cancer general population. MethodsLung cancer patients from the OncoLifeS data-biobank were included if they were treated with ICIs, irrespective of other treatments, at the University Medical Center Groningen between 2015 and 2021 and had completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTCQLQ-C30), both at the start of ICI treatment and after six months. Association of age as a continuous variable (per 10 years) and changes in HRQoL scores between baseline and 6 months was assessed using multivariable regression analyses. Clinical relevance of differences in HRQoL scores between OncoLifeS and the general population was classified into trivial, small, medium, and large, for three age groups (<60, 60–69 and ≥ 70 years). Results151 patients were included with a mean age of 65.8 years. An increase in age per 10 years was associated with a larger decrease in the summary HRQoL score(β = -3.28,CI95%-6.42;-0.14), physical(β = -4.8, CI95% −8.71;-0.88), cognitive(β = −4.51,CI95%-8.24;−0.78), role functioning(β = −5.41,CI95%-10.78;−0.05), symptom burden(β = −3.66,CI95%-6.6;-0.73), and smaller negative changes in financial difficulties(β = 6.5 95 % CI 3.16; 9.85). OncoLifeS HRQoL scores were lower than those of the general population and differences were most often classified as large and medium. ConclusionOlder lung cancer patients experience larger deteriorations in most HRQoL domains after 6 months of ICI treatment. Also, these patients showed significantly lower HRQoL scores compared to the general population.

IMMUNOTHERAPY AS NOVEL TREATMENT OF LUNG CANCER: A SYSTEMATIC REVIEW

Lung cancer is the top cause of cancer-related fatalities in both men and women around the world, and the second most commonly diagnosed cancer in both men and women. For many patients, traditional chemotherapy (CT) fails to give long-term benefit. Moreover, newer medicines targeting activating mutations in EGFR or ALK have shown increased response rates over CT in the minority of patients with these mutations; however, the majority of patients do not have actionable mutations and will not benefit from targeted therapies. In addition, several combinations of chemotherapeutic medicines with the angiogenesis inhibitor bevacizumab have provided only minor additional benefits. However, immunotherapy using checkpoint inhibitors has shown to have a lot of potential in the treatment of advanced non-SCLC (NSCLC) in recent trials. These new medications encourage the host immune system to recognize tumor cells as foreign invaders and halting their growth. They help alleviate immune system suppression, which allows tumor development to be tolerated. In checkpoint immunotherapy, humanized monoclonal antibodies targeting checkpoint signals such as programmed cell death receptor (PD-1) and programmed cell death ligand are employed (PD-L1). The immune system can be triggered to fight the tumor by inhibiting these receptors and signals. Immunotherapy for advanced lung cancer has created a new paradigm of therapeutic options, with increased survival and response rates and a less severe but distinct side profile when compared to CT. The PD-1 inhibitors nivolumab and pembrolizumab, as well as the PD-L1 inhibitor atezolizumab, have been approved by regulatory authorities for the treatment of advanced NSCLC. Hence, the current review article focuses on the role of immunotherapy, newer agents used for checkpoint inhibitors in lung cancer, their epidemiology, risk factors, side-effect profiles, therapeutic indications, and their mechanism of action for the successful treatment of lung cancer.

Immune Checkpoint Inhibitors in Lung Cancer

With the fast increase in morbidity and mortality, lung cancer has become one of the greatest threats to physical health in some countries. Immune checkpoint inhibitors (ICIs) have a significant influence on the treatment landscape of lung cancer, including non-small cell lung cancer (NSCLC). This review highlights the most important ICIs used in lung cancer at present, anti-CTLA-4 and PD-1/L1. The application status, efficacy, shortcomings and prospect of each drug, including Ipilimumab (CTLA-4), Nivolumab, Pembrolizumab, and Durvalumab (PD-1/L1), are listed to show the drug indication in the current market. By comparing different drugs, the direction of ICI drug development can be more precise, which can have an important influence on choosing drugs for lung cancer treatment.

The rest period between chemotherapy and immunotherapy influences the efficacy of immune checkpoint inhibitors in lung cancer.

BackgroundThe use of immune checkpoint inhibitors (ICIs) as first‐line treatment rather than as second‐line treatment makes a big difference in the drug efficacy and progression‐free survival. However, the mechanism for this is still not clear. This study aimed to analyze the effects of the rest period between chemotherapy and immunotherapy on the efficacy of ICIs.MethodsThis study included 100 patients with advanced NSCLC treated with PD‐1/PD‐L1 inhibitors at Chungnam National University Hospital (CNUH) between May 2016 and August 2019. The rest period was defined from the last dose of cytotoxic chemotherapy to the first dose of ICIs. We retrospectively reviewed patients' clinical data and blood test records and analyzed lymphocyte subsets using flow cytometry.ResultsThe median rest period was 64 days. The long rest period group (≥36 days) showed significantly higher clinical benefits than the short rest period group (<36 days) (69.4% vs. 39.5%, p = 0.003). White blood cell (WBC) count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and neutrophil‐lymphocyte ratio (NLR) just before chemotherapy were not different between the two groups. However, the blood test after chemotherapy immediately before immunotherapy showed significantly higher ANC and NLR in the short rest period group than in the long rest period group. The frequency of the Th1 subset and PD‐1 + CD8+ T cells were significantly higher in the long rest period group than in the short rest period group.ConclusionTime interval from chemotherapy to immunotherapy may affect immune cell status and efficacy of ICIs.

Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis.

We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy.

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations.

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies.

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

Ocular Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Lung Cancer.

Immune checkpoint inhibitors (ICIs) are novel immunotherapy-based drugs that have become increasingly popular in the treatment of lung cancer. Researchers have recognized ocular immune-related adverse events (irAEs) secondary to ICIs because of their vision-threatening characteristics. However, they are incompletely characterized and no studies have reported the ICI-related ocular irAEs in lung cancer. Therefore, we aimed to comprehensively illustrate the clinical characteristics, contributory factors, diagnosis, and management of ICI-related ocular irAEs in lung cancer, based on previously reported 79 patients. Ophthalmoplegia (40.51%), uveitis (20.25%), and dry eye (17.72%) were the most common ICI-related ocular irAEs in lung cancer. Ptosis was the most common (36.71%) and the highest mortality (23.33%) of ophthalmoplegia. Patients in Asia and patients who underwent combination therapy with programmed cell death-1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors demonstrated significantly higher frequency of ophthalmoplegia than other ocular irAEs. Most ICI-related ophthalmoplegia and uveitis in lung cancer were observed in the first 10 weeks following the initiation of ICIs. Furthermore, the onset time of dry eye and other ocular irAEs was much longer. In addition, 92.31% of the patients with ocular irAEs other than ophthalmoplegia could be remised. In conclusion, ocular irAEs secondary to ICIs in lung cancer are non-negligible, particularly ophthalmoplegia. Ethnicity and the type of ICIs play important roles in the distribution of ocular irAEs. ICI-related ophthalmoplegia in lung cancer presented with early onset and worse prognosis features, thus necessitating further attention.

Abstract 1613: A hypoxia-driven transcriptional program characterizes acquired resistance to immune checkpoint inhibitors in lung cancer

Abstract Immune checkpoint inhibitors (ICIs) that block negative regulators of T cell function can generate lasting responses in lung cancer patients, yet only a minority of tumors respond to therapy and ~50% of patients whose tumors initially respond eventually develop acquired resistance. Mechanisms of acquired resistance to ICIs in lung cancer are not fully understood and strategies to overcome resistance are lacking. To address this challenge, we developed a new mouse model of acquired resistance to ICIs by knocking out the DNA mismatch repair gene Msh2 in Kras mutant mouse lung adenocarcinoma cells, leading to a higher mutation burden in these cells. Unlike Msh2 WT controls, Msh2 KO tumors transplanted into syngeneic mice are sensitive to ICIs. Importantly, chronic treatment with αPD-1 or αPD-1 + αCTLA-4 led to Msh2 KO tumors that initially responded to therapy but then developed acquired resistance. Tumors remained resistant to ICIs upon transplantation to new hosts, suggesting that tumor-intrinsic programs drive resistance. Gene set enrichment analysis (GSEA) of single cell RNA sequencing data revealed that tumors with acquired resistance to ICIs downregulated antigen processing and presentation gene signatures compared to tumors that were regressing on therapy. Specifically, tumor cells with acquired resistance downregulated expression of MHC class II, which was confirmed by flow cytometry, and this was accompanied by a decrease in expression of Stat1, Irf1, and Ciita, which drive MHC-II expression in response to IFNγ. Depletion of CD4+ T cells during αPD-1 + αCTLA-4 treatment abrogated the response to therapy, suggesting a functional role for tumor cell MHC-II expression. GSEA also revealed that tumors with acquired resistance to ICIs upregulated hypoxia and glycolysis gene signatures compared to tumors responding to therapy. Consistent with these results, resistant tumor cells had increased hypoxia, detected by pimonidazole staining, compared to tumor cells responding to therapy. Tumor infiltrating lymphocytes have been shown to be excluded from hypoxic tumor regions, suggesting that hypoxia in the tumor microenvironment may contribute to acquired resistance to ICIs by excluding T cells from these regions. Moreover, we found that Msh2 KO tumor cells upregulated MHC-II in response to IFNγ under normoxic in vitro conditions, but had lower MHC-II expression under hypoxia. Our data suggest that tumor hypoxia may contribute to both tumor-cell intrinsic transcriptional programs, such as alterations in antigen processing and presentation machinery, as well as tumor-cell extrinsic effects, such as exclusion of T cells from the tumor microenvironment, which together may impact the development of acquired resistance to immune checkpoint blockade. Our results can inform strategies to overcome acquired resistance, addressing a critical unmet need in cancer therapy. Citation Format: Camila Robles-Oteiza, Katherine Hastings, Susan M. Kaech, Katerina Politi. A hypoxia-driven transcriptional program characterizes acquired resistance to immune checkpoint inhibitors in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1613.

Combination of computed tomography imaging-based radiomics and clinicopathological characteristics for predicting the clinical benefits of immune checkpoint inhibitors in lung cancer

BackgroundIn this study, we tested whether a combination of radiomic features extracted from baseline pre-immunotherapy computed tomography (CT) images and clinicopathological characteristics could be used as novel noninvasive biomarkers for predicting the clinical benefits of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs).MethodsThe data from 92 consecutive patients with lung cancer who had been treated with ICIs were retrospectively analyzed. In total, 88 radiomic features were selected from the pretreatment CT images for the construction of a random forest model. Radiomics model 1 was constructed based on the Rad-score. Using multivariate logistic regression analysis, the Rad-score and significant predictors were integrated into a single predictive model (radiomics nomogram model 1) to predict the durable clinical benefit (DCB) of ICIs. Radiomics model 2 was developed based on the same Rad-score as radiomics model 1.Using multivariate Cox proportional hazards regression analysis, the Rad-score, and independent risk factors, radiomics nomogram model 2 was constructed to predict the progression-free survival (PFS).ResultsThe models successfully predicted the patients who would benefit from ICIs. For radiomics model 1, the area under the receiver operating characteristic curve values for the training and validation cohorts were 0.848 and 0.795, respectively, whereas for radiomics nomogram model 1, the values were 0.902 and 0.877, respectively. For the PFS prediction, the Harrell’s concordance indexes for the training and validation cohorts were 0.717 and 0.760, respectively, using radiomics model 2, whereas they were 0.749 and 0.791, respectively, using radiomics nomogram model 2.ConclusionsCT-based radiomic features and clinicopathological factors can be used prior to the initiation of immunotherapy for identifying NSCLC patients who are the most likely to benefit from the therapy. This could guide the individualized treatment strategy for advanced NSCLC.

Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for lung cancer in recent years. These strategies consist of neutralizing antibodies against negative regulators of immune function, most notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1), thereby impeding the ability of tumor cells to escape immune surveillance. Though ICIs have proven a significant advance in lung cancer therapy, overall survival rates remain low, and lung cancer continues to be the leading cause of cancer-related death in the United States. It is therefore imperative to better understand the barriers to the efficacy of ICIs, particularly additional mechanisms of immunosuppression within the lung cancer microenvironment. Recent evidence suggests that regulatory T-lymphocytes (Tregs) serve as a central mediator of immune function in lung cancer, suppressing sterilizing immunity and contributing to the clinical failure of ICIs. Here, we provide a comprehensive summary of the roles of Tregs in lung cancer pathobiology and therapy, as well as the potential means through which these immunosuppressive mechanisms can be overcome.

Meta-analysis of immune-related adverse events in phase 3 clinical trials assessing immune checkpoint inhibitors for lung cancer.

The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment. We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23rd, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade ≥3) irAEs, drug discontinuation due to irAEs or toxic death. Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs. Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.

Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3–14 doses/person). In total, 12–30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1–2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.