Anti-programmed death-1 (PD-1) monotherapy induces a high response rate in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but complete remission (CR) is infrequently observed. As ...decitabine is known to boost T-cell function, we assessed the safety and efficacy of anti-PD-1 camrelizumab alone versus decitabine-primed camrelizumab in patients with relapsed/refractory cHL.
This two-arm, open-label, phase II study enrolled patients with relapsed/refractory cHL who had received at least two lines of previous therapy. Anti-PD-1 treatment-naïve patients were randomly assigned (1:2) to camrelizumab (200 mg) monotherapy or decitabine (10 mg/d, days 1 to 5) plus camrelizumab (200 mg, day 8) combination therapy every 3 weeks. Patients who were previously treated with anti-PD-1 were assigned combination therapy. Primary end point was CR rate and safety.
Overall, 86 patients were enrolled and evaluated for response, with a median follow-up of 14.9 months. In anti-PD-1-naïve patients, CR rate was 32% (six of 19 patients) with camrelizumab monotherapy versus 71% (30 of 42 patients) who were administered decitabine plus camrelizumab (
= .003). At the time of analysis, the response duration rate at 6 months was 76% on camrelizumab monotherapy versus 100% on decitabine plus camrelizumab. For patients who were previously treated with anti-PD-1, 28% achieved CR and 24% partial response after decitabine plus camrelizumab. Ten patients maintained a response at more than 6 months and 81% of responders were estimated to have a response at more than 1 year. For both treatments, the most common adverse events were clinically inconsequential cherry hemangiomas and leukocytopenia that were self-limiting.
CR rate in patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade was significantly higher with decitabine plus camrelizumab than with camrelizumab alone. Decitabine plus camrelizumab may reverse resistance to PD-1 inhibitors in patients with relapsed/refractory cHL.
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor ...neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.
Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance.
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Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of ...circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (
= 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders 5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35;
= 0.007 and HR 6.91; 95% CI, 1.37-34.97;
= 0.02, respectively, which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (
= 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.
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Tumor DNA contains specific somatic alterations that are crucial for the diagnosis and treatment of cancer. Due to the spatial and temporal intra-tumor heterogeneity, multi-sampling is needed to ...adequately characterize the somatic alterations. Tissue biopsy, however, is limited by the restricted access to sample and the challenges to recapitulate the tumor clonal diversity. Non-blood circulating tumor DNA are tumor DNA fragments presents in non-blood body fluids, such as urine, saliva, sputum, stool, pleural fluid, and cerebrospinal fluid (CSF). Recent studies have demonstrated the presence of tumor DNA in these non-blood body fluids and their application to the diagnosis, screening, and monitoring of cancers. Non-blood circulating tumor DNA has an enormous potential for large-scale screening of local neoplasms because of its non-invasive nature, close proximity to the tumors, easiness and it is an economically viable option. It permits longitudinal assessments and allows sequential monitoring of response and progression. Enrichment of tumor DNA of local cancers in non-blood body fluids may help to archive a higher sensitivity than in plasma ctDNA. The direct contact of cancerous cells and body fluid may facilitate the detection of tumor DNA. Furthermore, normal DNA always dilutes the plasma ctDNA, which may be aggravated by inflammation and injury when very high amounts of normal DNA are released into the circulation. Altogether, our review indicate that non-blood circulating tumor DNA presents an option where the disease can be tracked in a simple and less-invasive manner, allowing for serial sampling informing of the tumor heterogeneity and response to treatment.
CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA ...methylation in sputum and plasma.
This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (
= 150) had pathologic confirmation of node-negative (stages I and IIA) non-small cell lung cancer. Controls (
= 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (
, and
).
DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (
< 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 95% confidence interval (CI), 0.80-0.98 in sputum and 0.77 (95% CI, 0.68-0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection.
High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma.
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Ever since a lung cancer epidemic emerged in the mid-1900 s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report ...summarizes the key findings of this research.
A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk.
Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application.
Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers.
Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for ...hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management.
► Transient DAC or AZA sustains antitumor responses and reduces self-renewal ► Acute cytotoxicity does not appear to account for the lasting effects of the drugs ► Low-dose DAC causes sustained global DNA demethylation and gene reexpression ► Low-dose DAC or AZA sustains antitumor responses through key signaling pathways
Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification ...enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.
Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.
This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.
Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of ...patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up.
We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1-5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962).
Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% nine complete responses (CR); 36% in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival.
Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.
In the United States, the 20th century witnessed the emergence of a lung cancer epidemic that peaked and began to decline by the century's end, a decline that continues today. However, lung cancer ...continues to be an unabating pandemic. In research carried out over the last half of the 20th century, many factors were causally associated with lung cancer and studies were implemented to identify determinants of susceptibility to these factors. Cigarette smoking was identified as the single most predominant cause of the lung cancer epidemic, but other causes were found, including workplace agents (eg, asbestos, arsenic, chromium, nickel, and radon) and other environmental factors (passive smoking, indoor radon, and air pollution). Contemporary epidemiologic research on lung cancer now focuses on a new set of issues, primarily related to susceptibility to the well-identified causal factors, particularly smoking, and on the consequences of changes in tobacco products for risks to smokers. Diet and the possibility of reducing risk through chemoprevention remain a focus of research emphasis through experimental and observational approaches. Questions have also been raised about possible differences in susceptibility to lung cancer by sex and race. Population patterns in smoking prevalence will continue to be the most powerful predictor of the future occurrence of lung cancer. Evaluation of recent US patterns in smoking prevalence indicates that for the next approximately 10 to 15 years, lung cancer rates will decrease, but will then level off starting in approximately 2030. Unless further reductions in the prevalence of cigarette smoking are achieved over the next decade, lung cancer will remain as an all too common, but avoidable, disease.
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