Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an ...immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.
B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (
= 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8
tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.
B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8
TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8
TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8
TILs and recovery of effector function. CD8
T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8
T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.
B7-H3 expressed on tumor cells potentially circumvents CD8
-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.
.
The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.
We retrospectively identified 138 patients with
...-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing.
The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (
= 0.0010). Whereas CD8
and FOXP3
TIL densities were significantly lower after EGFR-TKI treatment than before, CD8
TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp,
= 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months,
= 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months.
EGFR-TKI treatment was associated with changes in the TME of
-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of ...tumors that express HER2 protein in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody–drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of fam‐ trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to fam‐ trastuzumab deruxtecan but not to conventional HER2‐targeted therapies. Furthermore, fam‐ trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2‐expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that fam‐ trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.
What's new?
HER2‐targeted therapies have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for tumors that express HER2 in the absence of HER2 amplification. fam‐ trastuzumab deruxtecan (DS‐8201a) is a novel antibody‐drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor. Here, DS‐8201a showed efficacy on colorectal cancer (CRC) cell lines that express HER2 in the absence of HER2 amplification. Furthermore, fam‐ trastuzumab deruxtecan exhibited a bystander killing effect in co‐culture models of HER2‐expressing cells and HER2‐negative cells. The results may offer a new treatment option against CRC according to HER2 expression levels.
Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects.
We performed a ...preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB).
Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8
T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8
T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice.
Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8
T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
The purpose of this study was to clarify the usage and understanding of denture adhesives among 1,825 denture wearers, aged 40 years and older in Japan, using a web-based survey. The NTTCom Online ...survey (a closed investigation) was conducted over a period of 4 days using a 13-item questionnaire about denture adhesives. Results showed that 67.1% of the respondents were satisfied with their dentures; 81.5% of respondents knew about denture adhesive, but only 347 (19.0%) had used the product. Products used by the 347 denture wearers included cream type (79.7%), cushion type (16.2%), and powder type (3.2%). The most common reason for the selection of a particular type was “Saw the product” (59.9%), followed by “Saw an advertisement” (19.3%), and “Explanation at a dental clinic” (8.4%). The response of “Ill-fitting denture” significantly affected the response of “Use of denture adhesives” (chi-square test; P < 0.001). Moreover, the sensitivity (0.56) was lower than the specificity (0.75). These findings show that denture adhesives were not always necessary for those with ill-fitting dentures.
Data on characteristics, outcomes, and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently ...lacking.
We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital.
A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09-2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3-7.2 months).
Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients ...with
EGFR
T790M–positive non–small cell lung cancer (NSCLC).
Methods
The study included patients with
EGFR
activating mutation–positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an
EGFR
tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance.
Results
We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in
PIK3CA
,
KRAS
, or
BRAF
and copy number gain for
EGFR
,
ERBB2
, or
MET
were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of
EGFR
after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib.
Conclusions
CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
•The EGFR T790M is the most common resistant mechanism of 1st or 2nd generation EGFR-TKIs.•Damaging nonsynonymous mutations in pre-EGFR-TKI was lower in T790M-mediated resistance.•Coexisting ...mutations in tumor before EGFR-TKI treatment may contribute to T790M resistance.
The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment.
A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software.
Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.049).
Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
BACKGROUND:Pro- and anti-inflammatory cytokines (adipokines) associated with adipose tissue can modulate inflammatory processes and lead to systemic inflammatory conditions such as metabolic ...syndrome. In the present pilot study, we investigated 3 major adipokines (leptin, adiponectin, and resistin) and 2 nonspecific proinflammatory cytokines (tumor necrosis factor α and interleukin-6) with regard to their association with postoperative pain intensity.
METHODS:We analyzed a total of 45 single-nucleotide polymorphisms of the adipokines in 57 patients with postlaparotomy pain. We adjusted for multiple testing to reduce the chance of false-positive results by controlling the false discovery rate. Serum levels of the adipokines and proinflammatory cytokines were measured in another 36 patients undergoing laparotomy. A stepwise multiple linear regression analysis using these measurements and opioid dosages as independent variables was performed to explore the factors associated with postoperative pain.
RESULTS:Only 1 variant of the resistin gene (rs3745367) demonstrated a significant association with postoperative pain (P < .002). Patients exhibiting homozygosity for the minor alleles (n = 7; numerical rating scale NRS, 2.3 ± 1.3) demonstrated lower pain intensity compared with those exhibiting homozygosity for the major alleles (n = 29; NRS, 3.8 ± 1.0; P = .004) and heterozygosity for the minor alleles (n = 21; NRS, 4.2 ± 0.8; P < .001). Only serum resistin levels showed a positive association with postoperative pain.
CONCLUSIONS:A genetic variant of resistin and serum resistin levels were associated with postoperative pain intensity, while other adipokines and cytokines exhibit no such association. Resistin can alter the inflammatory responses in postoperative wounds, although it could be a determinant factor that is independent of inflammatory processes. Resistin may be a novel marker for postoperative pain intensity.
BackgroundStudies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non–small cell lung cancer (NSCLC). However, potential selection bias in such ...studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.MethodsWe conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.ResultsA total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK genetic alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.ConclusionsAfter accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
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