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Following up the percentage of Ki-67 positivity in total and nivolumab-bound CD8 and CD4 T cells from patients who underwent sequential treatment. (A-C) Fresh whole blood samples from 8 non-small cell lung cancer patients were followed up in terms of percentage of Ki-67 positivity in total and nivolumab-bound CD8 and CD4 T cells. Display order is the same as in Figure 4. Black and green triangles indicate the points of progressive disease (PD) and tumor marker re-elevation without an increase in the size of the targeted tumor (as determined by CT scan), respectively. Red triangles indicate the absolute loss of CB of nivolumab in T cells. Unfilled triangles show the follow-up time point previous to those represented by the filled triangles, as described. (D) Ki-67 positivity in T cells was compared between 2 time points: at the time of PD (black triangles) versus previous follow-up (unfilled triangles) in Pt. 8, 9, 13, and 14 (top, n = 4) and at the time of loss of CB of nivolumab (red triangles) versus previous follow-up (unfilled triangles) in Pt. 6, 10, and 15 (bottom, n = 3). Difference was calculated based on the follow-up time point, which was used as a baseline. Data represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. Total Ki-67 + in CD8 T cells, P = 0.0013; IgG4 + Ki-67 + in CD8 T cells, P < 0.0001; total Ki-67 + in CD4 T cells, P = 0.0247; and IgG4 + Ki-67 + in CD4 T cells, P = 0.0029, Student's t test.
Source publication
Background:
The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.
Methods:
To define the durat...
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Citations
... However, a more pronounced difference was noted in patients with a shorter IFI of < 60 days. One plausible explanation for this difference could be that therapeutic levels of anti-PD-1 inhibitor present at chemotherapy initiation do not persist 30 . No significant differences were observed in outcomes based on the ramucirumab-free interval or previous treatment patterns, consistent with previous efficacy evaluations of VEGF inhibitors 19,22 . ...
The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.
... On this basis, residual activity of PD-1 antibody might produce a synergistic effect with chemotherapy, resulting in enhancement of the immune microenvironment. [33][34][35] In our present trial, previous treatment with cetuximab for R/M-HNSCC was allowed. Six patients had received previous cetuximab-containing chemotherapy for R/M-HNSCC. ...
... It is important to note that cholangitis can also occur some time after stopping pembrolizumab, up to 4 months after stopping pembrolizumab (Tanaka et al. 2022). A possible explanation is that after the last infusion of PD-1 inhibitors was stopped, anti-PD-1 antibodies continued to bind to lymphocytes in subsequent weeks (Osa et al. 2018). This may be a delayed immune-related event that is gaining attention as an emerging diagnostic complex (Couey et al. 2019). ...
Pembrolizumab induced hepatitis has received increasing attention, while pembrolizumab induced cholangitis is poorly understood. This study investigated the clinical features, treatment, and outcome of pembrolizumab induced cholangitis. Case reports, case series and clinical studies of pembrolizumab induced cholangitis were collected by retrieving English and Chinese database from inception until October 30, 2023. Fifty patients with cholecystitis entered our study with a median age of 68 years (range 48, 89). The median time to onset of cholecystitis was 1.1 months (range 0.3, 24), and the median number of cycles was 5 cycles (range 1, 27) after initial administration. Most of the patients had no clinical symptoms and only showed elevated biliary enzymes (24 cases, 48.0%), while some patients showed jaundice (12 cases, 24.0%), abdominal pain (10 cases, 20.0%) and fever (7 cases, 14.0%). The median alkaline phosphatase value was 1111 IU(range 130, 3515) and the median glutamyltransferase value was 649.5 IU(range 159, 3475). The imaging features of gallbladder were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Bile duct biopsy showed inflammatory infiltration, mainly CD8 + T cell infiltration. Immunosuppression treatment resulted in complete response in 4 cases (8.0%), partial response in 28 cases (56.0%), and poor response in 15 cases (30.0%). Cholangitis is a rare and serious adverse effect of pembrolizumab. Clinicians should be aware of the possibility of cholangitis when administering pembrolizumab. Steroids may not be effective in most patients with cholecystitis, and ursodeoxycholic acid may be an option.
... Despite the preventive administration of ICIs, early recurrence manifested in our patients, prompting further investigation into whether this is attributable to the relatively brief prophylactic period of ICIs application, at least up to 1 year following RFA. The ability of ICIs to engage T lymphocytes endures for a minimum of 20 weeks following cessation of ICIs therapy (25). Furthermore, administering ICIs at low doses subsequent to liver transplantation may serve as a preventive measure against HCC recurrence (26). ...
Hepatocellular carcinoma (HCC) presents a malignant pathology known for its high early recurrence rate following curative treatment, significantly impacting patient prognosis. Currently, effective strategies to mitigate early HCC recurrence remain undetermined. In this report, we document a case of HCC managed with curative radiofrequency ablation (RFA), particularly in a patient facing a high risk of early recurrence due to a substantial tumor size. In an effort to forestall recurrence, immune checkpoint inhibitors (ICIs) were preemptively administered for 6 months post-RFA. Despite this, early recurrence ensued upon ICIs cessation. Traditionally, the approach to advanced HCC has been conservative, yet recent years have seen promising outcomes with ICIs in advanced HCC. However, research on ICIs retreatment is limited. In the short term, this patient experienced widespread metastases post-ICIs discontinuation, yet exhibited prompt regression upon ICIs reinitiation. Notably, this represents the initial documented instance of employing ICIs to forestall recurrence subsequent to curative RFA in HCC. Following ICIs discontinuation, diffuse recurrence with multiple metastases emerged, with successful resolution upon ICIs retreatment.
... Moreover, the data on the appropriate observation period after the last dose of ICIs are lacking. Immune checkpoint inhibitors affect memory T cells in the blood for more than 20 weeks after the final dose [19]. Considering the evidence, past reports, and the present case, we propose that a follow-up of at least six months is required. ...
A 75-year-old male with diabetes mellitus was referred to our hospital with an abnormal shadow on chest radiography, based on which he was diagnosed with extensive-disease small-cell lung cancer (ED-SCLC; cT2bN2M1a).
The first-line therapy comprised atezolizumab, carboplatin, and etoposide. After four cycles, the patient achieved complete response (CR), and maintenance therapy was initiated with atezolizumab. However, even though CR was maintained, maintenance therapy was discontinued after 16 cycles due to persistent grade 2 anorexia and fatigue. Simultaneously, the HbA1c decreased to 5.5%, and antidiabetic therapy was discontinued. Six months after the last dose of atezolizumab, the patient visited the emergency room because of anorexia, dry mouth, and fatigue. Laboratory findings were as follows: blood glucose was 668 mg/dL, glycated hemoglobin (HbA1c) was 8.8%, urine ketone was 2+, sodium (Na) was 127 mmol/L, potassium (K) was 6.5 mmol/L, creatinine (Cre) was 1.43 mg/dL, and arterial pH was 7.29. Based on these findings, his presentation was consistent with fulminant type 1 diabetes mellitus (T1DM) complicated by diabetic ketoacidosis (DKA). Regular continuous insulin and saline administration was initiated in the intensive care unit, and acidosis and electrolyte abnormalities were corrected. His C-peptide was <0.03 ng/mL. His insulin secretory capacity was considered to be depleted, and he required continuous subcutaneous insulin injections. Glutamic acid decarboxylase and insulin autoantibodies were absent. The complete response persisted without further therapy until two years since the event.
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... We selected patients aged ≥ 20 years who had received subsequent systemic antineoplastic treatment that immediately followed regimens containing ICIs, and the cumulative incidence and features of DIILD were assessed in this treatment setting. Patients for whom subsequent systemic antineoplastic treatment was initiated after more than 6 months from the final dose of ICIs were excluded [20] because longer intervals, especially more than 6 months, from the last dose of ICIs would make the potential influence of prior ICIs on adverse events in subsequent regimens elusive [21]. If patients received multiple lines of ICI treatment in a non-consecutive manner, DIILD in a subsequent regimen following former ICIs was assessed. ...
Background
Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown.
Methods
This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel.
Results
Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12).
Conclusions
Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.
... Moreover, preclinical data have shown that nivolumab controls the levels of lymphocyte surface PD-1 for 2 months. 26 These findings suggest that prior nivolumab therapy affects the initial response to chemotherapy; however, these effects do not persist. In large clinical trials, concurrent administration of immune checkpoint inhibitors and chemotherapy in the first-line setting has demonstrated survival benefit in AGC. ...
Background
Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC.
Patients and methods
We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival.
Results
A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%).
Conclusions
The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.
... It has been reported that a method to monitor the binding of anti-PD-1 antibodies to CD8+ T cells was found, and anti-PD-1 antibodies remain bound to CD8+ T cells for more than 20 weeks after patients stop treatment [28]. Therefore, it is assumed that the therapeutic effect of lenvatinib was added to the prolonged effect of the ICIs, and that it exerted its effect on immune cells and tumor cells. ...
A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months–not reached) and 10.5 months (range, 8.2–12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months–not reached) and 4.0 months (range, 2.5–6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child–Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02–0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003–0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.
... TKIs could be selected as a further treatment after failure of ICI-based therapy for the following reasons: 1) There are some theoretical and clinical reasons that efficacy of TKIs after failure of ICI-based therapy might be promising, 2) clinicians can use third line therapy with confidence after second line sorafenib failure because efficacy of several TKIs such as Kudo [16] suggested that TKIs may be effective after failure of ICI-based therapy because TKIs such as lenvatinib, sorafenib, regorafenib, and cabozantinib are stronger vascular endothelial growth factor-A inhibitors than bevacizumab. Osa et al [17] showed that the binding of nivolumab to programmed death (PD)-1 receptors on lymphocytes can be sustained for around 20 weeks after administration of nivolumab in lung cancer patients. On the basis of that report, Kudo postulated that these TKIs may have more therapeutic efficacy through synergism with the persistent effect of PD-1 or PD ligand-1 (PD-L1) antibodies even though ICI administration has ceased. ...
Background: Immune check point inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKI) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue. Summary: Therefore, at present most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials. Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression, vascular invasion, etc. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options.
