Nivolumab Treatment In Patients Research Articles

Baseline neutrophil-to-eosinophil-ratio and outcome in metastatic clear-cell renal cell carcinoma treated with nivolumab or ipilimumab/nivolumab.

This study aims to evaluate neutrophil-to-eosinophil ratio (NER) as a prognostic and/or predictive biomarker in metastatic clear cell renal cell carcinoma (m-ccRCC) treated with nivolumab or ipilimumab/nivolumab. We performed a retrospective study on m-ccRCC patients treated with nivolumab or ipilimumab/nivolumab (2012-2022). Baseline NER was calculated and correlated with clinical outcomes: response rate (RR), progression free survival (PFS) and overall survival (OS). Corresponding transcriptomic data were analysed. We included 201 m-ccRCC patients, 76 treated with ipilimumab/nivolumab and 125 with nivolumab. Baseline NER was statistically significantly associated with International Metastatic RCC Database Consortium (IMDC) risk groups. Increased NER was associated with shorter PFS and OS in the total patient series and nivolumab-treated patients. In patients treated with ipilimumab/nivolumab, increased NER was only statistically significantly associated with shorter OS. The impact of baseline NER on PFS and OS was independent of IMDC risk stratification. No clear correlation was found between baseline NER and RECIST response or maximal tumour shrinkage. In two additional databases, NER was also associated with PFS and OS in first-line vascular-endothelial-growth-factor-receptor tyrosine-kinase-inhibitors (VEGFR-TKIs), but not to disease-free survival in the post-nephrectomy setting. Lower NER was associated with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. Lower baseline NER is associated with better PFS and OS, independent of IMDC risk score, in m-ccRCC patients treated with ipilimumab/nivolumab or nivolumab. It correlates with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. The predictive power of this biomarker is probably limited and insufficient for patient selection.

Outcomes With Postrecurrence Systemic Therapy Following Adjuvant Checkpoint Inhibitor Treatment for Resected Melanoma in CheckMate 238.

In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy. Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy). Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS. Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways.

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD-1 immune checkpoint inhibitor nivolumab 1 week prior to surgery, compared with control patients receiving salvage resection without prior nivolumab treatment. We observed saturating levels of nivolumab bound to intratumorally and tissue-resident T cells in the brain, implicating saturating levels of nivolumab reaching brain tumors. Following nivolumab treatment, significant changes in T-cell activation and proliferation were observed in the tumor-resident T-cell population, and peripheral T cells upregulated chemokine receptors related to brain homing. A strong nivolumab-driven upregulation in compensatory checkpoint inhibition molecules, i.e., TIGIT, LAG-3, TIM-3, and CTLA-4, was observed, potentially counteracting the treatment effect. Finally, tumor-reactive tumor-infiltrating lymphocytes (TIL) were found in a subset of nivolumab-treated patients with prolonged survival, and neoantigen-reactive T cells were identified in both TILs and blood. This indicates a systemic response toward GBM in a subset of patients, which was further boosted by nivolumab, with T-cell responses toward tumor-derived neoantigens. Our study demonstrates that nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, various anti-inflammatory mechanisms mitigate the clinical efficacy of the anti-PD-1 treatment.

Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan

BackgroundNivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan.MethodsWe performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]).ResultsThe overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population.ConclusionTo our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups.Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).

Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Assessing the prognostic value of IMDC risk score for nivolumab-treated patients with renal cancer and malignant melanoma.

The response of Renal Cell Cancer (RCC) to tyrosine kinase inhibitors (TKI) has been well established. Although these stratifications have been established for TKI response and prognosis, these parameters have recently been used to predict immunotherapy response in RCC. We aimed to use a combination of clinical parameters of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups and metastatic sites at the time of diagnosis to predict the effectiveness of immune checkpoint inhibitors in malignant melanoma (MM). In this cross-sectional study, we retrospectively analyzed the demographic information, metastatic sites, and IMDC risk group data. The blood parameters were included in the first cycle of nivolumab treatment. The OS was statistically different between the RCC and MM groups in terms of the IMDC. In univariate analysis of stage at diagnosis, CRP levels and bone and bone marrow metastases were confirmed to be prognostic factors in the MM population in terms of OS. Brain metastasis was a prognostic factor for RCC, whereas sex, line of treatment, LDH, bone, and splenic metastasis remained significant in patients with MM in terms of OS. Brain metastasis was prognostic in both cancer types in multivariate analysis in terms of PFS. In addition to brain metastasis, LDH levels and lung, liver, and splenic metastases also affect PFS in patients with MM undergoing nivolumab treatment. In our study, the IMDC was confirmed to be a prognostic factor for MM. The IMDC groups were similar, except for the favorable RCC and MM groups. Different metastatic sites were prognostic, similar to the IMDC risk group in the MM group.

Nivolumab for newly and recurrent glioblastoma multiforme treatment: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis aiming to assess the efficacy and safety of Nivolumab treatment in patients with newly diagnosed and recurrent glioblastoma multiforme (GBM). Our study followed the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations. The protocol for this review can be found in the International Prospective Register of Systematic Reviews Database (CRD42022340071). We performed searches on the Medline, PubMed, Embase, Scopus, and Web of Science databases. A total of 545 studies were identified through our comprehensive search across the five databases (PubMed: 78, Embase: 82, Medline: 173, Scopus: 138, Web of Science: 74). After conducting a thorough analysis, our meta-analysis indicated that treatment with Nivolumab led to improved overall survival (OS) outcomes in newly diagnosed glioblastoma patients, as evidenced by a prolonged median OS based on trial data. However, there was no significant beneficial effect observed in terms of median progression-free survival (PFS), as well as OS at 6, 12, and 24 months. Furthermore, our results demonstrated no efficacy of Nivolumab in the treatment of recurrent GBM patients. In conclusion, Nivolumab demonstrated promising results that warrant further investigation for its use in newly diagnosed glioblastoma patients. However, its effectiveness was not observed in the context of recurrent GBM.

Outcome of Immunotherapy in Adrenocortical Carcinoma - A retrospective cohort study.

Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at six German reference centres between 2016 and 2022. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAE) were assessed. In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR 24% (16-41). PFS was 3.0 months (95%CI 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs. 2.5 (2.0- 3.0) months (HR 0.29, 95%CI 0.13-0.66, p=0.001) and OS of 28.2 (9.5-46.8) vs. 7.0 (4.1-10.2) months (HR 0.34, 95%CI 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs. 2.3 (1.6-3.0, p<0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. In the real-life setting we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab treated patients require confirmation.

The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancer.

Although phase III trials have reported improved overall survival in patients with advanced esophageal squamous cell carcinoma following treatment with nivolumab, as compared with chemotherapy (paclitaxel or docetaxel), the treatment was effective only in a limited number of patients. Therefore, the aim of this study is to determine whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer in patients treated with taxane or nivolumab therapy. The medical records of 35 patients who received taxane monotherapy (paclitaxel or docetaxel), for advanced esophageal cancer between October 2016 and November 2018 (taxane cohort) were reviewed. The clinical data of 37 patients who received nivolumab therapy between March 2020 and September 2021 (nivolumab cohort) were collected. The median overall survival was 9.1 months for the taxane cohort and 12.5 months for the nivolumab cohort. In the nivolumab cohort, patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (18.1 vs. 7.6 months, respectively, p = 0.009, classified by prognostic nutritional index, 15.5 vs. 4.3 months, respectively, p = 0.012, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This suggests that the pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for treatment with nivolumab.

Evaluation of deep learning techniques (DL) in RNA sequencing data for the prediction of response to immune checkpoint inhibitors in patients with metastatic renal cell cancer m(RCC).

641 Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab.

Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Baseline Radiomic Signature to Estimate Overall Survival in Patients With NSCLC

IntroductionWe aimed to define a baseline radiomic signature associated with overall survival (OS) using baseline computed tomography (CT) images obtained from patients with NSCLC treated with nivolumab or chemotherapy. MethodsThe radiomic signature was developed in patients with NSCLC treated with nivolumab in CheckMate-017, -026, and -063. Nivolumab-treated patients were pooled and randomized to training, calibration, or validation sets using a 2:1:1 ratio. From baseline CT images, volume of tumor lesions was semiautomatically segmented, and 38 radiomic variables depicting tumor phenotype were extracted. Association between the radiomic signature and OS was assessed in the nivolumab-treated (validation set) and chemotherapy-treated (test set) patients in these studies. ResultsA baseline radiomic signature was identified using CT images obtained from 758 patients. The radiomic signature used a combination of imaging variables (spatial correlation, tumor volume in the liver, and tumor volume in the mediastinal lymph nodes) to output a continuous value, ranging from 0 to 1 (from most to least favorable estimated OS). Given a threshold of 0.55, the sensitivity and specificity of the radiomic signature for predicting 3-month OS were 86% and 77.8%, respectively. The signature was identified in the training set of patients treated with nivolumab and was significantly associated (p < 0.0001) with OS in patients treated with nivolumab or chemotherapy. ConclusionsThe radiomic signature provides an early readout of the anticipated OS in patients with NSCLC treated with nivolumab or chemotherapy. This could provide important prognostic information and may support risk stratification in clinical trials.

Outcome following nivolumab treatment in patients with advanced non-small cell lung cancer and comorbid interstitial lung disease in a real-world setting.

Up to 10% of patients with advanced non-small cell lung cancer (aNSCLC) have pre-existing interstitial lung disease (ILD). These patients are usually excluded from immunotherapy clinical trials. Consequently, knowledge on outcomes following nivolumab treatment in these patients remains limited. The primary objective of this study was to evaluate survival outcome following nivolumab treatment in ILD patients with pre-treated aNSCLC in the real-world setting. The study included all patients with aNSCLC recorded in the French hospital database, starting nivolumab in 2015-2016. Patients were stratified by pre-existing ILD and three subgroups were studied [auto-immune or granulomatous (AI/G) ILD, other known causes ILD and idiopathic ILD]. Time to discontinuation of nivolumab treatment [time to treatment duration (TTD)] and overall survival (OS) were estimated using Kaplan-Meier survival analysis. Of 10,452 aNSCLC patients initiating nivolumab, 148 (1.4%) had pre-existing ILD. Mean age at nivolumab initiation was 64.6 ± 9.4 years in ILD and 63.8 ± 9.6 years in non-ILD. Compared to non-ILD, patients in the ILD group were more frequently men (p < 0.05) and had more comorbidities (p < 0.001). There was no significant difference between ILD and non-ILD groups for median TTD (2.5 versus 2.8 months; p = 0.6) or median OS (9.6 versus 11.9 months; p = 0.1). Median OS in AI/G ILD (n = 14), other known causes ILD (n = 75), and idiopathic ILD (n = 59) were 8.6, 10.7, and 9.6 months, respectively. In this large cohort of aNSCLC patients with ILD, outcomes are similar to those obtained in the non-ILD population. Immunotherapy could be beneficial for these patients.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated with Expansion and Maturation of NK Cells

ABSTRACT Background. Hodgkin Lymphoma (HL) Hodgkin Lymphoma (HL) is a B-Cell neoplasia characterized by a high degree of response to chemotherapy and an overall favourable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL are either refractory or eventually relapse (R/R) after first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT). Immune checkpoint inhibitors (CI) have demonstrated clinical activity in HL patients relapsing after ASCT, although only 20% complete response (CR) rate are usually observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Aims. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI) and to investigate the lymphocyte subpopulation involved in the mechanism of response to CI in HL. Results. Seventeen patients with relapse/refractory (R/R) HL (median age 29 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 12 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 5 responding patients received ALI alone, as a control cohort. Most patients showed CMV seropositivity at the time of enrolment, without signs of active infection (positive anti-CMV IgG, negative IgM and undetectable CMV DNA). No adverse events were recorded, specifically, no immune-related toxicity was observed and none of the patients showed CMV reactivation. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR and 11/12 are alive and disease-free after a median follow-up of 33 months. The only relapse occured 23 months after last ALI. Six of the responding patients underwent subsequent allogeneic SCT in a CR status and 1 patients are currently waiting for transplantation. Two of the patients in the control arm relapsed after a median of 6 months (4-8 months) Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients (Fig.1). In detail, different patterns of NK cell development could be identified. Indeed, starting from one month after transplantation, in the group of patients undergoing ALI plus nivolumab, a relevant fraction of NK cells displayed a mature phenotype characterized by a CD56dimCD16bright expression (Fig. 1). On the contrary, in control patients, NK cells were characterized by a more immature phenotype (high frequencies of CD56brightCD16neg/dim NK cells) even at late time points (three months) after transplantation (Fig. 1). This event occurred in all the treated (ALI + nivolumab) patients analyzed (Fig. 1). Finally, PB from patients undergoing ALI + nivolumab was enriched in unconventional CD56dimCD16dim NK cells (Fig. 1). One month after transplantation, CD94/NKG2A+ KIR- NK cells were largely predominant in all patients, whereas CD94/NKG2A- KIR+ NK cells were present in low proportions. An increase of CD94/NKG2A- KIR+ subset occurred primarily in treated patients starting from t2. At t3, the significant increase of CD94/NKG2A- KIR+ NK cells occurred in the treated group but not in the control group . This event occurred in all the treated (ALI + nivolumab) patients analyzed, regardless of their serological status for HCMV, but was more evident in treated patients who were seropositive for HCMV. Remarkably, PB from HCMV seropositive patients undergoing ALI + nivolumab became enriched over time in differentiated NK cells characterized by high expression of NKG2C receptor (the activating counterpart of NKG2A), as compared to HCMV+ control patients. This subset represents the so-called "adaptive" NK cell population that usually increases during HCMV infection/reactivation. In this case, however, this event occurred in the absence of HCMV reactivation, and only in HCMV seropositive patients treated with ALI + nivolumab. Conclusions. Our data show anti-tumour activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favour the expansion of the "adaptive" NK cell compartment, especially in patients with CMV seropositivity, in the absence of CMV reactivation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Metformin keeps CD8+ T cells active and moving in NASH-HCC immunotherapy

Metformin keeps CD8+ T cells active and moving in NASH-HCC immunotherapy

C-reactive protein and immune-related adverse events as prognostic biomarkers in immune checkpoint inhibitor treated metastatic renal cell carcinoma patients

ABSTARCT Background There is an ongoing need to identify biomarkers for correct patient selection for immune-oncology treatments in metastatic renal cell carcinoma (mRCC). The aim of our study was to evaluate the prognostic role of elevated C-reactive protein (CRP) values and immune-related adverse events (irAEs) to indicate immune checkpoint inhibitors’ (ICIs) efficacy in nivolumab-treated mRCC patients. Materials and methods Data from 96 mRCC patients treated with nivolumab at Comprehensive Cancer Center, Helsinki University Hospital in a real-life setting were collected between 2006 and 2020 retrospectively. Patients’ baseline CRP, on-treatment (<12 weeks) CRP, and reported irAE association to median survival and outcome were analyzed using Kaplan–Meier and Cox regression. Results Patients with elevated baseline CRP were associated with worse overall survival (OS) and progression-free survival (PFS) when compared with normal baseline CRP. This significant correlation was also observed with patients with elevated on-treatment CRP. In multivariate survival analyses both elevated baseline and on-treatment CRP had shorter OS and PFS than patients with normal CRP: hazard ratio (HR) 2.84 (95% CI 1.48–5.42), HR 3.68 (95% CI 1.92–7.03) and PFS: HR 1.77 (95% CI 1.06–2.97), HR 2.88 (95% CI 1.75–4.73), respectively. A significant difference in OS was also seen between patients without irAE and with irAE during treatment. In multivariate survival analyses, patients without irAE had shorter OS HR 1.93 (95% CI 1.03–3.62) compared with patients with reported irAE. Conclusions Elevated baseline CRP, on-treatment CRP, and absence of irAE correlate with poor outcome in nivolumb-treated mRCC patients. These results suggest that monitoring CRP values as well as potential irAEs during treatment may be of use in clinical decision making.

The tissue-resident marker CD103 on peripheral blood T cells predicts responses to anti-PD-1 therapy in gastric cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer. We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1+CD8+ T cells and treatment responses using multicolor flow cytometry. The tumors, lymph nodes, and peripheral blood of gastric cancer patients who underwent gastrectomy following nivolumab treatment were collected, and nivolumab-binding PD-1+CD8+ T cells in these tissue samples were characterized. Patients with a high frequency of CD103 among PD-1+CD8+ T cells in peripheral blood 2weeks after the start of treatment had significantly better progression-free survival than the low group (P = 0.032). This CD103+PD-1+CD8+ T cell population mainly consisted of central memory T cells, showing the high expression of Ki-67 and few cytotoxic granules. In contrast, effector memory T cells were more frequently observed among CD103+PD-1+CD8+ T cells in tumors, which implied a change in the differentiated status of central memory T cells in lymph nodes and peripheral blood to effector memory T cells in tumors during the treatment with ICIs. A high frequency of CD103 among PD-1+CD8+ T cells 2weeks after nivolumab treatment in patients with advanced gastric cancer may be a useful biomarker for predicting the efficacy of anti-PD-1 therapy.

Can Previous Chemotherapy Affect the Outcome of Nivolumab Treatment in Non-small Cell Lung Cancer?

This study compared the results of nivolumab treatment in patients with pulmonary adenocarcinomas based upon previous chemotherapeutic regimens. The data source for this retrospective study was the Czech VILP registry of patients with nivolumab-treated adenocarcinomas in second and higher lines of treatment. In relation to objective response rate, progression-free interval, and overall survival, three comparisons of patient were made: A: Those treated in first line with cisplatin and pemetrexed versus carboplatin with paclitaxel or vinorelbine; B: treatment with cisplatin and pemetrexed versus carboplatin with paclitaxel/vinorelbine and bevacizumab; and C: treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) versus treatment with taxane (first-line carboplatin and paclitaxel only plus those treated with second-line docetaxel). We observed no differences in objective response rate or progression-free survival between patients treated with the stated chemotherapeutic regimens. We observed a trend towards better overall survival for patients treated with carboplatin plus taxanes or vinorelbine with/without bevacizumab. From our overall survival data, a chemotherapeutic regimen of carboplatin plus taxanes or vinorelbine with/without bevacizumab might be a better partner for immunotherapy than a cisplatin and pemetrexed-based one.

Identifying Early Predictive Markers for Immune-Related Adverse Events in Nivolumab-Treated Patients with Renal Cell Carcinoma and Gastric Cancer.

Background:Neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios can indicate poor disease prognosis and are inflammation markers. We investigated the role of NLR and PLR as effective predictive markers of immune-related adverse event (irAE) onset in patients treated with nivolumab. Methods:We retrospectively analysed 73 gastric and renal cancer patients treated with nivolumab at the Hokkaido Cancer Centre from January 2017 to June 2020. NLR and PLR were calculated at the initiation of nivolumab treatment and irAE onset. We identified the risk factors for Grade 3-4 irAE onset using NLR, PLR, sex, cancer type, and age. Overall survival (OS) and progression free survival (PFS) were calculated from the initiation of nivolumab treatment to the date of death or censored at last follow-up. Results:Among the 73 patients included, 17 (18%) had at least one grade3-4 irAE. Multivariable logistic regression analyses revealed that pretreatment NLR<4.3 was significantly associated with a reduced risk for onset of grade3-4 irAEs, whereas rate of NLR change after treatment, ΔNLR>120% was significantly associated with an increased risk. Conclusions:NLR is an effective marker for prognosis and onset of grade 3-4 irAEs.

Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma.

Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.