Immune-related Response Research Articles

Neoadjuvant nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) versus chemo for resectable (IB–IIIA) non-small cell lung cancer (NSCLC): Association of pathological regression with event-free survival (EFS) in CheckMate 816.

LBA8511 Background: Several studies have shown an association of pathological response, a common efficacy endpoint in neoadjuvant therapy trials, with survival for chemo in various cancers including resectable NSCLC. However, the association between pathological complete response (pCR) and survival as well as the degree of pathological regression that may be predictive of EFS for neoadjuvant immunotherapy has not been rigorously studied. CheckMate 816 (NCT02998528), a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC, met both of its primary endpoints with a statistically significant and clinically meaningful improvement in EFS and pCR. Here, we report a post hoc analysis from CheckMate 816, characterizing the association between pathological regression and EFS. Methods: Adults with resectable NSCLC were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo alone Q3W for 3 cycles. Primary endpoints were EFS and pCR (0% residual viable tumor [RVT] in the primary tumor [PT] and lymph nodes [LN] based on immune-related pathological response criteria), both assessed by blinded independent review. Major pathological response (MPR; ≤10% RVT in the PT and LN) was a secondary endpoint. In this post hoc analysis, EFS was assessed based on depth of pathological regression (measured by %RVT) in the PT only. Also, a time-dependent receiver operating characteristic curve analysis assessed the predictive ability of %RVT (PT only) for EFS outcome at 2 years, using area under the curve (AUC) to summarize the overall diagnostic accuracy (0.5 = random chance; 1 = perfect accuracy). Results: Baseline characteristics in patients (pts) with pathologically evaluable samples were well balanced between the NIVO + chemo and chemo arms, similar to the overall population. In both treatment arms, EFS (minimum follow-up, 21 months) was improved in pts with vs without pCR or MPR (Table). %RVT appeared to be predictive of EFS at 2 years for NIVO + chemo (AUC = 0.74) but an association was not clear for chemo (AUC = 0.54). 2-year EFS rates for NIVO + chemo were 90%, 60%, 57%, and 39% for pts with 0–5%, >5–30%, >30–80%, and >80% RVT, respectively. Conclusions: In CheckMate 816, pathological response (pCR and MPR) in the PT was associated with improved EFS with neoadjuvant NIVO + chemo. Additionally, depth of pathological regression appeared to be predictive of improved EFS. Clinical trial information: NCT02998528. [Table: see text]

Construction of Immune-Related ceRNA Network in Dilated Cardiomyopathy: Based on Sex Differences.

Background: Immune targeted therapy has become an attractive therapeutic approach for patients with dilated cardiomyopathy (DCM) recently. Genetic predisposition and gender play a critical role in immune-related responses of DCM. This study aimed to perform a bioinformatics analysis of molecular differences between male and female samples and identify immune-related ceRNA network in DCM. Methods: The gene expression microarray and clinical features dataset of GSE19303 was downloaded from the GEO. The raw data were preprocessed, followed by identification of differentially expressed genes (DEGs) between male and female DCM samples. Crucial functions and pathway enrichment analysis of DEGs were investigated through GO analysis and KEGG pathway analysis, respectively. A lncRNA–miRNA–mRNA network was constructed and a central module was extracted from the ceRNA network. Results: Compared with the female group, the male group benefits more from IA/IgG immunotherapy. Male patients of DCM had a significant positive correlation with the abundance of inflammatory cells (B cells, memory B cells, CD8+ Tem cells, and NK cells). Sex difference DEGs had a widespread impact on the signaling transduction, transcriptional regulation, and metabolism in DCM. Subsequently, we constructed an immune-related ceRNA network based on sex differences in DCM, including five lncRNAs, six miRNAs, and 29 mRNAs. Furthermore, we extracted a central module from the ceRNA network, including two lncRNAs (XIST and LINC00632), three miRNAs (miR-1-3p, miR-17-5p, and miR-22-3p), and six mRNAs (CBL, CXCL12, ESR1, IGF1R, IL6ST, and STC1). Among these DEGs, CBL, CXCL12, and IL6ST expression was considered to be associated with inflammatory cell infiltration in DCM. Conclusions: The identified ceRNA network and their enriched pathways may provide genetic insights into the phenotypic diversity of female and male patients with DCM and may provide a basis for development of sex-related individualization of immunotherapy.

Impact of Lung Microbiota on COPD.

There is a fine balance in maintaining healthy microbiota composition, and its alterations due to genetic, lifestyle, and environmental factors can lead to the onset of respiratory dysfunctions such as chronic obstructive pulmonary disease (COPD). The relationship between lung microbiota and COPD is currently under study. Little is known about the role of the microbiota in patients with stable or exacerbated COPD. Inflammation in COPD disorders appears to be characterised by dysbiosis, reduced lung activity, and an imbalance between the innate and adaptive immune systems. Lung microbiota intervention could ameliorate these disorders. The microbiota’s anti-inflammatory action could be decisive in the onset of pathologies. In this review, we highlight the feedback loop between microbiota dysfunction, immune response, inflammation, and lung damage in relation to COPD status in order to encourage the development of innovative therapeutic goals for the prevention and management of this disease.

Examination of survival, physiological parameters and immune response in relation to the thermo-resistant heterosis of hybrid oysters derived from Crassostrea gigas and C. angulata

High temperature is an important environmental stressor leading to summer mass mortality of oysters. Significant survival heterosis in summer were observed in hybrids between two phylogenetically closely-related oysters, Crassostrea gigas and C. angulata, but an explicit understanding of heterosis has been lacking. Here, we investigated the survival performance, oxygen consumption rate (OR) and enzyme activity (i.e., SOD, CAT and MDA) in C. gigas (GG), C. angulata (AA) and their hybrids C. gigas ♀ × C. angulata ♂ (GA) and C. angulata ♀ × C. gigas ♂ (AG) under acute heat stress containing five levels: 22, 26, 30, 34 and 38 °C. Compared with parental strains, the hybrid strains exhibited higher cumulative survival rate at all temperatures, indicating heterosis for thermal tolerance. Cox regression analysis showed that hybrid strains challenged with heat shock exhibited lower hazard ratio and longer expected lifetime. Moreover, OR in hybrid strains were significantly higher (P < 0.05) than those in parental strains under 34 and 38 °C. Arrhenius break-point temperature (ABT) and temperature coefficient (Q10) revealed that hybrids had broader temperature range of aerobic metabolism and lower sensitivity to rising temperature. In addition, the activities of SOD and CAT of hybrid strains were significantly higher than the parental strains at 34 and 38 °C-level treatment after 6 h and at 34 °C-level treatment after 3 h, whereas the MDA content were reduced, indicating their stronger antioxidant capacity. Accordingly, the enhanced aerobic capacity and antioxidant ability of hybrids under high temperature may contribute to the improvement of thermal tolerance. Our findings can facilitate our understanding of the physiological and immune mechanisms underlying thermo-resistant heterosis and facilitate the breeding of thermo-resistant oyster varieties.

Pembrolizumab activity in patients with Fanconi anemia repair pathway competent and deficient tumors

BackgroundGiven the observed antitumor activity of immune-checkpoint-inhibitors in patients with mismatch-repair deficient (MSI-H) tumors, we hypothesized that deficiency in homologous-recombination-repair (HRR) can also influence susceptibility.MethodsPatients with disease progression on standard of care and for whom pembrolizumab had no FDA approved indication received pembrolizumab. Patients with MSI-H tumors were excluded. Objectives included immune-related objective response rate (iORR), progression-free survival (PFS) and 20-weeks-PFS. Pembrolizumab was given every 3 weeks and scans performed every six. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) functional assay of the Fanconi Anemia (FA) pathway: FATSI, in treated patients’ archived tumors. The two-stage sample size of 20/39 patients evaluated an expected iORR≥20% in the whole population vs. the null hypothesis of an iORR≤5%, based on an assumed iORR≥40% in patients with functional FA deficiency, and < 10% in patients with intact HRR. An expansion cohort of MSI stable endometrial cancer (MS-EC) followed. Exploratory stool microbiome analyses in selected patients were performed.ResultsFifty-two patients (45F,7M;50-evaluable) were enrolled. For the 39 in the two-stage cohort, response evaluation showed 2CR,5PR,11SD,21PD (iORR-18%). FATSI tumor analyses showed 29 competent (+) and 10 deficient (−). 2PR,9SD,17PD,1NE occurred among the FATSI+ (iORR-7%) and 2CR,3PR,2SD,3PD among the FATSI(−) patients (iORR-50%). mPFS and 20w-PFS were 43 days and 21% in FATSI+, versus 202 days and 70% in FATSI(−) patients. One PR occurred in the MS-EC expansion cohort.ConclusionsPembrolizumab has meaningful antitumor activity in malignancies with no current FDA approved indications and FA functional deficiency. The results support further evaluation of FATSI as a discriminatory biomarker for population-selected studies.

Comprehensive immune profiling unravels evolution of spatial distribution and immune repertoire in tumor microenvironment from primary to metastatic triple-negative breast cancer.

1079 Background: Immune checkpoint inhibitors (ICI) have improved PFS and OS in metastatic triple-negative breast cancer (mTNBC), but benefit is limited to PD-L1 positive tumors. Metastatic tumors are notorious for deficient immune cell infiltration and immunosuppressive features that may limit responses to ICI in mTNBC. However, the underlying mechanisms for the weak immunogenicity of the metastatic tumor immune microenvironment (TIME) and related poor ICI responses are still not well understood. The current study was designed to investigate the evolution of the TIME between paired primary and metastatic TNBCs. Methods: Spatial distribution of 37 key immune regulators using the NanoString digital spatial profiling (DSP) platform was analyzed. 452 regions of interests (ROIs) from 33 primary tumors (PT) and 29 metastatic tumors (MT) including 28 paired specimens, were selected based on CD45+ immune hotspots, and the protein expression levels of the key immune regulators were quantified within pan-cytokeratin (panCK) and CD45 masked regions, respectively. In parallel, we examined the clonality of tumor infiltrating B cell receptors by reconstructing the immune repertoire from bulk RNA-seq data. Results: Using the DSP platform, we confirmed reduced immune infiltration (e.g., CD3 and CD20) in both panCK and CD45 masked regions of MT, while CD8A and CD11c (padj = 2.8×10-7 and 2.1×10-6) expression was only observed in panCK masked regions of MT compared with PT. A significant shift in myeloid composition between PT and MT as evidenced by increased CD68 signal (padj = 5.8×10-4) in CD45 masked regions of MT was identified. Within MT, PD-L1 signal was substantially higher (padj = 0.030) in CD45 masked regions only, while PD1 counts were lower (padj = 0.035) in panCK masked regions. This suggests the limited responses to ICI for MT may stem from relatively low expression of activated and targetable T cell subsets in MT islands. In support of the lower CD20 counts in MT, immune repertoire analysis revealed B cell receptor (BCR) repertoire diversity (represented by Gini index) was substantially lower in MT than PT (p = 0.041) suggesting that the ability of B cells to recognize a wide variety of tumor antigens in MT is greatly reduced in contrast to PT. Conclusions: Through comprehensive analysis of the TIME spatial organization within paired PT and MT, a significant reduction in dendritic cell/macrophage ratios (CD11c/CD68), reduced tumor localized T cell activation (CD8, PD1, PD-L1), and reduced B cell diversity (BCR clonality) are key features of the reduced immunogenicity of the metastatic TIME in TNBC. Further work to understand key mechanistic features driving the evolution of these differences in TIME between primary and metastatic tumors are ongoing.

Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy.

9514 Background: A phase II study of nivo and rela was designed to evaluate the antitumor activity and mechanism of this combination and components for first-line treatment of pts with advanced melanoma. Pts received lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy. We assessed the effect of each lead-in treatment on immune-related pathological response (irPR) at 4-wk biopsy to develop early biomarkers of antitumor response. Methods: Core biopsy of an index lesion was performed at baseline and after 4 wk on-treatment. Immune characteristics of pathological response were assessed on H&amp;E sections, including presence of tumor-infiltrating lymphocytes (TIL), neovascularization, proliferative fibrosis, plasma cells, and lymphoid aggregates. irPR score was calculated as described by Stein JE et al Ann Oncol 2019, from 0 (no irPR features) to 3 (major pathologic response on biopsy [MPRbx], ≤10% residual viable tumor). We assessed the association between irPR and radiological response (RECIST v1.1) at 4-wk evaluations. Results: The current cohort includes 22 pts, median age = 67, male = 13. Pts were randomized to nivo = 7, rela = 7, and nivo-rela = 8 lead-in groups. Two pts had no irPR evaluation due to early progression and unscorable tumor. Among 20 evaluable pts, proliferative fibrosis, neovascularization, plasma cells, brisk TIL, and lymphoid aggregates were identified in 50%, 35%, 26.3%, 25%, and 5% of cases, respectively. Lead-in nivo (n = 2/6), rela (n = 0/6), and nivo-rela (n = 3/8) resulted in irPR = 3 in 25% of pts. Radiological response was identified as partial response (PR) = 1/22 (4.5%), stable disease (SD) = 12/22 (54.5%), and progressive disease (PD) = 9/22 (41%). Among pts with PD, 44% received rela-, 33% nivo-, and 22% nivo-rela- lead-in. Pts with irPR score = 3 had radiological PR = 1, SD = 3, and PD = 1 at 4wks. No association was found between MPRbx and radiological response at 4 wks. Conclusions: Four-wk MPRbx may serve as an early biomarker of treatment response in advanced melanoma. Lead-in treatment resulted in MPRbx of 25% and was greatest with nivo-rela lead-in. Correlations between 4 wk MPRbx and later radiological responses, survival and other endpoints will be made at completion of trial accrual. Clinical trial information: NCT03743766. [Table: see text]

A retrospective study of ipilimumab plus nivolumab in anti–PD-L1/PD-1-refractory merkel cell carcinoma.

9521 Background: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma with a high recurrence and mortality rate. Immune checkpoint inhibitors (ICIs) targeting the PD-L1/PD-1 axis have shown significant clinical benefit with durable responses in patients with advanced MCC leading to regulatory approvals by the U.S. Food and Drug Administration for two agents: avelumab (anti-PD-L1) and pembrolizumab (anti-PD-1). However, many patients (̃50%) with advanced MCC treated with ICI do not experience tumor regression. Studies regarding systemic therapy options following progression due to primary or acquired resistance to immunotherapy are limited and management remains a clinical challenge. In this retrospective study, we evaluated objective clinical response to combination ipilimumab and nivolumab (ipi-nivo) salvage therapy in advanced MCC refractory to anti-PD-L1/PD-1 treatment. Methods: We reviewed the electronic medical record at Mass General Brigham associated institutions to identify patients with advanced MCC that progressed on upfront immunotherapy (e.g., pembrolizumab, avelumab or nivolumab) and were re-challenged with combination ipi-nivo between 2016 to 2021. Patients treated with prior surgery, radiation, or cytotoxic chemotherapy after progressing on immunotherapy were not excluded. Responses to ipi-nivo were evaluated for every patient at each re-staging/interval assessment following baseline analysis utilizing Response Evaluation Criteria in Solid Tumors (RECISTv1.1) as well as immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) to ensure conventional RECIST did not underestimate the benefit of ipi-nivo. Results: Four patients (31%) experienced grade III/IV immune-related adverse events. No patients (0/13) in this case series achieved an objective response via RECISTv1.1/irRECIST. Stable disease was seen in 23% (3/13) and the median progression-free survival was 1.3 months (90% CI, 1.1-1.5). The median overall survival from the initiation of ipi-nivo was 4.7 months (95% CI, 3-17). Conclusions: This study suggests limited, if any, clinical benefit of ipi-nivo in patients with advanced anti-PD-L1/anti-PD-1-refractory MCC. New strategies for second-line treatment of MCC are needed and referral to innovative clinical trials should be a priority for patients with refractory metastatic MCC.

Primary analysis of a phase 2, open-label, multicenter trial of talimogene laherparepvec (T-VEC) plus pembrolizumab (pembro) for the treatment (Tx) of patients (pts) with advanced melanoma (MEL) who progressed on prior anti–PD-1 therapy: MASTERKEY-115.

9518 Background: Despite advances in anti–PD-1–based Tx for MEL, an unmet need remains for immunotherapy failure in advanced metastatic or unresectable MEL. Also, there is a growing population of pts who received adjuvant anti–PD-1 and recurred; yet trials to address this population are lacking. Combination Tx with T-VEC, an oncolytic viral intratumoral Tx designed to produce GM-CSF, and pembro, an anti–PD-1 agent, may overcome immunotherapy failure. We report the MASTERKEY-115 primary analysis on the efficacy and safety of T-VEC + pembro in pts with advanced MEL who had progressive disease (PD) on prior anti–PD-1. Methods: This open-label, single-arm, multicenter, phase 2 study (NCT04068181) enrolled pts at 26 international sites (Jan 2020‒Feb 2021). Cohorts 1 and 2, primary and acquired resistance, respectively, received anti–PD-1 in a locally recurrent or metastatic setting and had PD within 12 wks of the last anti–PD-1 dose. Cohorts 3 and 4 included only pts who received adjuvant anti–PD-1 and were disease-free for &lt; 6 mos (Cohort 3) or ≥ 6 mos (Cohort 4) before confirmed PD. Eligible pts had histologically confirmed unresectable or metastatic stage IIIB–IVM1d MEL, measurable and injectable disease, ECOG PS 0/1, and progressed on anti–PD-1 directly before enrollment. T-VEC at standard dosage and pembro 200 mg were given Q3W. The primary endpoint was objective response rate (ORR). Key secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Tx decisions were per modified immune-related response criteria (irRECIST). Results: 72 pts (median age, 65 y) were enrolled. Of the 71 evaluable pts, 37 (52.1%) had stage IVM1b‒d disease, 30 (42.3%) had confirmed PD-L1–positive tumor (CPS ≥ 1%), 20 (28.2%) had a BRAFV600 mutation, and 21 (29.6%) had LDH &gt; 1ULN. At data cutoff (Aug 2021), 47 (65.3%) pts remained on study. ORR was 0%, 6.7%, 40%, and 46.7% in cohorts 1–4, respectively (table). Any-grade Tx-related adverse events (TRAEs) were reported in 54 (76.1%) pts; the most common were pyrexia (29.6%), fatigue, and influenza-like illness (15.5% each). Grade ≥ 3 TRAEs occurred in 9 (12.7%) pts. Conclusions: T-VEC + pembro showed manageable safety in pts with advanced MEL after anti–PD-1 failure; the promising ORR observed in pts who progressed on prior adjuvant anti–PD-1 warrants further analysis. Clinical trial information: NCT04068181. [Table: see text]

New Challenges in Evaluating Outcomes after Immunotherapy in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

In many recurrent and/or metastatic cancers, the advent of immunotherapy opens up new scenarios of treatment response, with new phenomena, such as pseudoprogression and hyperprogression. Because of this, different immune-related response criteria have been developed, and new therapeutic strategies adopted, such as treatment beyond progression. Moreover, the role of progression-free survival as a surrogate has been questioned, and new surrogate endpoint hypotheses have arisen. A proper understanding of radiological imaging, an assessment of the biological events triggered by therapy, and the clinical evolution of the lesions and of the patient performance status are all factors that should be considered to guide the oncologist’s treatment choice. The primary aim of this article is to discuss how all these concepts apply to recurrent/metastatic head and neck squamous cell carcinoma patients when treated with immunotherapy.

A phase II multi-arm study to test the efficacy of oleclumab and durvalumab in specific sarcoma subtypes.

TPS11594 Background: Anti-PD 1/PD-L1 blockade alone or in combination with anti-CTLA4 have yielded suboptimal results in most sarcoma subtypes. CD73, an ectonucleotidase, catalyzes the rate-limiting step for adenosine production in the extracellular space, which then aids tumors in evading immune recognition and destruction. Oleclumab, a monoclonal antibody (mAb) selectively binds and inhibits the activity of CD73, and preclinical data suggests additive activity with durvalumab, a mAb that blocks PD-L1. We designed a trial combining oleclumab and durvalumab in certain sarcoma subtypes, selected based on modest activity with anti-PDL-1 and intense staining with CD73 in the tumor microenvironment. Methods: This phase 2 study (NCT04668300) is enrolling patients with age ≥18 years with recurrent/metastatic angiosarcoma (cohort 1) or dedifferentiated liposarcoma (DLPS) (cohort 2) and ≥12 years with recurrent/metastatic osteosarcoma (cohort 3), who have received at least one prior systemic therapy but are checkpoint inhibitor naïve and have measurable disease. Each treatment cycle is 28 days with oleclumab administered at 3000 mg i.v. every 2 weeks x 5 doses, and then every 4 weeks and durvalumab administered at 1500 mg i.v every 4 weeks. Tumor assessments are based on RECIST 1.1 and immune-related response criteria (irRC) and performed at baseline, and every 8 weeks after start of therapy, with an additional scan at 12 weeks for confirmation of response. Planned sample size is ≤ 25 pts in each arm. The primary efficacy endpoint for cohorts 1 and 2 is response rate (RR) at 4 months (per RECIST 1.1). The primary efficacy endpoint for cohort 3 is event free survival (EFS) rate at 4 months. If there is a high probability that the RR4 months is unlikely to be at least 20% for cohorts 1 and 2 or the EFS4 months is unlikely to be at least 40% for cohort 3 then the accrual of the corresponding cohort will be halted. The cohorts will be monitored separately for both futility and toxicity in groups of 5 after a minimum of 10 patients have been enrolled in each cohort. Secondary endpoints for the study include safety, best RR by RECIST and irRC, median PFS, and OS. Core needle biopsies and blood samples are collected at baseline and early on-treatment (week 6). Fresh flow cytometry is being performed to assess changes in T-cell activation, proliferation, and function and CD73 expression in the membrane and cytoplasm is being assessed by immunohistochemistry. Localization of tumor-infiltrating lymphocytes and engagement of the PD-1/PDL1 axis is being assessed using multiplex immunofluorescence staining. As of Jan 30th, 2022, twenty-two patients have initiated study treatment, 3 in cohort 1, 12 in cohort 2, and 7 in cohort 3. Clinical trial information: NCT04668300.

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non–small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial

BackgroundDostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non–small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284). Materials and MethodsHere, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety. ResultsAs of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients. ConclusionDostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.

Chronic Inflammation Modulates Opioid Receptor Gene Expression and Triggers Respiratory Burst in a Teleost Model

Simple SummaryThe natural presence of opportunistic pathogens in aquatic rearing systems in alignment with favorable conditions (compromised fish immune status and/or inappropriate rearing conditions) might result in serious acute disease episodes that can develop into chronic immune responses. The present study characterizes molecular, cellular and humoral markers of chronic inflammation in a fish species with high commercial value. The intense recruitment of immune cells to the inflammatory focus 21 days after triggering an immune response illustrates a clear chronic character. The cellular response was also noticed with circulating leukocyte numbers rising in the blood of the inflamed fish. Furthermore, the cellular-mediated respiratory burst peaked at 21 days post-injection, suggesting that phagocytes were still actively fighting the inflammatory agent. Regarding the molecular analysis, certain genes appear to be good markers of a chronic inflammation response due to their importance in pathways with high relevance in chronic inflammation settings. The present study can serve as a baseline to assess long-term immune-related responses in future studies.Stress-inducing husbandry and rearing conditions, bacterial infections or parasitic diseases may all lead to chronic inflammation. The immune response will then channel energy away from growth, reproduction and other important physiological processes, to fuel immune-related metabolic responses. The present study aims to unravel the mechanisms and contribute with new information on the molecular, cellular and humoral parameters of European seabass (Dicentrarchus labrax) undergoing chronic inflammation that can be used as health indicators for application in fish health management. European seabass individuals were intra-peritoneally injected with either Freund’s Incomplete Adjuvant (FIA) to induce inflammation or Hanks Balanced Salt Solution (HBSS) to serve as sham. Fish were sampled at 24 h, 7, 14 and 21 days post-injection and blood, plasma and head-kidney were collected. The results found were clear indicators of an inflamed peritoneal cavity and an ongoing systemic immune response that persisted for at least 21 days. Locally, inflammation was characterized by an intense recruitment of immune cells that was still evident 21 days after injection, thus illustrating the chronic character of the immune response. Cellular response was also noticed peripherally with leukocyte numbers rising in the blood of FIA-injected fish. Furthermore, the cellular-mediated respiratory burst peaked at 21 days post-FIA injection, suggesting that phagocytes were still actively fighting the phlogistic agent. Regarding the head-kidney molecular analysis, cxcr4 and il34 appear to be good markers of a chronic inflammation response due to their importance for pathways with high relevance in chronic inflammation settings. In addition, opioid receptor nopr seems to be a good marker of a chronic inflammation response due to its role in detecting noxious stimuli. The present study can serve as a baseline to assess long-term immune-related responses in future studies. For that, more research is nonetheless required to select more responsive and specific molecular markers.

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy.

Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body’s immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, despite impressive tumor effects and extended patient survival, only a small proportion of patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs. Therefore, strategies to increase the proportion of patients gaining a benefit from these treatments and/or increasing the durability of immune-mediated tumor response are still urgently needed. Currently, measurement of blood or tissue biomarkers has demonstrated sampling limitations, due to intrinsic tumor heterogeneity and the latter being invasive. In addition, the unique response patterns of these therapies are not adequately captured by conventional imaging modalities. Consequently, non-invasive, sensitive, and quantitative molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using specific radiotracers, have been increasingly used for longitudinal whole-body monitoring of immune responses. Immunotherapies rely on the effector function of CD8+ T cells and natural killer cells (NK) at tumor lesions; therefore, the monitoring of these cytotoxic immune cells is of value for therapy response assessment. Different immune cell targets have been investigated as surrogate markers of response to immunotherapy, which motivated the development of multiple imaging agents. In this review, the targets and radiotracers being investigated for monitoring the functional status of immune effector cells are summarized, and their use for imaging of immune-related responses are reviewed along their limitations and pitfalls, of which multiple have already been translated to the clinic. Finally, emerging effector immune cell imaging strategies and future directions are provided.

Analysis of biomarkers in melanoma patients receiving ICI treatments: pre- vs post in responders and progressors

Abstract Markers of immune related adverse events and response in patients treated with immune checkpoint inhibitors (ICI) may shed light into ICI resistance, T cell exhaustion and other combinatorial therapies. The elevated levels of these biomarkers have potential to predict if PD-1 or PD-1/CTLA-4 antagonist combination will be effective in a certain Melanoma patient. Therefore, it may potentially guide healthcare providers to change treatment plans. In this study, the ICI treatments we focused on were PD-1 or combination of PD-1/CTLA-4 blockades. The measurement of the biomarkers was conducted at Mayo Clinic, from serum samples obtained in 2 time points, pre-treatments and 2–3 months after the first ICI treatments. Validated IVD kits were used per manufacture’s instruction. Biomarkers could be measured using stored frozen serum samples according to the instructions on how the biomarkers will be measured. We investigated 13 biomarkers in the sera of 76 melanoma patients who received immune checkpoint therapies. The biomarkers tested were, Human ELAFIN ELISA, Human IL-18 ELISA, Reg3α + Universal kit, Anti-Nuclear Antibody Test System, FLUORO AID-1 Test for anti-mitochondrial antibodies, anti-smooth muscle antibodies and anti-parietal cell antibodies, Anti-MDA5 ELISA Kit, Anti-synthetase ELISA Skin, Antineutrophil cytoplasmic antibodies MPO-ANCA ELISA, Antineutrophil cytoplasmic antibodies PR3-ANCA ELISA, Dsg1, Dsg3 ELISA, BP180, BP230, type-VII collagen. When compared with the samples obtained before treatments, IL-18 levels significantly elevated (p value &amp;lt; 0.0001) in post treatment samples of non-responders. Further studies are needed to confirm if elevated IL-18 contribute to the biology of resistance to ICI therapies. Supported by MBLI

Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial

BackgroundCancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the...

Phase II trial of efficacy, safety and biomarker analysis of sintilimab plus anlotinib for patients with recurrent or advanced endometrial cancer

BackgroundAlthough co-inhibition of the angiogenesis and programmed death 1 (PD-1) pathways is proposed as an effective anticancer strategy, studies in Chinese patients with endometrial cancer are sufficient. Anlotinib is an...

Imaging of Cancer Immunotherapy: Response Assessment Methods, Atypical Response Patterns, and Immune-Related Adverse Events, From the AJR Special Series on Imaging of Inflammation.

The introduction of immunotherapy with immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment paradigms. Since FDA approval of the first ICI in 2011, multiple additional ICIs have been approved and granted marketing authorization, and many promising agents are in early clinical adoption. Due to the distinctive biologic mechanisms of ICIs, the patterns of tumor response and progression seen with immunotherapy differ from those observed with cytotoxic chemothera-pies. With increasing clinical adoption of immunotherapy, it is critical for radiologists to recognize different response patterns and common pitfalls to avoid misinterpretation of imaging studies or prompt premature cessation of potentially effective treatment. This review provides an overview of ICIs and their mechanisms of action and discusses anatomic and metabolic immune-related response assessment methods, typical and atypical patterns of immunotherapy response (including pseudoprogression, hyperprogression, dissociated response, and durable response), and common imaging features of immune-related adverse events. Future multicenter trials are needed to validate the proposed immune-related response criteria and identify the functional imaging markers of early treatment response and survival.

Elevated tumor markers for monitoring tumor response to immunotherapy

SummaryBackgroundAs the immune-related response evaluation criteria in solid tumors (irRECIST) by imaging greatly underestimated the objective response to immunotherapy, we established the response evaluation criteria in solid tumors based on tumor markers (RecistTM) to explore whether RecistTM can compensate for the deficiencies of the irRECIST criteria.MethodsThis was an observational study, which consisted of two parts. The first part (Group A) was a retrospective study including the patients with malignant solid tumors. The second part (Group B) was a prospective study, which were EGFR-negative and ALK-negative patients with stage IIIB-IV non-small cell lung cancer receiving first-line treatment. From January 2017 to September 2020, one hundred and ten patients with a three-time increase in tumor markers receiving immunotherapy were recruited. The treatment response to immunotherapy was evaluated by irRECIST and RecistTM. Efficacy, overall survival (OS), first evaluation time and earliest response time under the different evaluation criteria were compared by statistics.FindingsThe treatment response evaluated by the RecistTM criteria was not consistent with that evaluated by the irRECIST criteria (Kappa = 0.386, p < 0.001). RecistTM had a higher completed response (CR) rate compared to irRECIST criteria (20.9% vs 1.8%, p < 0.001). The earliest response time under the RecistTM criteria was 3.42 weeks earlier than that under the irRECIST criteria (u = -5.233, p < 0.001). There were significant differences in median OS between tumor marker-related complete response (tmCR) and tumor marker-related partial response (tmPR), as well as between tmPR and tumor marker-related stable disease (tmSD) (χ2 = 15.572, p < 0.001; χ2 = 7.720, p = 0.005), but not between tmSD and tumor marker-related progressive disease (tmPD) (χ2 = 1.596, p = 0.206). When applying both criteria together, for patients with immune-related CR / immune-related PR (irCR/irPR) (n = 54) under irRECIST criteria, there was a significant difference in median OS between achieving tmCR (n = 22) and tmPR (n = 32) (χ2 = 14.011, p < 0.001). RecistTM criteria can predict 1-year and 2-year OS more accurately than irRECIST criteria (AUCs:0.862 vs 0.552, 0.649 vs 0.521, respectively;both p < 0.001). In RecistTM, 4 patients had been observed with pseudoprogression in tumor markers.InterpretationThe RecistTM criteria could effectively distinguish CR, PR, and SD, which may help resolve the shortcomings of the RECIST criteria in evaluating the treatment response to immunotherapy, especially in assessing whether patients can achieve deep or even complete response as soon as possible.FundingThis work was supported by the Key projects of Chongqing Health and Family Planning Commission (to Xueqin Yang, 2019ZDXM011).

MALT1 in asthma children: A potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance-mediated inflammation.

BackgroundMucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) participates in the immune‐related allergic response and inflammation flare, while its clinical role in asthma children is still unknown. Herein, this study aimed to investigate MALT1 expression, and its correlation with exacerbation risk, T helper (Th)1, Th2 cells (and their secreted cytokines), as well as inflammatory cytokines in asthma children.MethodsSixty children with asthma exacerbation and 60 children with remission asthma were enrolled in this study; then their blood MALT1, Th1, Th2 cells, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interferon‐gamma (IFN‐γ), and interleukin‐4 (IL‐4) were detected. Besides, blood MALT1 in another 20 health controls was also determined.ResultsMucosa‐associated lymphoid tissue lymphoma translocation protein 1 was highest in children with asthma exacerbation, followed by children with remission asthma, and lowest in health controls (p < 0.001). MALT1 could distinguish children with asthma exacerbation from children with remission asthma (area under the curve (AUC): 0.757, 95% CI: 0.670–0.843). In children with asthma exacerbation, MALT1 was negatively linked with IFN‐γ (p = 0.002) and Th1 cells (p = 0.050), but positively related to Th2 cells (p = 0.027) and exhibited a positive correlation trend (without statistical significance) with IL‐4 (p = 0.066); meanwhile, MALT1 was positively correlated with exacerbation severity (p = 0.010) and TNF‐α (p = 0.003), but not linked with IL‐6 (p = 0.096). In children with remission asthma, MALT1 only was negatively associated with Th1 cells (p = 0.023), but positively linked with TNF‐α (p = 0.023).ConclusionMucosa‐associated lymphoid tissue lymphoma translocation protein 1 serves as a potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance‐mediated inflammation of asthma children.