bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of super-exhausted T cells: A novel population predictive of response to immunotherapy.
Authors: Peyraud Florent , Guegan Jean-Philippe , Rey Christophe , Cousin Sophie , Roubaud Guilhem , Cabart Mathilde , Brunet Maxime , Oflazoglu Gruyters Ezogelin , Savina Ariel , Le Moulec Sylvestre , Dadone-Montaudon Bérangère , Barlesi Fabrice , Besse Benjamin , Loriot Yohann , Marabelle Aurelien , Soria Jean-Charles , Scoazec Jean-Yves , Le Loarer François , Bessede Alban , Italiano Antoine 
Published: June 2022

2596 Background: Given that most of cancer patients treated with anti-PD1/PD-L1 immune checkpoint blockers (ICB) do not derive benefit, there is a crucial need to identify reliable predictive biomarker of response. Besides PD-1, several key immune checkpoints, such as CTLA4, LAG3, TIM3 and TIGIT, are associated with a T cell exhausted phenotype and play a crucial role in leading to cancer immune evasion. The impact of simultaneous expression by T cells of distinct inhibitory receptors on outcome of patients treated with ICB is still unknown. Methods: We analyzed the tissue samples, collected before ICB initiation, from patients with solid tumors and included in an institutional molecular profiling program (NCT02534649). We used multiplexed-immunohistofluorescence with the following panel CD3/PD1/TIM3/LAG3/TIGIT/CTLA4, and performed immune cell characterization using multispectral images analysis. We then investigated the correlation between coexpression of T cell-associated exhaustion markers, clinical response rate, progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards models. Results: Four hundred thirty five patients were included in the analysis (NSCLC: n=207, 47.6%; sarcoma: n=42, 9.7%; urothelial: n=30, 6.9%; others: n=156, 35.9%). Digital pathology analysis allowed us to identify a population of “super-exhausted” T cells characterized by the co-expression of PD1, LAG3, TIGIT and TIM3 which was enriched in 125 cases (28.7%), and was significantly associated with better PFS (HR 1.60, CI95 1.26-2.04, p<0.001) and OS (HR 1.42, CI95 1.07-1.89, p=0.016) in the whole cohort. Patients with super-exhausted high tumors had higher objective response rate (38.4%) compared to super-exhausted low tumors (19.7%, p<0.001). The presence of super-exhausted T cells was significantly higher in responders (10%) versus non responders (4%, p<0.001). Correlation with better outcome was observed whatever the subgroup considered (NSCLC vs other tumors, CD8 T cells density and presence of tertiary lymphoid structure [TLS]). In multivariate analysis (n=372, 85.5%), increased tumor infiltration by super-exhausted T cells (>1 %) was significantly associated with better PFS (HR 0.61, CI95 0.46-0.81, p<0.001, Table) and OS (HR 0.68, CI95 0.48-0.97, p=0.033, Table). Conclusions: The presence of super-exhausted T cells may represent a new predictive biomarker of response to ICB and pave the way for the development of effective ICB combinations. Data from an independent validation cohort will be presented at the meeting. [Table: see text]
Association between body mass index and treatment efficacy with immune checkpoint inhibitor therapy: A retrospective study.
Authors: Wang Hannah , Ali Atif , Prather Lyndsey L , Du Wendy , Chen Nan , Sheth Aakash , Sandulache Vlad , Sabichi Anita Lyn , Wang Daniel Ying , Kemnade Jan Ole 
Published: June 2022

2598 Background: Increased body mass index (BMI) has been associated with improved efficacy of immune checkpoint inhibitor therapy (ICI) in cancer patients. We aimed to retrospectively assess the relationship between patient BMI and response to ICI at two unique health care systems in our institution Methods: We identified patients treated with ICI from 2015-2021 at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) Cancer Center and Baylor St. Luke’s Medical Center (BSLMC), a private hospital-based cancer center, both academic affiliates of Baylor College of Medicine. Clinical details, including BMI, and treatment efficacy were collected. We defined BMI categories as follows: underweight ( < 18.5), normal weight (18.5-24.9), overweight (25-29.9), and obese (≥30). Progression free survival (PFS), overall survival (OS), and overall response rate (ORR) were the primary end points calculated for treatment efficacy. Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with log-rank test. Cox regression analysis was used to determine whether BMI at ICI initiation was associated with survival. Chi-square testing was used to determine any association between BMI and ORR. Results: We identified 430 patients treated with ICI, 257 (60%) from BSLMC and 173 (40%) from MEDVAMC. 341 patients (79%) were male and 89 (21%) female. Cancer types included 127 (30%) lung, 49 (11%) kidney, 40 (9.3%) bladder, 38 (8.8%) melanoma, and 38 (8.8%) mesothelioma, 34 (7.9%) head and neck, and 104 (24%) other. 160 (37%) patients had a normal BMI at ICI initiation, 37 (8.6%) underweight, 132 (31%) overweight, and 101 (23%) obese. Mean BMIs of different cancer types were as follows: lung (24.7), kidney (29.2), bladder (26.0), melanoma (29.9), mesothelioma (25.25), head and neck (23.7). 292 (68%) patients were treated with ICI monotherapy. The ORR for patients with normal vs. obese BMIs treated with ICI were 28% and 42%, respectively (p = 0.03). In a subset of patients evaluable for survival (n = 322), patients with an obese BMI had a significantly improved median PFS compared to those with normal BMI (36.4 vs. 23.5 months, respectively, p < 0.0001). Multivariable analysis demonstrated that patients with an obese BMI had significantly improved overall survival compared to patients with a normal BMI (HR 0.64, 95% CI 0.44-0.91, p = 0.014). This relationship was also seen in the subset of patients treated with ICI monotherapy (HR 0.66, 95% CI 0.45-0.95, p = 0.029). This association was noted regardless of health care systems. Conclusions: Increased BMI in cancer patients treated with ICI may predict better treatment efficacy and survival outcomes. More research is needed to define this relationship more clearly.
A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb), in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Ganju Vinod , Cooper Adam , Gao Bo , Wilkinson Kate 
Published: June 2022

2602 Background: YH001 is a humanized anti-hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard "3+3" design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2021 data cut-off, 24 pts with advanced solid tumors were enrolled and dosed at 0.05 mg/kg (n=2), 0.1 mg/kg (n=3), 0.3 mg/kg (n=3),1mg/kg (n=5), 2mg/kg (n=5), 4mg/kg (n=3) and 6mg/kg (n=3). Baseline ECOG scores were 0 (n=14), 1 (n=10) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-5) including 5 pts progressed after prior immunotherapy of anti-PD-1 antibody. Overall, 6 cases of Grade(G) 3 or above treatment-related AEs (TRAEs) have been reported in 5 pts at 0.3 mg/kg, 4 mg/kg and 6 mg/kg dose level respectively, including 1 G3 colitis, 1 G4 thrombocytopenia, 1 G3 Enterocolitis, 1 G3 Rash, 1 G3 Pruritus and 1 G3 hepatitis. There were no death events due to TRAEs. 18 pts (75%) had 63 TRAEs of any level, including 28 G1 TRAEs, 29 G2 TRAEs. 2 of the first 3 pts at MAD (6mg/kg) met protocol defined DLT in Combo phase. Among the 23 pts having imaging tumor assessment by RECIST v1.1, 4 achieved PR and 9 achieved SD in Best of Response. 1 subject with gastroesophageal junction carcinoma at 0.3 mg/kg has achieved PR since the 2nd tumor assessment, target lesion decreased by up to 84.5% from baseline. 1 subject with urothelial carcinoma at 2 mg/kg progressed after prior anti-PD-1 antibody has achieved PR since the 2nd tumor assessment, target lesion decreased by up to 74% from baseline. 1 subject with uterine carcinosarcoma at 2 mg/kg has achieved PR since the 1st tumor assessment, target lesion decreased by up to 52.3% from baseline. 1 subject with vulva adenocarcinoma at 6 mg/kg has achieved PR since the 1st tumor assessment, target lesion decreased by up to 71.4% from baseline. ORR (CR+PR) and DCR (CR+PR +SD) were 17.4%, 56.5% respectively. Conclusions: YH001 was well tolerated up to 4 mg/kg dose levels when combined with toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04357756.
Retrospective analysis of the effect of angiotensin receptor blockers and angiotensin converting enzyme inhibitors on the efficacy of anti-PD-1/PD-L1 immunotherapy in patients with advanced cancer.
Authors: Suh Jason , Rutledge John R. , Friedlander Philip Adam 
Published: June 2022

2605 Background: Components of the renin angiotensin system (RAS) are expressed in tumors with activation leading to tumor and stromal cell release of immunomodulatory cytokines promoting an immunosuppressive microenvironment and increased infiltration of tumor associated macrophages. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are anti-hypertensives that inhibit the RAS. It is unknown if ACEi and ARB treatment modulates the efficacy of anti-PD-1/PD-L1 immunotherapy. Methods: A retrospective chart review was conducted to identify patients with unresectable malignancies initiating treatment with a PD-1 or PD-L1 inhibitor based regimen between 1/1/13 and 6/1/19 at Valley Hospital in New Jersey. IRB approval was obtained. Efficacy of treatment was measured by medical oncologist documentation of clinical benefit (CB = stable disease / treatment response) versus disease progression. Chi-square tests were performed to assess relationship between ACEi or ARB exposure and immunotherapy benefit. To assess for a broader anti-hypertensive effect, the relationship in patients on a beta-blocker but not ACEi/ARB was assessed. Results: 197 patients were identified of which 190 had documentation of clinical outcome. The mean age was 72.8 years with 54% female and 46% male. 56 patients were exposed to ACEi (N = 28) or ARB (N = 28) and 141 patients to neither. 37 patients were exposed to beta blocker but not ACEi or ARB. 60 patients had nonsquamous NSCLC (16 on ACEi or ARB), 26 squamous NSCLC (7 on ACEi or ARB) and 24 melanoma (10 on ACEi or ARB). 71% of ACEi/ARB exposed patients had CB by clinician assessment as opposed to 47% in those not on ACEi or ARB (p = 0.003). In ACEi exposed patients, 71% had CB versus 51% in unexposed patients (p = 0.048). In ARB exposed patients, 70% had CB versus 51% in unexposed patients (p = 0.069). By contrast, 51% of beta-blocker treated patients had CB versus 55% in untreated patients (p = 0.72). 36% of ACEi/ARB exposed patients remained on treatment at 12 months versus 22% of ACEi/ARB unexposed patients. Subset analyses were performed on the 3 largest patient populations: squamous NSCLC, nonsquamous NSCLC and melanoma. ACEi/ARB exposed melanoma patients had CB rate of 70% versus 43% in those unexposed. ACEi/ARB exposed squamous NSCLC patients had CB rate of 86% versus 47% in unexposed patients. By contrast, ACEi/ARB exposed nonsquamous NSCLC patients had a 56% CB rate versus 48% in unexposed patients. Conclusions: Based on retrospective analysis, advanced cancer patients treated with anti-PD-1/PD-L1 regimens had a statistically significant increase in clinical benefit if administered in the context of renin angiotensin system blockade. Prospective disease specific trials can further validate these findings and define the degree of clinical benefit.
Predictors of response to immune checkpoint inhibitors (ICI) rechallenge post-disease progression in solid tumors: A systematic review and meta-analyses.
Authors: Abushukair Hassan Mohammed , Al-Kraimeen Leen Mohammad , Saeed Anwaar 
Published: June 2022

2612 Background: Rechallenge with the same or different ICI has been proposed as a second line option in patients who progress on an initial ICI course. Considering rechallenge risks of limited benefit and further toxicity, identifying predictors for patients benefiting from rechallenge would provide much needed guidance for practice. We present a systematic review and meta-analyses of response predictors to ICI rechallenge after disease progression in solid tumors. Methods: A systematic search of PubMed, Cochrane database and ASCO meeting library was done for studies published up to Jan 2022 evaluating the efficacy of ICI rechallenge in patients with advanced solid tumors after disease progression on initial ICI. Predictors of interest included duration of the initial ICI course using a cutoff point of 6 months, and best overall response (BOR) to initial ICI: stratified into responders (complete or partial response or stable disease) and non-responders (progressive disease). Odds ratios (OR) for ICI rechallenge response were calculated & pooled in reference to initial ICI duration and its BOR using the fixed effects model. ORs with a 95% confidence interval [CI] not overlapping the null value (1) were considered statistically significant. Results: A total of 56 studies reporting on ICI rechallenge upon progression, comprising 3579 patients, of which 31 studies have switched their second ICI regimen. Initial ICI was anti-PD-1 in 37 studies, anti-CTLA-4 in 14 studies, and anti-PD-L1 in 10 studies. Involved solid cancers included melanoma (n = 30), NSCLC (n = 15), RCC (n = 6), and others (n = 5). Pooled objective response rate for rechallenge was 18.4% ([15.4-21.4], I2 = 84.6%), with the highest being among melanoma patients (21.2% [17.2-25.2], I2= 83.4%). For BOR, no significant difference was found for the entire cohort (OR = 1.34 [0.86 - 2.09], I2 = 27.1%). In melanoma studies, response to ICI rechallenge was significantly higher in patients responding to the initial ICI prior to progression (OR = 1.87 [1.03-3.39], I2 = 24.5%). For treatment duration, there was no difference in the entire cohort concerning ICI rechallenge (OR = 1.54 [0.86-2.75], I2 = 14.2%), yet melanoma patients showed a significant difference favoring those who had longer response durations on initial ICI (OR = 2.05 [1.01-4.16], I2 = 0.0%). Conclusions: Response to rechallenge in advanced melanoma patients was more common in initial ICI responders with a longer course duration ( > 6 months). More homogeneous studies are needed to validate our findings and investigate other potential markers for rechallenge such as PD-L1 status & mutational burden. [Table: see text]
Association of proton pump inhibitor use with survival outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Chen BaoQing , Yang Chen , Dragomir Mihnea-Paul , Chi Dongmei , Chen Wenyan , Calin George , Li Qiaoqiao 
Published: June 2022

2613 Background: Proton pump inhibitors (PPIs) were revealed to regulate gut microbiome alterations and further impact the response to immune checkpoint inhibitors (ICIs). Contradictory impacts on survival were observed in ICI-treated patients when concomitantly use PPI or not. We performed this systematic review and meta-analysis to analyze the association of PPI use with survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases and major oncology conferences proceedings were comprehensively searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI use and PPI non-use in ICI-treated cancer patients were included. Data regarding the characteristics, ICI and PPI treatments and survival outcomes for patients were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effect models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among study results. Results: A total of 20 studies were included, comprising 2812 ICI- and PPI-treated patients and 3990 ICI-treated and PPI-free patients. The pooled HR is 1.30 (95% CI, 1.17-1.45; P <.001) for OS and 1.20 (95% CI, 1.08-1.34; P <.001) for PFS, indicating a significant negative association between PPI use and survival of ICI-treated patients. Subgroup meta-analyses by factors including cancer types, ICI types and time window of PPI use, revealed such associations were in patients with non-small cell lung cancer (OS: HR = 1.40, 95% CI = 1.23 to 1.59, P <.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P <.001) or urothelial cancer (OS: HR = 1.50, 95% CI = 1.26 to 1.80, P <.001; PFS: HR = 1.37, 95% CI = 1.17 to 1.60, P <.001), patients treated with anti-PD-1/PD-L1 (OS: HR = 1.41, 95% CI = 1.30 to 1.53, P <.001; PFS: HR = 1.29, 95% CI = 1.20 to 1.38, P <.001), patients receiving PPI as baseline treatment (OS: HR = 1.43, 95% CI = 1.21 to 1.69, P <.001; PFS: HR = 1.29, 95% CI = 1.16 to 1.44, P <.001) or 60 days before ICI treatment initiation (OS: HR = 1.28, 95% CI = 1.11 to 1.48, P <.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P <.001), rather than concomitantly with ICI initiation. Conclusions: PPIs use in patients treated with ICIs is associated with a shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled, and appear to not impact survival if given temporarily after ICIs initiation. These detailed observations could provide basis for clinical guidelines when concomitantly use PPIs and ICIs.
Analysis of the contribution of macrophages to the overall tumor PD-L1 microenvironment using a screening multi-tumor tissue microarray and rapid multiplex fluorescence digital phenotyping approach.
Authors: Cumberbatch Marie , Wood Douglas , Chatterjee Gourab , Womack Christopher , Bhagat Milan , Sherry Lorcan 
Published: June 2022

2620 Background: Programmed death ligand-1 (PD-L1) contributes to immune suppression in the tumor microenvironment (TME) by interacting with programmed cell death-1 (PD-1) on infiltrating T lymphocytes leading to tumor immune escape. Application of omics technologies has shed light on the relevance of the TME for response to immunotherapies and development of novel treatment options. Here we have applied a multi-plex immunofluorescence/multi-tumor tissue microarray (TMA) approach to examine the immunobiology of different TMEs with respect to the contribution by tumor cells and macrophages to overall PD-L1 expression. Methods: A TMA comprising 11 tumor types and a total of 144 different donors, each represented by two cores [1mm; 1 from invasive margin (IM) and 1 from tumor center (TC)], was stained using Ultivue’s Immuno8 FixVUE panel (CD3, CD4, CD8, FOXP3, CD68, PD-1, PD-L1, pan-CK/SOX10). Whole slide images from two rounds of imaging (x20 magnification; four markers in each round) were aligned using Ultivue's UltiStacker software based on the nuclear counterstains from the two imaging rounds, to provide precise marker colocalization data. Cell phenotype data for each core was generated using Visiopharm software. Results: Overall PD-L1 positivity was greatest for NSCLC, SCLC, TNBC and gastric cancer ranging from approximately 600-1000 PD-L1+ cells/mm2/core, compared with CRC, breast, pancreatic, liver, and gastric esophageal junction (GOJ) cancers (approx. 50-300 PD-L1+ cells/mm2/core). Contribution by macrophages to overall PD-L1 expression (dual CD68+/PD-L1+) varied by tumor type representing 25-35% for NSCLC (SCC and ADC) and gastric cancer, whereas a converse pattern was apparent for SCLC, TNBC, breast (ER+ and Her2+) and pancreatic cancers where PD-L1+ macrophages accounted for a large proportion (approx. 60-85%) of overall tumor PD-L1 expression. Interestingly, as a proportion of total macrophage infiltration, approximately 65% of CD68+ macrophages were PD-L1+ for SCLC and TNBC, compared with less than 10% for pancreatic and liver cancer. Spatial analysis revealed PD-L1+ macrophage infiltration to be generally higher for IM versus TC, and the distribution between tumor (CK+) and stroma (CK-) remained similar despite exclusion of CD3+/CD8+ cytotoxic T cells from CK+ tumor regions for pancreatic and liver cancer. Conclusions: Taken together, these data illustrate the benefits of combining multiplexed immunofluorescence staining, with digital analysis of cell phenotypes within well characterized tumor samples to better understand the relative immunobiology of different TMEs. Here we demonstrate that the relative contribution of macrophages to the overall PD-L1 microenvironment varies between tumor types, which may help guide options for successful immunotherapy strategies.
Correlation between MSI, TMB, and RAS gene mutation in solid tumors.
Authors: Li Qingchang , Bian Zhengying , Ma Juan , Lu Guanghua , Chen Siqi , Ding Ran , Bu Fanfeng 
Published: June 2022

2624 Background: RAS gene family encodes a protein that is a member of the small GTPase super family and plays an important role in the regulation of cell proliferation and promoting oncogenic events. Studies have reported that RAS gene shows a high mutation frequency in lung cancer, colorectal cancer and pancreatic cancer. However, the relation between RAS-mutant and RAS-wild type tumors in tumor mutation burden (TMB) and microsatellite instability (MSI) remain unclear in pan-cancer. Methods: We retrospectively analyzed 15188 Chinese patients with pan-cancer from laboratory of Simcere Diagnosis (Nanjing, China) during 2019-2021. Somatic mutations in tumor samples were assessed by next-generation sequencing (NGS). We evaluated RAS (KRAS, NRAS and HRAS) mutation frequency, TMB and MSI in RAS-mutant and RAS wild-type tumors. Results: RAS mutations were detected in 2663 (17.5%) samples, including 88.7% of KRAS mutations, 9.1% of NRAS mutations and 3.5% of HRAS mutations. The top 6 frequently cancers were colorectal cancer (829, 31.1%), lung cancer (747, 28.1%), pancreatic cancer (358, 13.4%), biliary tract cancer (210, 7.9%), liver cancer (78, 2.9%), and gastric cancer (73, 2.7%). We found that the incidence of MSI-H in patients with RAS-mutant solid tumors was 3.3% and the frequency of MSI-H was significantly higher in RAS-mutant gastric cancer than that in RAS wild-type (RAS-MUT vs RAS-WT, 20.5% vs 3.5%, p < 0.001). Contrary to our assumption, it was not observed in colorectal cancer (RAS-MUT vs RAS-WT, 5.8% vs 6.9%). In the analysis of TMB, RAS gene mutation was associated with higher TMB (P < 0.01). 27.4% of RAS-mutant gastric cancer and 10.8% RAS wild-type gastric cancer were classified as TMB-H (TMB ≥10 muts/Mb) (P＜0.01), while 13.4% of RAS-mutant colorectal cancer was TMB-H, with no significant difference between RAS wild-type. However, we did not observe a close association between MSI, TMB and RAS gene mutations in lung cancer, pancreatic cancer, biliary tract cancer, and liver cancer. Conclusions: We analyzed RAS gene mutations in Chinese patients with solid tumor. Our data showed that RAS mutations were associated with TMB-H and MSI-H in solid tumors, especially gastric cancer. In colorectal cancer, RAS mutations were associated with higher TMB, but not TMB-H. It was showed that RAS mutations in specific cancer types, such as gastric cancer and colorectal cancer, may be related to the efficacy of immunotherapy.