bluuebunny/crossref_metadata_2025_split huggingface dataset:
PSGL-1 is a novel macrophage checkpoint in immuno-oncology.
Authors: Nowakowska Dominika , Phennicie Ryan , Kauffman Kevin , Zafari Mohammad , Rooney Kathryn , O’Nuallain Brian , Sazinsky Steve , Wahle Joe , Feldman Igor , Novobrantseva Tatiana 
Published: May 2020

e15090 Background: Macrophages are both antigen presenting and effector cells of the innate immune system and play an important role in tissue homeostasis as well as in activation and modulation of the adaptive immune response in disease. They display phenotypic heterogeneity in different tissue environments but can be broadly subdivided into pro-inflammatory M1 macrophages, which promote immune response, and anti-inflammatory M2 macrophages, which are associated with immune suppression. Under steady-state conditions, the populations of immune-stimulatory and immune-regulatory macrophages are balanced, but disruption of this balance can result in disease. In the tumor microenvironment, tumor-associated macrophages (TAMs) acquire an M2-like phenotype and maintain suppression of the immune system and promotion of tumor progression. Methods: For functional screening of anti-PSGL-1 antibodies, monocytes were isolated from peripheral blood mononuclear cells (PBMC) obtained from healthy donors and differentiated into M2 macrophages in the presence or absence of anti-PSGL-1 antibodies. On day 8 of the assay, phenotypic profile of cells was analyzed by flow cytometry and chemokines / cytokines were measured by Luminex. Mixed-lymphocyte reaction assay, SEB assay and an ex vivo tumor model were used to further assess antibody functionality in a multi-cellular assay format. For T cell assays, purified T cells from PBMC were stimulated in the presence or absence of anti-PSGL-1 antibodies and responses were characterized by flow cytometry and Luminex. Results: We have identified PSGL-1 as a novel macrophage checkpoint. Our work demonstrates that targeting PSGL-1 via an antagonistic antibody re-polarizes human primary M2 macrophages to a more M1-like state both phenotypically and functionally. We observe this M2-to-M1 switch to have an impact on immune cell communication in complex multi-cellular assays. Moreover, targeting of PSGL-1 in an ex vivo tumor system demonstrates that anti-PSGL-1 treatment can increase pro-inflammatory cytokine and chemokine production known to be associated with beneficial clinical response. These effects can be predominantly attributed to macrophage modulation, as antibody targeting PSGL-1 on purified T cells has a very small, if any, impact on their activation and effector function. Conclusions: Our results demonstrate that treatments inducing macrophage phenotypic switches can promote an immune response in a tumor setting across multiple tumor types and provide support for targeting the novel macrophage checkpoint PSGL-1 across multiple cancer indications.
Correlation of HLA-B*35 and DRB1*11 alleles with a high risk of interstitial aseptic pneumonitis in cancer patients receiving PD-1/PDL1 immune-checkpoint blockade.
Authors: Correale Pierpaolo , Saladino Rita Emilena , Bianco Giovanna , Stranges Alessia , Giannarelli Diana , Sergi Andrea , Mazzei Maria Antonietta , Giannicola Rocco , Iuliano Eleonora , Nardone Valerio , Altomonte Maria , Pastina Pierpaolo , Tini Paolo , Luce Amalia , Caracciolo Daniele , Calandruccio Natale Daniele , Caraglia Michele , Tassone Pierfrancesco , Pirtoli Luigi , Tagliaferri Pierosandro 
Published: May 2020

e15094 Background: Tumor infiltrating CTL-rescue by PD-1/PDL1 immune-checkpoint blockade is a recommended treatment for several malignancies including non-small-cell-lung-cancer (NSCLC), malignant melanoma, head and neck, kidney, and urothelial cancer. MAbs to either PD-1 (Nivolumab and Pembrolizumab) or PDL1 (Atezolizumab and Durvalumab) are considered as active drugs in these patients, however, their use may be complicated by unpredictable immune-related adverse events (irAEs) and in less extent by a dreaded interstitial aseptic pneumonitis (IAP). Methods: We carried out a retrospective multi-institutional analysis aimed to investigate possible clinical and biological parameters correlated with the occurrence of IAP in a cohort of 256 cancer patients (188 with mNSCLC and 78 with other malignancies) who received PD-1/PDL-1 blockade since November 2015. Association of IAP with clinical/biological factors was assessed by the chi-square test. Statistics were performed by the SPSS software 23.0. HLA molecular analysis was performed by reverse SSO DNA typing assays on patients’ PBMCs. Results: A centralised radiological review recorded a IAP in 29 patients (11.3%) whose 15 (5.8%) were free of symptoms. There was no correlation of IAP risk with tumor type, specific PD-1 or PDL1 blocking mAb, radiation therapy, inflammatory markers, and other irAEs. IAP was more frequent in males than females [RR = 2.03, (95% CI: 0.63-5.61) p > 0.05] and occurred more often in mNSCLC patients who had received metronomic chemotherapy +/- bevacizumab [RR = 3.05 (95% CI: 1.32-7.06),P = 0.005] or TKI [RR = 1.73 (95% CI: 0.75-4.00),P > 0.05] compared with other treatments prior PD-1/PDL1 blockade. Finally, IAP occurrence was strictly correlated to the expression of HLA-B*35 [RR = 1.73 (95% CI: 0.81-3.71) P < 0.05] and DRB1*11 [RR = 2.34 (95% CI: 1.02-5.39); P = 0.03], two alleles associated to common autoimmune diseases. Conclusions: Taken together, our findings may have relevant implications in predicting the risk of IAP in mNSCLC receiving PD-1/PDL1 blockade and provide the rationale for further immunological and clinical investigations.
Is chronic refractory colitis from immune checkpoint inhibitor associated with good cancer outcome?
Authors: Ma Weijie , Thomas Anusha , Wang Yinghong 
Published: May 2020

e15102 Background: Immune checkpoint inhibitors (ICIs) are efficacious in treating many advanced malignancies. However, drug induced colitis limits their use significantly. We present cases with chronic refractory ICI colitis requiring long term immunosuppressive therapy and favorable cancer outcomes. Methods: We identified 3 cases who developed ICI colitis and persisted for longer than 6 months requiring long term immunosuppressant therapy. The patients’ clinical data was collected. Results: All patients were male, with median age of 55. Two had melanoma, one urothelial cancer. All patients received PD-1(L)-1 agents with colitis onset about 3-6 months after ICI treatment. All patients were taken off ICI permanently due to colitis over a duration of 19-30 months (peak grade of 3). Endoscopy of all three were grossly unremarkable, with lymphocytic colitis on pathology in all three. Patient A’s colitis achieved clinical and histological remission after 5 doses of vedolizumab, however recurred after 9 months with biopsy proven recurrence. Current management is anti-diarrheal medication given mild symptom. Patient B had more aggressive disease, with first recurrence after 2 doses of infliximab and steroid, achieved initial histological remission after 3 doses of vedolizumab and 2 additional infliximab, then had 2nd recurrence after 3 months. Fecal microbiota transplantation as compassionate treatment was not effective. Thereafter, patient was resumed on vedolizumab ever since with clinical remission. Last histology evaluation showed persistent lymphocytic colitis 30 months after initial diagnosis. The third case had initial histological remission after 3 doses of vedolizumab, followed by recurrence after 4 months, which triggered another 3 doses of vedolizumab, with persistent grade 3 diarrhea despite resolution of histological inflammation after total 6 doses of vedolizumab. Patient was subsequently treated with steroid and ustekinumab with clinical remission. At the end of follow up, all three patients have sustained cancer remission over 19-31 months. Conclusions: IMC is a common adverse event from ICI, and could progress to a chronic inflammatory condition that require long term treatment. Histological remission does not preclude future recurrence of colitis. Persistent toxicity could be a surrogate marker for enduring ICI effect which may be associated with favorable cancer outcome. Long term immunosuppression can be essential for refractory ICI colitis cases for clinical remission.
PTPRD/PTPRT mutations as potential positive predictor for response of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC).
Authors: Zeng Jian , Wang Guoqiang , Yan Zhengqing , Zheng Hao , Li Jianqiang , Tao Feng 
Published: May 2020

e15112 Background: Immune checkpoint inhibitors (ICIs) have demonstrated positive results in non-small cell lung cancer (NSCLC) patients, with durable responses and prolonged overall survival (OS). Nevertheless, the response rate to immunotherapy is still limited. It is necessary to identify clinically useful biomarkers that can distinguish patients who can respond to ICIs. PTPRD/PTPRT are the phosphatases of JAK-STAT signaling, which may be associated with response to ICIs. Here we aimed to demonstrate the association between PTPRD/PTPRT and ICIs. Methods: Genomic and survival data of NSCLC patients administrated with anti–PD-1/PD-L1 or anti–CTLA-4 antibodies (Rizvi2015; Hellmann2018; Rizvi2018 Samstein2019) were retrieved from publicly accessible data. Genomic, survival and mRNA data of 1007 patients with NSCLC was obtained from The Cancer Genome Atlas (TCGA). Association between PTPRD/PTPRT mutation and progression-free survival (PFS) and overall survival (OS) were analyzed. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: PTPRD/PTPRT mutations were significantly associated with better PFS in Rizvi2015 cohort (HR = 0.16; 95% CI, 0.02-1.17; P = 0.03), Hellmann2018 cohort (HR, 0.49; 95% CI, 0.26-0.94; P = 0.03) and Rizvi2018 cohort (HR = 0.64; 95% CI, 0.44-0.92; P = 0.01). PTPRD/PTPRT mutation was also significantly associated with better OS in Samstein2019 cohort (HR, 0.66; 95% CI, 0.45-0.97; P = 0.03). In TCGA, no association between PTPRD/PTPRT mutations and OS was observed (P = 0.91), suggesting that PTPRD/PTPRT mutations were not prognostic factor. PTPRD/PTPRT mutations were associated with increased TMB (P < 0.0001). The mRNA expression of STAT1 and CD4 was higher in patients with PTPRD/PTPRT mutant type than PTPRD/PTPRT wild type. Gene Set Enrichment Analysis revealed prominent enrichment of signatures related to inflammatory response, interferon gamma response and antigen processing and presentation in patients with PTPRD/PTPRT mutation. Conclusions: Our results suggest that PTPRD/PTPRT mutation is associated with better PFS and OS in NSCLC patients receiving ICIs by increasing immune-related gene signatures. The role of PTPRD/PTPRT in immunotherapy is needed to be further studied.
Immune checkpoint inhibition-induced myocarditis in cancer patients: Proposal of a detection and management strategy.
Authors: Rao Anjali , Zaha Vlad , Bermas Bonnie , Lohrey John , Courtney Kevin Dale , Hammers Hans J. , Gerber David E. , Garg Sonia , Mammen Pradeep P 
Published: May 2020

e15116 Background: Monoclonal antibodies against the immune checkpoint inhibitors (ICI) programmed cell death protein-1 (PD-1), its ligand (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4) have had a transformative effect on the field of oncology. Autoimmune myocarditis (AIM) is a rare but potentially severe complication associated with these medications, without specific management guidelines. The aim of this observational report is to present four cases of AIM following ICI and propose a detection and treatment strategy. Methods: Four patients who received anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors (ICI) developed severe cardiac manifestations within two weeks to several months after initiation. Demographic, historical, laboratory, and imaging data were collected by retrospective chart review. Results: Manifestations included LV systolic dysfunction, ventricular arrhythmias, and elevated cardiac enzymes. Myocardial ischemia was ruled out by coronary catheterization. Abnormal myocardial tissue characteristics on CMRI and biopsy were used to establish the diagnosis of myocarditis. Patients had endocrine, rheumatologic and neurologic irAEs (Table) and were managed by a multi-disciplinary team including oncology, rheumatology and cardiology. Management included prompt administration of high-dose steroids with rapid taper. Steroid sparing and escalation therapies included mycophenolate mofetil, methotrexate, rituximab, abatacept (CTLA4 agonist), as well as plasma exchange. This combination of tiered therapies resulted in substantial improvement in AIM. Conclusions: Clinical improvements seen in these cases highlight potential key elements for controlling autoimmune myocarditis response to ICI. We propose rapid diagnosis including CMRI and biopsy and initiation of high dose prednisone. We also recommend prompt initiation of steroid sparing agent within one month of diagnosis. Importantly, these patients should be managed by a multi-disciplinary team. [Table: see text]
Radiotherapy with sequential αnti-PD-1 mAb compared with concurrent αnti-PD-1 mAb for enhancing the abscopal effect by promoting the inflammatory tumor microenvironment.
Authors: Zhu Xiaoxia , Li Shangbiao 
Published: May 2020

e15122 Background: Radiotherapy (RT) is one of the main approaches for treatment of lung cancer. A large number of preclinical and several clinical studies revealed that RT can activate the host’s anti-tumor immune system and induce abscopal effect. However, the optimal timing and its underlying mechanism of the combination of RT and immune checkpoint inhibitor (CHI) are unclear. Methods: MC38 cells were used for subcutaneous tumor formation in the left lower limbs (irradiation field) and the right lower limbs (non-irradiation field) of six-eight weeks old male C57BL/6 mice. When the tumor volume reached 150mm3, the mice were randomly assigned to receive RT (8Gy × 3F) with concurrent anti-PD-1 monoclonal antibody (mAb) or RT with sequential (1 week after the first irradiation) anti-PD-1 mAb (group B). The changes of immune microenvironment in irradiated and non-irradiated tumors in the two groups were analyzed by flow cytometry. Results: Both RT with concurrent anti-PD-1 mAb and RT with sequential anti-PD-1 mAb could inhibit the growth of tumors in non-irradiation field. The number of CD4+T cells (CD45+CD44+CD4+T) and effector CD4+T cells (CD44+CD4+IFNγ + T) in non-irradiated tumors in the sequential group was significantly higher than that in the concurrent group, but which showed no significant difference between the two groups in irradiated tumors. Interestingly, CD8+T cells (CD45+CD44+CD8+T) and effector CD8+T cells (CD44+CD8+IFNγ + T) increased both in the irradiation and non-irradiation field in the sequential group compared with that in the concurrent group, while tumor associated macrophages (TAM, F4/80+CD11b+) and Treg cells (CD4+FoxP3+) in the sequential group decreased significantly. RT with sequential anti-PD-1 mAb reduced more exhausted CD8+T cells (PD-1+Eomes+of CD8+T) and induced more reinvigoration of exhausted T cell (Ki-67+PD-1+Emoes+CD8+T). The decrease of MDSCs (Gr1+CD11b+) in the non-irradiated tumors was observed in both groups, but there was no difference in the extent of this decrease between two groups. Conclusions: Compared with the concurrent combination, RT with sequential anti-PD-1 mAb is more effective in promoting the inflammatory tumor microenvironment in out-field tumors and inducing the abscopal effect, which provides a new perspective for further exploring the mechanism of optimal timing of combination. Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033.
Incidence and outcomes of immune checkpoint inhibitor-related myositis.
Authors: Aldrich Jeffrey , Pundole Xerxes , Tummala Sudhakar , Andersen Clark , Shoukier Mahran , Abdel-Wahab Noha , Palaskas Nicolas , Deswal Anita , Suarez-Almazor Maria E. 
Published: May 2020

e15128 Background: Data from immune checkpoint inhibitor (ICI) clinical trials show a higher incidence of ICI-related myositis with single agent ICI compared to combination therapy, but the true frequency in clinical practice is unknown. We sought to determine the incidence and clinical course of patients with ICI-related myositis at our institution. Methods: We performed a retrospective cohort study of patients treated with ICIs at MD Anderson Cancer Center between 2016 and 2019. Suspected cases of ICI-related myositis were identified using International Classification of Disease version 10 codes and confirmed by reviewing medical records, muscle enzymes and pathology. Patients treated with single agent anti-programmed death-1/ligand-1 (monotherapy) were compared to patients treated with nivolumab and ipilimumab (combination therapy) with Fischer’s exact tests, t tests, and Kaplan Meier analysis. Results: A total of 8,705 patients received ICI (7,428 monotherapy and 1,277 combination therapy), of which 31 (0.36%) were diagnosed with myositis. Estimated incidence of myositis was 0.28% and 0.78% (p=0.004), in the monotherapy and combination therapy groups, respectively. One patient was treated with ipilimumab alone (excluded from pooled data). Overall median age was 69 years (range: 40-95) with median follow up of 4 months after presentation for myositis. Thirteen (43%) patients had myositis alone and 17 (57%) had overlap with myasthenia gravis or myocarditis or both. After myositis resolution, 5 (17%) patients were rechallenged on ICI, of which 1 (20%) patient experienced a myositis flare. Differences between combination and monotherapy are summarized in the table. Patients treated with combination had shorter time to symptoms, but similar symptom grade at presentation, median length of hospitalization, and initial tumor response, compared to patients given monotherapy. Median overall survival (OS) was longer in combination vs monotherapy. Conclusions: Patients receiving combination ICI therapy had higher incidence of myositis with earlier onset than monotherapy; however, no differences in cancer outcomes or hospitalizations were observed between groups. Creation of multi-center databases are needed to develop treatment guidelines for ICI-related adverse events that will improve outcomes. [Table: see text]
Cumulative steroid doses and response rates to immune checkpoint inhibitors in metastatic cancer.
Authors: Tawagi Karine , Maslov Diana , Simenson Victoria , Yuan Helen , Parent Cameron , Bamnolker Adi , Goel Richa , Blake Zoe , KC Madhav , Matrana Marc Ryan , Johnson Daniel H. 
Published: May 2020

e15133 Background: Steroids are the mainstay of immune-related adverse effect (irAE) management, as well as for other indications in cancer treatment. Previous studies evaluating whether steroids have an effect on immune checkpoint inhibitor (CPI) efficacy compared patients receiving steroids vs. no steroids. This comparison may be confounded by different rates of irAEs and a known association of irAEs with higher response rates to CPIs. There is a paucity of CPI efficacy data in relation to the total dose of concomitant steroids. Methods: We retrospectively collected data from patients treated with CPIs alone, who received steroids during their CPI treatment at a single institution. IrAEs were defined using the CTCAEv5 criteria. Response rate (RR) and progression were defined per RECIST v1.1. Kaplan Meier and Cox proportional hazard regression methods were used to estimate the survival probability and hazard ratios (HR). Results: We identified 260 patients with stage IV cancer who received steroids concurrently with CPI treatment. A total of 111 patients (42.7%) received ≥1000mg prednisone equivalence during the course of their CPI treatment, and the remaining 149 patients (57.3%) received < 1000mg PED. There was no difference in progression free survival (PFS) between the two cohorts [HR of 0.923 for < 1000 mg PED group; p = 0.6016] or in overall survival (OS) [0.854 for < 1000 mg PED group, p = 0.3308]. Median PFS for the < 1000mg group was 5.9 months (mo), vs 6.3 mo in the ≥1000mg group. Median OS for the < 1000mg group was 15.76 mo, vs 11.53 mo in the ≥1000mg group. The RR was numerically higher in the prednisone < 1000mg cohort at 29.53% vs 20.72% in the ≥1000mg cohort, however not statistically significant (p = 0.1082). Basic characteristics including sex, race, tumor type, and smoking status, were similar between the two groups. There was a statistically significant difference in BMI distribution and steroid indication (irAE indication higher in >1000 mg PED cohort than non-irAE) between the two groups. Conclusions: PFS, OS, and RR were not different between patients who received >1000mg vs. < 1000mg PED during CPI therapy. These data suggest that even high doses and protracted courses of corticosteroids may not hinder CPI efficacy. However, differences in our primary endpoint PFS may be confounded by difference in BMI and rates of irAEs between each cohort, which are both known to be associated with improved CPI efficacy. Further analyses to account for these differences along with how timing of steroid initiation affects CPI-efficacy will be completed by time of presentation.
Impact of STK11 and KRAS co-mutations on outcomes with immunotherapy in non-small cell lung cancer.
Authors: Basher Fahmin , Saravia Diana , Fanfan Dino , Cotta Jared Addison , Lopes Gilberto 
Published: May 2020

e15135 Background: While the use of monoclonal antibodies targeting the PD-1 axis in metastatic non-small cell lung cancer (NSCLC) continues to expand since initial FDA approval in 2015, factors predictive of response still remain to be determined. Mutation status may provide insight as to which subgroups exhibit resistance to checkpoint inhibitor therapy. Methods: We conducted a single center retrospective analysis of patients with metastatic NSCLC treated at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) and identified patients that harbor either STK11 mutation alone (S) or co-mutations with STK11 and KRAS (S/K). Genomic results were obtained from Guardant360 and Foundation One testing in blood and tissue, respectively. Results: We identified 37 S patients and 36 S/K patients and determined no significant differences in progression-free survival (PFS). However, overall survival (OS) was significantly increased in patients with S/K co-mutation (20.3 ± 4.1 months) vs. patients with S alone (11.9 ± 1.9 months, p = 0.028). Furthermore, S/K patients who received immunotherapy had longer OS (20.7 ± 5.6 months) vs. S patients (13.6 ± 3.4 months, p = 0.049). We further investigated any population-specific factors that may contribute to the enhanced survival in the S/K cohort that had received immunotherapy, as previous studies have reported that STK11/KRAS co-mutations may confer a resistance to PD-1 axis-directed therapy. We found that S/K patients were older at diagnosis and were more likely to have received nivolumab (as compared to newer therapies pembrolizumab and atezolizumab). In addition, S/K patients were more likely to have longer smoking histories (81% smoked more than 30 pack-years at diagnosis) vs. S patients (53%, p = 0.01) and also had a higher number of additional targetable mutations found on NGS (4.7 ± 0.4 vs. 2.9 ± 0.3, p = 0.001). The most commonly identified mutations were TP53 (30%), KEAP1 (19%), CDKN2A/B (18%), SMARCA4/BRG1 (16%), and ARID1A (11%). Conclusions: Our study reveals an interesting analysis of potential predictors of resistance to immunotherapy with the utilization of precision medicine in combination with patient characteristics to identify the most appropriate treatment regimens for patients with NSCLC. Further studies will explore whether patients receiving immunotherapy as first line could overcome any inherent resistance to PD-1 axis-directed therapy from non-modifiable factors at diagnosis.