bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring early clearance of circulating tumor DNA as an effective tool to predict clinical benefits of immune checkpoint inhibitors in lung cancer patients: The preliminary results from clinical trial NCT04203095.
Authors: Zheng Di , Ni Jian , Zhong Yi , Ziliang Qian , Wang Baiyun
Published: May 2020

e15056

Background: Immuno-checkpoint inhibitors (ICI)is the stand-of-care of lung cancer treatment nowadays. But it’s still challenging to find an effective biomarker to predict clinical benefits from ICIs. Early data suggested that monitoring early clearance of circulating tumor DNA (ctDNA) as a tool to predict clinical benefits. Here we started a clinical trial (NCT04203095) to further validate it. Methods: 19 advanced non-small cell lung cancer patients who were planned to be treated with ICIs with or without chemotherapy were recruited consecutively since April 2019 ( NCT04203095 ). Clinical response was evaluated by RECIST 1.1 assessments at 12 weeks of treatments and afterward during 3-month interval visiting in the first year. Fresh plasma samples were collected -1 (before),+3 weeks and +12 weeks after the first dose. Plasma cell-free DNA(cfDNA) was send to low-coverage whole genome sequencing, followed by chromosomal instability (CIN) analyses by a customized workflow (UCAD). CIN scores were calculated by summarizing the copy number variations genome wide. Results: Early clearance of ctDNA was defined as Pearson correlations co-efficiency of copy number variations of cf DNA was below 0.65 between the baseline and 3 weeks after ICIs were administered. These 19 patients included 11 squamous cell carcinoma (SCC) and 8 adenocarcinomas. 8 of 11 respoonding patients showed early clearance of ctDNA, and 7 of 8 patients with SD or PD didn’t obtain early clearance of ctDNA. Meanwhile, clinical stage, histology, treatments (PD1 single or PD1+chemo combinations), sequence of treatment (first line, second line or multiple lines) did not predict clinical response, and baseline CIN score was not significantly correlated with clinical responses. In summary, only ctDNA early clearance was statistically significantly associated with clinical response (P = 0.020). Conclusions: Early clearance of plasma circulating tumor DNA at 3 weeks after treatments might be used a predictive biomarker of immune-checkpoint inhibition response. Clinical trial information: NCT04203095 .
Analysis of the management of immunotherapy-derived toxicity in the Stockholm region.
Authors: Villabona Lisa Elena Esther , Huopaniemi Oona
Published: May 2020

e15069

Background: The debut of immune-checkpoint inhibitors (ICPis) has changed the prognosis of many cancer patients. The immune-related adverse events (irAEs) caused by these monoclonal antibodies are common and can affect nearly any organ system. International guidelines on management of irAEs have been published in recent years. The aim was to investigate the identification and management of irAEs in the Stockholm region, as well as how the patients respond to the management they received. Methods: All adult patients who had received ICPis at the Karolinska University Hospital in 2018 were included. Patients who had enrolled in another study on ICPis were excluded. 62 eligible patients enrolled. Data was collected from the patients’ medical records. In addition to the irAEs documented by clinicians, irAEs were also identified retrospectively. Variables recorded were grade of irAE, management, date of first documentation and date of re-challenge, among others. Management was compared to the guidelines. Descriptive statistics as well as linear correlation analysis and Kaplan-Meier analysis were then performed. Results: 62 patients proved eligible. 121 irAEs were recorded. Nurses at Advanced Home Health Care (AHHC) were first to document grade 3-4 irAEs in 58% of the cases. Kaplan-Meier analysis (p-value 0.043) showed that patients whose irAEs were managed according to the guidelines reached re-challenge sooner. A negative correlation (p-value 0.003) was observed between management according to guidelines and identification by a clinician. Conclusions: Increased knowledge at AHHC and at oncological clinic is necessary to improve the identification and management of irAEs.
A multidisciplinary immune-related toxicity (IR-Tox) program for immune-related adverse events: A two-year experience.
Authors: Balaji Aanika , Zhang Jiajia , Suresh Karthik , Mammen Jenna , Melia Joanna , Kim Amy K. , Berkenstock Meghan , Sander Inbal , Monroy-Trujillo Jose Manuel , Ostrow Lyle Wilfred , Riemer Joanne , Lipson Evan J. , Forde Patrick M. , Sharfman William Howard , Brahmer Julie R. , Cappelli Laura , Naidoo Jarushka
Published: May 2020

e15074

Background: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) that may require multidisciplinary input. We developed an IR-Tox program consisting of an electronic irAE referral platform +/- in-person consultation, and a monthly irAE tumor board, run by an IR-Tox team comprising 38 organ-specialists and oncologists. Herein, we present our 2-year experience. Methods: Electronic referrals for patients (pts) treated with ICIs at an academic center were sent to the IR-Tox team between 08/2017-12/2019. Demographic, treatment, and irAE data, including in-person consultations and hospitalizations, were collected in an IRB-approved database. Results: The IR-Tox Team received 270 referrals from 227 discrete pts (outpt: 64% inpt: 36%). Median age was 63 years (range: 3-91), 52% were male, 23% had a prior autoimmune condition, and 28% had a prior irAE. Pts had thoracic (30%), gastrointestinal (18%) or melanoma/skin cancers (17%). The majority of pts received ICI monotherapy (56%) vs. combination (44%). Referrals were for suspected irAE (92%, 209/227) or pre-ICI assessment for known autoimmune disease (8%, 18/227). Referrals for confirmed irAEs (147/209) were mainly for high-grade toxicity (G1 = 8%, 2 = 37%, 3 = 54%), 49% were hospitalized (72/147), and 86% (127/147) improved/resolved. In those who did not have a confirmed irAE (n = 62), an alternative medical condition was the most frequent diagnosis (27%, 17/62). The most common irAEs were pneumonitis (51%), dermatitis (11%), arthritis (7%), hepatitis (6%), and colitis (5%). In the entire cohort, organ-specialists were consulted electronically in 92% of pts (209/227), and 73% were subsequently seen in-person (166/227), with the majority (90/166; 54%) undergoing an invasive diagnostic procedure to confirm the irAE. Of outpatients referred, 64% (94/146) required subsequent in-person consults from organ-specialists and only 12% (18/146) were hospitalized. After all irAE-hospitalizations, continued irAE management was delivered in conjunction with organ-specialists in 51% of cases (32/72). Conclusions: A multidisciplinary IR-Tox program is a utilized service that has assisted in irAE identification and management over 2+ years. Use of an electronic referral platform may impact subsequent need for in-person specialist consultations and/or hospitalizations for irAEs. Ongoing management of complex irAEs is now commonly delivered in a multidisciplinary fashion.
Personalized treatment of immune checkpoint inhibitor-related severe hemophagocytic lymphohistiocytosis (HLH).
Authors: Obeid Michel , Özdemir Berna C. , Latifyan Sofiya , Michielin Olivier
Published: May 2020

e15079

Background: HLH is a rare but potentially lethal immune related adverse event (irAE) with an incidence of 0.03-0.4 % in cancer patients undergoing immune checkpoint inhibition (ICI). Given the rarity of HLH there are currently no diagnostic or therapeutic guidelines and the majority of the reported cases have been treated with corticosteroids alone with very variable response rates. There is currently no established therapy for corticosteroid resistant HLH occurring in the context of immunotherapies. We investigated the treatment possibility of severe HLH according to the cytokine profile. Methods: We report the clinical presentation, the cytokine profile and the outcome of three melanoma patients with ICI-related HLH not responding to high dose corticosteroid therapy alone who were treated with additional anti-IL-6R at the Centre Hospitalier Universitaire Vaudoise. We collected the following data: treatment setting, ICIs received, duration of each treatment, HLH criteria, bone marrow biopsy, cytokine profile, response to corticosteroid and to anti-IL-6R therapy. Results: We identified a severe HLH in three metastatic melanoma patients treated with ipilimumab and nivolumab for 2 of them and 1 with pembrolizumab. HLH occurred in a median of 10 weeks after initiation of immunotherapy. The patients met at least five of the HLH-2004 criteria including high ferritin levels ( > 100.000 ng/ml). High levels of interferon-gamma (IFNγ), IFNγ-induced chemokines, particularly CXCL9, CXCL10, CXCL13, IL-18 and IL-6 were found in all patients. For 2 of them we identified a highly infiltrated bone marrow by activated CD8+ T and NK cells. Median duration of corticosteroids therapy was 6.5 weeks. The evolution of the three patients was rapidly favorable in a median of 2.5 weeks after the addition of an anti-IL-6R therapy targeting the IFNγ/Th1 axis. Conclusions: HLH is a potentially life-threatening irAE necessitating emergency therapy. CXCL9 and Th1 cytokines are markedly elevated in patients with ICI-related HLH due to the activation of the IFNγ pathway. High CXCL9 and Th1 cytokines levels appear to be potential specific biomarkers for ICI-related HLH diagnosis. Blocking this axis by anti-IL-6 therapy seems a very promising strategy for severe ICI-related HLH allowing rapid resolution of symptoms and normalization of the abnormal laboratory results.
Molecular alterations with hyperprogression in lung cancer patients treated with immune checkpoint inhibitors in a large health system.
Authors: Tadesse Eyob ale , Heslin Kayla , Hendawi Mohamed , Hirsch Jonathan , Idyro Christopher , Thompson Michael A.
Published: May 2020

e15082

Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of lung cancer treatment. However, not all NSCLC patients (pts) benefit, a subset paradoxically experience accelerated tumor growth while on immunotherapy. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various molecular alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR aberrations, and STK11/LKB1 mutations. Kato et al. ( http://ow.ly/2n8a30nQpZv ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. Methods: Lung cancer pts treated with ICI from Jan 2017 to Jan 2019 at Aurora Health Care were reviewed after IRB approved. Pts with NSCLC histology (ICD diagnosis codes and / or manual chart review), ICI treatment, and molecular testing were identified via the real world data (RWD) integrated in the Syapse platform. Additional chart review to ascertain HP was performed, and molecular results obtained via Syapse molecular lab integrations were analyzed. Pts had various forms of real world biomarker testing including oligo NGS panels. HP is defined as: 1) time-to-treatment failure (TTF) < 2 months (time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥2 during the first 2 months of treatment. HP > = 3, Progression 1-2, non-progressor 0 criteria fulfilled.Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 1536 lung cancer patients 350 (22.8%) were treated with ICI including: atezolizumab (35), durvalumab (6), nivolumab (177), pembrolizumab (145). Some pts were treated with more than one ICI. 64/350 (18.2%) pts had HP. 79/350 (22.5%) pts had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. Conclusions: Only the STK11/LKB1 mutation was associated with HP (P = < 0.0001) with 5 of 6 STK11 pts treated with ICI showing HP. Other potential HP biomarkers will be assessed prospectively as larger panels are utilized. [Table: see text]
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.
Camrelizumab in advanced or metastatic solid tumor patients with microsatellite instability–high/mismatch repair-deficient: Results from an open-label exploratory study.
Authors: Chen Jingde , Quan Ming , Chen Zhiqin , Zeng Tianmei , Li Yandong , Zhou Ying , Hai Yanan , Gao Yong
Published: May 2020

e15140

Background: PD-1 checkpoint inhibitor has been shown a significant effect in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumor. Herein, we assessed the efficacy and safety of camrelizumab, a PD-1 checkpoint inhibitor, in advanced or metastatic solid tumor pts with MSI-H/dMMR. Methods: Pts with MSI-H/dMMR solid tumor who had received at least one line of prior systemic chemotherapy were recruited in this single-arm exploratory study. Pts received camrelizumab (200mg, ivd, D1/2W) until disease progression or intolerable toxicity. Response was assessed every 8 weeks. The primary endpoint was objective response rate (ORR) according to RECIST v1.1 criteria. This study was registered at Chinese Clinical Trial Registry, ChiCTR-OIC-17013249. Results: From November 2017 to February 27, 2019, 12 eligible pts were recruited, which covered 9 cancer types. The median age was 58 (range 27-72) years; male/female was 58.3/41.7%. 11 pts were confirmed as MSI-H status, and 1 patient as d-MMR status. All pts were included in efficacy and safety analysis. 2 pts achieved complete response (CR), 6 pts partial response (PR), 4 pts stable disease (SD), yielding the ORR of 66.7% (95% CI: 34.9-90.1), and the disease control rate of 100% (95% CI 73.5-100) at best. What’s more, cancer types of CR pts covered rectal cancer and bladder cancer (1 patient each); PR pts included colon cancer, liver cancer, endometrial cancer, ureteric cancer, intrahepatic cholangiocarcinoma, and small intestine cancer (1 patient each); SD pts contained 3 colon cancer pts and 1 retroperitoneal leiomyosarcoma patient. The overall incidence of adverse incidences (AEs) was 100%. The incidence of Grade ≥3 AEs was 58.3%, which mainly included anemia (16.7%), increased γ-transglutaminase (16.7%), increased alkaline phosphatase (16.7%), increased blood bilirubin (16.7%). As of Oct 30, 2019, 11 pts were still on study medication. Conclusions: Camrelizumab resulted in encouraging objective response and tolerable toxicity in MSI-H/dMMR advanced or metastatic solid tumor. The survival benefits will be further observed. Clinical trial information: ChiCTR-OIC-17013249 .
Hyperprogression on immune checkpoint inhibitors: A single institution, real-world retrospective analysis.
Authors: Paydary Koosha , Moturi Krishna Rekha , Baral Binav , Farooq Muhammad Zain , Lad Thomas E. , Mangla Ankit
Published: May 2020

e15143

Background: Hyper progressive disease (HPD) refers to the paradoxical acceleration of tumor growth following immune-checkpoint inhibitor (ICI) therapy. We aimed to evaluate the factors associated with HPD and its impact on overall survival (OS) in patients treated with ICI in our institution. Methods: We retrospectively reviewed the charts of 104 patients with solid tumors diagnosed from 04/01/2011 to 06/30/2018 who received ICI at John H. Stroger Jr. Hospital of Cook County, Chicago, IL. The OS, incidence of HPD and their demographic, clinical and laboratory correlates were recorded. HPD was defined as tumor growth ratio > = 2 on CT imaging after treatment with at least 2 cycles. The Log-rank method survival analysis was done to compare survival of patients with and without HPD. Results: Majority of patients were treated with either nivolumab (71.1%) or pembrolizumab (21.2%) in the second (50%) or third line (29.8%) setting. After excluding two patients without follow up scans, 14 out of 102 patients (13.7%) had HPD during the course of study. The patients with small cell lung cancer had higher incidence of HPD (4 out of 9). Patients who had evidence of HPD had significantly shorter OS (22.21±16.23 months versus 37.52±230.8 months, P value = 0.01). The variables associated with HPD were liver metastasis (Pearson Chi squared = 18.68, P value < 0.001) and persistently high LDH ( > 240 IU/L) during therapy (Pearson Chi squared = 16.85, P value < 0.001). Other variables that were significantly associated with HPD on univariate analysis, but not on multivariate analysis are as below. Conclusions: Although the etiopathogenesis of HPD is incompletely understood, the correlation of LDH to HPD is intriguing and warrants further studies as possible predictive marker of HPD. [Table: see text]
Hypocalcemia with immune checkpoint inhibitors: The disparity among various reports.
Authors: nalluru swarna sri , Piranavan Paramarajan , Ning Ying , Ackula Haritha , Siddiqui Ahmad Daniyal , Trivedi Nitin
Published: May 2020

e15153

Background: Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPI). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently published by Piranavan et al. KEYNOTE-189 and CHECKMATE-067 trials reported a 21-29% hypocalcemia event rate. The purpose of our study is to identify the hypocalcemia incidence in patients receiving ICPI at a single institution with multiple sites. Also, we aimed to investigate hypoparathyroidism as the etiology in these patients, if hypocalcemia was detected. Methods: A chart review to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Results: Group 1 (N = 83) includes patients with no calcium altering conditions or medications. Group 2 (N = 98) includes patients on calcium supplements (N = 17), vitamin D (N = 44), bisphosphonates (N = 24), > stage IIIB CKD (N = 5), and bone metastasis (N = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (N = 1). No further workup was done to investigate the etiology as that patient passed away. Conclusions: Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.
Awareness of immune-related adverse events among medical residents in a community hospital.
Authors: Kulkarni Ajinkya , Kulkarni Mrunal , Edlukudige Keshava Vinay , Ellangovan Rithikaa , Thirumaran Rajesh
Published: May 2020

e15154

Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.
Predictors of immune-related adverse events associated with checkpoint inhibitors.
Authors: Alsayed Alhareth , Manne Ashish , Escobar Daisy E , Sharma Gaurav , Prodduturvar Pranitha , Alkharabsheh Omar
Published: May 2020

e15159

Background: Immune-related adverse events (irAE) remain a significant challenge with the expansion of checkpoint inhibitors (ICI) indications. Unlike previous studies published, we investigated risk factors for irAE development, including lymphocytes and neutrophils counts in lung cancer and melanoma treated with all available ICIs in current clinical practice. Methods: This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute. Between 2015-2019. A total of 160 patients with a diagnosis of melanoma (N = 54) or lung cancer (N = 106) who received at least two doses of ICI including ipilimumab (15%), nivolumab (32%), pembrolizumab (35%), dual nivolumab/ipilimumab (5%), durvalumab (9%) and atezolizumab (4%). The patient's baseline characteristics were extracted with irAE (grade 3/4) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, and Wilcoxon rank sum test for continuous variables using JMP software. Results: The median age at diagnosis was 64 years (range 17-93), with 51% females. Race distribution with 76% Caucasians and 26% African Americans. Around 30% of the cohort was treated for recurrence, and 39% did receive prior systemic chemotherapy. Median overall survival (OS) was 13.5 months (m) for melanoma and 16 m for lung cancer with CI 95% [16-24] and [15-23], respectively. Twenty-nine (29%) percent of the cohort (N = 46) had grade 3/4 irAEs. Median of baseline hematological parameters including total white blood count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC ratio, and platelet to ALC ratio of these patients were not statistically different from the cohort without grade 3/4 irAEs. Interestingly, if a patient has baseline ALC < 1K/μL, the risk of irAE recurrence is low when ICI is re-initiated, p = .0143 (after symptomatic recovery from irAEs). Conclusions: Irrespective of ICI used, baseline lymphocyte count, and its relation to other blood counts have no clear impact on irAE. Larger cohorts or prospective studies are needed to make stronger conclusions about the relationship between the immune system and the occurrence of irAEs