bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.
Authors: Berg Stephanie A. , Wesolowski Michael , Burke Brianna , Wagner Courtney Regan , Clark Joseph I , Guevara Jose
Published: May 2019

e14037

Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.
Correlation between peripheral CD8+PD-1+ T cells diversity, tumor mutation burden (TMB) and T cell clones with anti-PD-1 antibody treatment of lung cancer patients: TCR repertoire as a novel predictive biomarker.
Authors: Matsumoto Seiji , Matsutani Takaji , Fujita Yoshiko , Kitaura Kazutaka , Nakamura Yukio , Nakamichi Toru , Nakamura Akifumi , Kuroda Ayumi , Hashimoto Masaki , Kondo Nobuyuki , Shini Tadasu , Suzuki Ryuji , Hasegawa Seiki
Published: May 2019

e14041

Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers. There is a demand for less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells, tumor mutation burden and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P < 0.05, P < 0.05, P < 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P < 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. TCR repertoire was proportional to TMB. Clones found in multiple patients were more frequent in indel than in SNP. Conclusions: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy.
Integrating liquid biopsy with advanced imaging analysis to improve the prediction of response to immunotherapy in patients with NSCLC.
Authors: Del Re Marzia , Fontanelli Lorenzo , Romano Alessandra , Pasquini Giulia , Gri Nicole , Rofi Eleonora , Vivaldi Caterina , Crucitta Stefania , Belluomini Lorenzo , Frassoldati Antonio , Petrini Iacopo , Falcone Alfredo , Porta Camillo , Vasile Enrico , Neri Emanuele , Danesi Romano
Published: May 2019

e14054

Background: Immunotherapy has revolutionized the treatment of NSCLC. However, response rate is variable, with a substantial failure rate. Thus, the identification of predictive biomarkers of response to immunotherapy is an area of great interest. Methods: Patients with locally advanced or metastatic NSCLC treated with nivolumab or pembrolizumab were enrolled. Disease response was defined following RECIST criteria (v. 1.1). Four ml of plasma were collected for the analysis of exosomal mRNA levels of PD-L1 (e-PD-L1) and IFN-γ (e-IFN-γ) at baseline and at the time of first radiological assessment. Exosome isolation and mRNA extraction was obtained by the exoRNeasy kit (Qiagen, Valencia, CA). e-PD-L1 and e-IFN-γ were evaluated by the QX100 ddPCR (Bio-Rad, Hercules, CA) and expressed as allele frequency (%). Chest computed tomography (CT) scan at baseline was used for the radiomic analysis. Tumor segmentation was performed on DICOM-formed images taken from the picture archiving, and the regions of interest were delineated manually and analyzed using the QUIBIM SL software. Survival was calculated stratifying patients based on e-PD-L1 and e-IFN-γ median values. Results: Nivolumab was given to 17 patients as 2nd line and to 8 subjects as further line of treatment, while 13 patients received 1st line pembrolizumab. Median PFS was 11 vs 16.2 months (mos) in patients with baseline e-PD-L1 of < 0.3% vs ≥0.3%, respectively (p = 0.16). e-PD-L1 significantly increased in disease progression (PD) vs partial response (PR) and disease stabilization (SD) (p = 0.01) after 2 mos of treatment. In patients with e-IFN-γ ≥4.1% vs < 4.1% at baseline, median PFS was 5.6 mos vs not reached, respectively (p = 0.003). The multiparametric radiomic analysis identified the Cluster Prominence Value (CPV, p = 0.012) and the Cluster Shade Value (CSV, p = 0.034) as significantly correlated with treatment outcome. Moreover, the D2d parameter and e-IFN-γ were inversely correlated (p < 0,0001). CPV and D2d reflect the intra-tumor architecture, including necrosis, cell proliferation, and angiogenesis. Conclusions: Liquid biopsy data correlate with radiomic parameters and predict response to immunotherapy.
Immunotherapy with checkpoint inhibitors in mismatch repair deficient (dMMR) cancers: Looking for a needle in a haystack— But, joy on finding one.
Authors: Rauthan Amit , Patil Poonam , Sood Tanvi , Kulkarni Shriniwas Subhash , Yashas Nitin , Nigade Gaurav , Somashekhar S.P. , Zaveri Shabber
Published: May 2019

e14073

Background: Pembrolizumab is approved for deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) metastatic solid tumors with objective response rate (ORR) of 39.6% and response lasting for more than 6 months in 78% patients. Nivolumab is also approved in dMMR metastatic colorectal cancers (mCRC) with ORR of 28% and response lasting greater than 6 months in 67% patients. But finding these patients is difficult as only about 5% of metastatic cancers have dMMR. There is limited data from India in this population. We report our experience with testing and treatment in these patients. Methods: This is a single centre, retrospective study of metastatic solid tumors which had progressed on standard treatment. 137 patients were tested between May 2017 and Dec 2018. MMR testing was done by immunohistochemistry (IHC). The aim was to identify patients with dMMR; and to see their ORR, progression free survival (PFS) at 1 year, and adverse events on treatment with Nivolumab. Results: 137 metastatic cancer patients were tested. 75 had colorectal cancer (mCRC), 30 gastric, 10 hepatobiliary, 10 pancreatic, 8 endometrial, 2 small bowel cancer and 2 had breast cancer. 15 (11%) patients had dMMR. 3 (37%) of endometrium, 5 (16.6%) of stomach, 6 (8%) of mCRC and 1(10%) of hepatobiliary tree cancer had dMMR. 5 of the 15 dMMR patients received immunotherapy with Nivolumab - 2 in mCRC, 2 in stomach and 1 in endometrium. ORR was 60% with 3 partial responses, stable disease was seen in 1 (20%) and progression in 1 (20%). PFS at 1 year was 80%. Treatment was well tolerated.1 patient had hypothyroidism and 1 patient had grade 1 skin toxicity. Conclusions: Testing for dMMR is important in metastatic solid tumors as these patients are ideal for treatment with immunotherapy. But finding dMMR is difficult due to its infrequent presentation, and has been seen in 11% of our unselected patients. We recommend testing for dMMR by IHC in our Indian patients, as this is fast and cost effective. Finding dMMR cancers, and then treating with immunotherapy is rewarding irrespective of the site of origin. High ORR of 60% and 1 year PFS of 80% is very heartening to see in this relapsed metastatic patient group. Treating more dMMR patients and longer followup, will further elucidate the benefit of immunotherapy in our patients.
Is inmunotherapy a safe treatment in bladder cancer? A retrospective study in daily practice.
Authors: Vidal Casinello Natalia , Aguado De La Rosa Carlos , Puente Javier , Gonzalez-Larriba Jose-Luis
Published: May 2019

e14083

Background: Several checkpoint inhibitors antibodies have been approved to treat bladder cancer, and many trials are still ongoing. However, few data about their efficacy and safety outside of a clinical trial have been published. Here we report our experience in managing immune-related toxicity in our daily practice. Methods: We performed a retrospective analysis of 23 patients (pts) with metastatic bladder cancer treated with checkpoint inhibitors in Clínico San Carlos University Hospital from April 2016 to September 2018. The aim of this study is to evaluate the safety of checkpoint inhibitors in daily practice. Results: Median age was 75 years (range 53-92) and 75% were men. The performance status at the beginning of immunotherapy treatment was 0 in 4 pts (17.4%), 1 in 16 pts (69.6%) and 2 in 3 pts (13%). Thirteen pts (56.5%) received the treatment as first line, 6 (26.1%) as second line and 4 (17.4%) as third line and beyond. 18 pts (78.3%) received immunotherapy as monotherapy (15 pts Atezolizumab and 2 pts Pembrolizumab), 3 pts (13%) received an immunotherapy combination with Durvalumab plus Tremelimumab, and 2 pts (8.7%) received chemotherapy plus immunotherapy (Carboplatin plus Avelumab or Atezolizumab). Of the analyzed patients, 36% did not develop any immune related adverse event (irAE). However, 64% did present some side effect. The most common side effect was asthenia (12.5%), cutaneous (8.3%), endocrine (5.6%), gastrointestinal (4.2%) and hepatic (2.8%). Only16.6% of the events required some kind of treatment (9.7% required steroids). Three patients had grade 3 or 4 toxicity, 1 patient on Atezolizumab presented with grade 3 diarrhea and grade 3 hepatic toxicity, another patient on Atezolizumab presented two heart attacks after the two infusions and eventually died, lastly a patient on Durvalumab + Tremelimuab suffered grade 3 hypophysitis. Conclusions: Incidence and therapeutic management of irAEs occurring in our clinical setting closely resembles that reported in retrospective series even though they were mostly elderly patients and many of them were heavily pretreated. Increasing our experience and knowledge in the clinical setting will improve and optimize the use of these drugs.
Comparison of panendoscopy directed biopsies with percutaneous and image-guided biopsies during immune checkpoint inhibitor therapy.
Authors: Hashmi Ahmad F , Smith Daniel Arnold , Rahnemai-Azar Amir Ata , Ravishankar Pavitra , Pfau David , Nelson Ariel Ann , Hoimes Christopher J. , Ramaiya Nikhil H.
Published: May 2019

e14084

Background: Immune checkpoint inhibitors (ICI) have been shown to be helpful in the treatment of a several cancers. Response to ICI therapy is varied. The goal of this study was to examine the role of pan-endoscopy guided biopsies as well as image-guided and percutaneous biopsies as a means to tailor treatment regimens for patients receiving ICI therapy. Methods: A retrospective chart review was performed on oncology patients at a single institution from 2010 from 2018 undergoing treatment with ICI (n = 1044). Patients undergoing biopsies within the treatment period and up to one month following conclusion of treatment were analyzed and separated into a pan-endoscopy guided biopsy cohort or image-guided/percutaneous biopsy cohort. Data regarding biopsy results and subsequent treatment plans was then gathered and compared. Results: 5.3% of patients underwent pan-endoscopy guided biopsy (n = 55). 6.0% of patients underwent image-guided/percutaneous biopsy (n = 63). The most common endoscopic procedures included EGD 42.6%, bronchoscopy 38.9%, and flexible sigmoidoscopy/colonoscopy 20.4%. The most common image/percutaneously sampled tissues included skin/soft tissue 24.6%, lymph nodes 19.7%, and liver 16.4%. Breakdown of treatment complications in the pan-endoscopy group included pneumonitis 3.2%, inflammatory or infectious esophagitis 6.4%, or colitis 4.3%. Treatment complications in the image guided/percutaneous group included skin reactions 2.2% and inflammatory mediastinal changes 1.1%. Conclusions: In our cohort, Pan endoscopy and image guided/percutaneous biopsies were successfully performed along multiple cancer cell lines and helped in the decision making process.[Table: see text]
Prevalence of immunotherapy-related adverse events due to checkpoint inhibitors: First report in Mexico.
Authors: Rodriguez Melendez Elina Alexandra , Martinez Herrera J. Fabian , Olivares Guillermo , Villalobos Alberto , Serrano Juan Alberto , Perez-Zincer Fernando , Aguayo Alvaro , Rivera Rivera Samuel , Lazaro Leon Jesus Miguel , Salcedo Ivonne , Regalado Porras Gabriela Olivia , Alatorre Alexander Jorge , Camacho Limas Christian Patricio , Imaz Victoria , Gerson Raquel
Published: May 2019

e14090

Background: Since 2010, immune checkpoint inhibitors (ICI) have been approved for the treatment of several neoplasms. Their immune-mediated toxicity profile, used as monotherapy (nivolumab [N], Ipilimumab [Ip], pembrolizumab [P]) or in combination (Nivolumab/Ipilimumab [N/Ip]) and their management is still being described, recently. Methods: A retrospective review of medical records, included all cancer patients treated, in our institution, with ICI from January 2014 to February 2018. Frequency, type and grade of immune related adverse events (irAE) by neoplasm, individual agent or combination were recorded. Time to first ir-AE (TTF-irAE) was estimated by Kaplan Meir Method and compared by Cox regression model. Results: 140 patients were evaluated, all in pretreated metastatic setting. Median age 65.8+/-11.8, men in 59.3%. The most frequent neoplasms treated with ICI were: lung (34%), melanoma (33%), genitourinary (17%), H&NC (6%), and GI (6%). Ip alone was indicated in 11.4% cases; N, 30%; P, 54.29%; N/Ip 4.29%. Median number of cycles per drug: Ip: 3 cycles, N/Ip: 4; N: 6; and P: 4 cycles. Toxicity (G1-4) was seen in Ip: 62.5%, N/Ip: 50%, N: 40.5%, P: 31.6%, p > 0.05. The most frequent irAE's were: dermatological 40%, gastrointestinal 18.3%, and endocrine 13.4%; other irAE´s were reported in: pulmonary 7.3%, ophthalmologic 6%, muscle-skeletal 6%, neurologic 2.4%, renal 1.2%, hematologic 1.2%. Severe toxicities (G3-4) were observed with N/Ip: 33.3%, P: 17.4%, Ip: 10%, N: 5.6%. TTF-ir-AE per drug: I: 1st cycle (dermatitis, pruritus, colitis), N/Ip: 2nd cycle (dermatitis, conjunctivitis), N: 3rd cycle (dermatitis, thyroiditis, colitis, hepatitis), P: 1st cycle (pruritus, neuritis, adrenalitis). Ipilimumab was an independent prognostic factor for developing severe ir-AE´s [OR = 12.8, p = 0.038], and any grade toxicity [OR = 1.9 (IC95% 0.92 - 4.1, p = 0.079)]. Conclusions: In this study, the dermatological, gastrointestinal and endocrine toxicities were the most frequent ir-AE´s, and they were observed in a low grade toxicity. The irAE´s profile is different among ICI or their combination and number of cycles administered. Ipilimumab alone or combined was associated to higher risk of severe irAEs.
Impact of IDO1 expression and inhibition on the sensitivity of anti-PD-1.
Authors: Zhu Jian , Zhu Rebecca L
Published: May 2019

e14094

Background: Concurrent inhibition of IDO1 and PD-1 may have enhanced anti-tumor effects. However, inhibition of IDO1 failed to enhance efficacy of anti-PD-1 in late phase clinical trials. In this study, computational models were established to identify factors involved in interactions between these two types of agents. Methods: Abstracts published on IDO1, PD-1, PD-L1, anti-PD1/PD-L1 were downloaded from PubMed, and analyzed by text mining. The information on interactions among gene, compound/therapy, cell/animal model, pathway/disease, and clinical study was extracted. Networks were constructed to simulate effects of IDO1 inhibition on anti-PD-1. Results: The IDO1/anti-PD-1 network consists of 79 nodes, 227 interactions with 1277 possible regulatory paths from IDO1 to anti-PD-1. 675 paths are associated with agonism and 602 with antagonism between IDO1 inhibition and anti-PD-1. Up-regulation of [TNF-alpha, IFN-gamma, type I immunity & CD8+ T cells], and down-regulation of [Tregs, MDSC, JAK/STAT pathway, IL-6 and PD-L1] are associated with enhancement of anti-PD-1 by IDO1 inhibition. Besides, treatments with PARP inhibitor, EGFR inhibitor or radiation may enhance the combination efficacy of IDO1 and PD-1 inhibitors. Up-regulation of TIM-3 and NK cells are associated with reduced activities of anti-PD-1 upon IDO1 inhibition. PD-L1 is a predictive biomarker for anti-PD-1 response and its expression can be regulated by IDO1. The IDO1/PD-L1 network consists of 83 nodes, 204 interactions and 318 paths. Up-regulation of IL-6, AhR, MDSC, JAK/STAT, HIF1A, IL10, NF-kappaB & MYC was associated with induction of PD-L1 by IDO1. Conclusions: As the network analyses revealed, inhibition of IDO1 could either up- or down-regulate PD-L1, and enhance or reduce efficacy of anti-PD-1. Multiple factors, other than PD-L1, play roles in determining the efficacy of combining IDO1 and PD-1 inhibitors.
Evaluation of radiotherapeutic and immune-modulatory response to whole brain radiotherapy or stereotactic radiosurgery in patients with brain metastases from malignant melanoma treated with or without ipilimumab (ELEKTRA).
Authors: Hassel Jessica Cecile , Smetak Heiko , Salzmann Martin , Haefner Matthias , Bernhardt Denise , Hülsmeyer Ingrid , Enk Alexander , Debus Juergen , Beckhove Philipp
Published: May 2019

e14104

Background: Immune checkpoint blockers have dramatically improved the survival of patients (pts) suffering from advanced metastasized melanoma. In pts with melanoma brain metastases (MBM) a combination with radiotherapy (RT) is routinely used. Methods: We prospectively included 106 pts with MBM in a non-randomized observational trial with 7 treatment cohorts. Patients in cohort 1-4 were treated with ipilimumab (+/- nivolumab) and either stereotactic (up to 3 MBM) or whole brain RT (≥ 4 MBM) before or after the start of immunotherapy. Cohort 5 and 6 included pts who received RT with an ipilimumab-free systemic treatment and cohort 7 pts were treated with ipilimumab (+/- nivolumab) and no RT. Primary endpoints were immunological response in the peripheral blood (FACS of T cell subsets, ELISpots against melanoma antigens) and radiological response, secondary endpoints were progression free and overall survival. Results: Included pts were in median 61 years old, 72% were male. At trial inclusion, 31% of pts had an elevated LDH. 39% of ipilimumab treated pts received combination therapy with nivolumab. Clinically, ipilimumab treated pts in the early RT groups had better responses of both intra- and extracranial disease (p = 0.04 for both). Multivariate analyses showed a better PFS for pts with early RT (p = 0.02) and normal LDH (p = 0.049). Type of radiation (p = 0.6) and immune therapy (p = 0.8) had no significant influence in this small cohort of pts. Immune monitoring revealed that ipilimumab leads to an increase in activated CD4+ and CD8+ T cells in the peripheral blood which was maintained in responding pts and higher in pts receiving early RT. Treg were not depleted in general but activated by ipilimumab. However, responders displayed a temporary decrease of Treg and activated Treg under treatment. An increase in the detection of melanoma antigens could be observed after 2 cycles of ipilimumab which was higher in pts with combined radioimmunotherapy compared to ipilimumab only. Conclusions: Preliminary data from this small observational trial might lead to a preference of a treatment sequence with radiotherapy first, followed by checkpoint inhibition in pts with MBM.
Gastrointestinal, pancreatic, and hepatic toxicity profile of CTLA-4 immune checkpoint inhibitors alone and in combination with PD-1/PD-L1 inhibitors: A meta-analysis of clinical trials.
Authors: Ali Faisal , Hussain Maryam R , Deep Aman , Abu-Sbeih Hamzah , Alrifai Taha , Myint Phyo Thazin , Gong Zimu , Kozma Kelley Elizabeth
Published: May 2019

e14117

Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]
Clinical and immunological analyses of immune checkpoint inhibitor-associated neuromuscular (NM) toxicities.
Authors: Siddiqui Bilal A. , Durand Jean-Bernard , Gao Jianjun , Wang Jianbo , Aparicio Ana , Campbell Matthew T , Siefker-Radtke Arlene O. , Tannir Nizar M. , Corn Paul Gettys , Msaouel Pavlos , Shah Amishi Yogesh , Zurita Amado J. , Tu Shi-Ming , Suarez-Almazor Maria E. , Sudhakar Tummala , Logothetis Christopher , Sharma Padmanee , Subudhi Sumit Kumar
Published: May 2019

e14118

Background: A rare and often fatal spectrum of NM immune-related adverse events (irAEs) includes myositis, myocarditis, and myasthenia gravis (MG). A deeper understanding of their clinical and immunologic features may improve outcomes. Methods: Sixteen patients (pts) with genitourinary cancers who were treated with ICI and developed myositis, myocarditis, MG, or overlap syndrome (≥2) were identified. Diagnostic criteria included serum CK (n=16), aldolase (n=14), troponin (n=12), BNP (n=15), autoantibodies (n=16), and cytokines (n=9). Biopsies of skeletal muscle (n=13) and endomyocardium (n=4) were also obtained. Immune profiling is being performed on blood and tissue for pts consented to an institutional-approved laboratory protocol. Results: ICI-associated NM irAEs consisted of isolated myositis (n=8, 50%), myocarditis (n=1, 6%), MG (n=1, 6%), or overlap syndrome (n=6, 38%), with the most common presenting symptom being weakness (n=9, 56%). CK levels were elevated in 15 (94%) pts, and autoantibodies were detected in 9 (56%). Muscle biopsies showed predominantly T cell infiltration. All 16 pts received corticosteroids, 12 (75%) were treated with other immunosuppressive agents, and 14 (88%) underwent plasmapheresis. Five pts (50%) with isolated irAEs achieved symptom resolution, and none in the overlap group. (Table) Conclusions: NM irAEs occurred more frequently with combination ICI, and were associated with weakness, and elevated CK level and serum autoantibodies. Both T and B cells appear to drive disease pathogenesis. The presence of one toxicity on the spectrum warrants evaluation for associated irAEs. Compared to isolated NM irAEs, the overlap syndrome appears to be more treatment refractory. Current guidelines require refinement to identify effective treatments to improve outcomes. [Table: see text]
Multidisciplinary approach to immune related adverse events as a potential biomarker: Single institution experience in non-small cell lung cancer.
Authors: Martin Sooyoung , Laukamp Kai , Gupta Amit , Ansari-Gilani Kianoush , Kikano Elias , Smith Daniel Arnold , Dowlati Afshin , Ramaiya Nikhil H.
Published: May 2019

e14124

Background: Immune checkpoint inhibitor (ICI) has emerged as a novel systemic treatment for advanced cancers. As ICI modulates immune signaling pathways by targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) or its ligands (PD-L1), a number of immune related adverse events (IRAE) have been reported. Whether IRAE can be a predictor for treatment response has remained controversial and we evaluated the association between IRAE and outcome. Methods: Retrospective chart and Computed Tomography (CT) review of patients with stage IV NSCLC treated with single agent Nivolumab or Pembrolizumab was performed. Any abnormalities in lab values, imaging finding or clinical signs to suggest pneumonitis, thyroiditis, hepatitis, nephritis, pancreatitis, colitis, pleural/pericardial effusion, arthritis or myositis between the start of the therapy and six months after the end of the therapy were recorded in a binary fashion. Abnormality in the setting of baseline abnormal values or due to clear cause other than IRAE has been excluded. Overall survival as well as best response based on RECIST 1.1 was also recorded. Results: 88 patients treated between January 2012 and March 2017 were identified. 62 patients, 42 patients and 50 patients demonstrated abnormalities in lab values, CT and clinical signs, respectively. When each subcategory was correlated with OS using ANOVA, thyroid function test abnormality (n = 15) and liver function test abnormality (n = 36) were associated with increased OS (p = 0.021, p = 0.038, respectively). Interestingly, elevated C-reactive protein was associated with decreased OS (p = 0.01). Initially, each score was given depending upon the number of abnormal categories (lab, imaging or clinical signs), ranging from score 0 (n = 7), 1 (n = 19), 2 (n = 33) and 3 (n = 17). Increased score was associated with increased OS (p = 0.03). For more detailed analysis, we came up with scoring system which sums up each score given for any abnormality in each subcategory. On Multivariate analysis, there was significant positive correlation between higher score and increased OS (p = 0.001). Conclusions: We have identified several IRAE parameters that were associated with increased OS. Furthermore, scoring system used in the study which encompassed clinical, radiologic and laboratory aspect, showed positive association with increased OS, indicating IRAE’s potential role as a biomarker.
Preclinical functional characterization of AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody for the treatment of patients with early and advanced malignancies.
Authors: Waight Jeremy , Manrique Mariana , Gombos Randi , Costa Matthew , Iyer Priyadarshini , Vincent Sylvia , Ward Rebecca , Paltrinieri Elena , Chand Dhan , Wilson Nicholas , Buell Jennifer , Savitsky David
Published: May 2019

e14126

Background: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor that modulates T cell priming and CD28-dependent T cell activation. Modulation of this pathway by CTLA-4 antibodies has demonstrated clinical responses in patients with advance disease, however the mechanism of action of these antibodies remains controversial. It is currently understood that anti-CTLA-4 antibodies mediate antitumor effects through receptor-ligand blockade, and, in preclinical models, through depletion of intratumoral regulatory T (Treg) cells via an Fc-dependent mechanism. Recently, we reported a novel Fc-mediated contribution to T cell priming underscored the importance of Fc selection for optimal CTLA-4 antibody activity. AGEN1181 is a clinical stage Fc-engineered IgG1 antibody that leverages this novel mechanism for enhanced functionality. Methods: Fab-mediated biology of AGEN1181 was confirmed by assessing binding affinity, specificity, and blockade of CTLA-4:CD80/86 interactions. Fc-mediated functions of AGEN1181 were evaluated by FcγR binding, reporter-based FcγR signaling, and antibody-mediated Treg cell cytotoxicity assays. In vitro and in vivo pharmacology of AGEN1181 (alone or in combination with anti-PD-1) were evaluated in superantigen (staphylococcal enterotoxin)-mediated T cell stimulation assays and in a non-human primate (NHP) model. Safety and tolerability of AGEN1181 were assessed in cynomolgus monkeys administered 5 once-weekly intravenous bolus infusions at doses of 5, 30, or 100 mg/kg. Results: AGEN1181 bound to CTLA-4 with high affinity and specificity and demonstrated a range of enhanced functional activities relative to first-generation CTLA-4 antibodies. This included superior CD16 (FcγRIIIA) binding, Treg depletion and T cell priming (as measured by ZAP70 phosphorylation and interleukin-2 secretion). In NHP studies, a single dose of AGEN1181, alone or in combination with anti-PD-1 antibody upregulated Ki67 and ICOS expression on peripheral T cells. Finally, AGEN1181 exhibited an acceptable toxicologic profile in multi-dose NHP studies. Conclusions: AGEN1181, an Fc-engineered anti-CTLA-4 antibody exhibits a range of enhanced functional attributes relative to first-generation anti-CTLA-4 antibodies in preclinical studies. Phase 1 clinical studies for AGEN1181 will be initiated imminently.
Characteristics and treatment of rheumatologic adverse events associated with immune checkpoint inhibitors: A multicentric prospective cohort study.
Authors: Mouamnia Amine , Desbarbieux Renaud , Mortier Laurent , Scherpereel Arnaud , Dubucquoi Sylvain , Flipo René-Marc , Philippe Peggy , Cortet Bernard , Vieillard Marie-Helene
Published: May 2019

e14133

Background: To characterise the specific rheumatologic immune-related adverse events (irAEs) in patients with cancer treated by immune checkpoint inhibitors (ICI), and to propose a treatment flowchart of irAEs. Methods: A multicentric prospective study was performed to characterise the irAEs. Results: From December 2016 to December 2018, 39 patients were referred to the Department of Rheumatology. There were 22 men and 17 women. The middle age was 64,72 years old. The average time to continue ICI treatment after the onset of the irAEs was 3 months. 24 patients were followed for a melanoma, 10 for non-small cell lung cancers and five patients for various other neoplasia (glioblastoma, urothelial carcinoma, Merkel cell carcinoma, esophageal carcinoma, renal cell carcinoma). 43% had inflammatory pain (n = 17), whose 17% had arthritis (n = 7). The diagnosis was polymyalgia rheumatica for 10 patients, eosinophilic fasciitis for one patient, erosive Rheumatoid arthritis for one patient, non-erosive Rheumatoid arthritis for one patient. The other patients (57 %) had mechanical rheumatological involvement. Treatment of irAEs was glucocorticoids for 7 patients with a satisfying response, methotrexate for 1 patient, and sulfasalazine for one patient. The non-inflammatory pain was treated by antalgics and physiotherapy. The ICI was stopped (due to irAEs) for only one patient. Conclusions: In the light of these findings, a logigram of management is proposed and is being validated on a larger prospective cohort. irAEs is a good example of collaboration between oncologist and rheumatologist to improve the patients’ quality of life.
Real-world outcomes with immuno-oncology (IO) therapies: A prospective, observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE).
Authors: Kirkwood John M. , Kottschade Lisa A. , McWilliams Robert R. , Khushalani Nikhil I. , Jang Sekwon , Hallmeyer Sigrun , McDermott David F. , Tawbi Hussein Abdul-Hassan , Wan Yin , Wang Rosa , Ritchings Corey , Rao Sumati , Ramsey Scott
Published: May 2019

e14144

Background: There is little real-world evidence evaluating treatment patterns and outcomes with IO therapies for pts with advanced melanoma (aMEL). We present results from the OPTIMIzE (NCT02780089) study in pts with aMEL receiving IO therapies. Methods: OPTIMIzE is a US-based multisite (150 sites), community-based study of adult pts with aMEL. Pts receiving first-line (1L) nivolumab (NIVO)+ipilimumab (IPI), anti-PD-1 (NIVO/pembrolizumab), or IPI between 2011-2018 with a minimum 1 y of follow-up were included. Baseline characteristics, objective response rate (ORR), overall survival (OS), treatment-related adverse events (TRAEs), and quality of life (QoL) were analyzed. QoL assessments included the Functional Assessment of Cancer Therapy–Melanoma (FACT-M), EQ-5D index, and visual analog scale (VAS). Results: Cohort size: 81 NIVO+IPI, 147 anti-PD-1, and 16 IPI (IPI arm not included in the analysis). Overall, mean age was 64.5 y; 42% had BRAF mutation. Mean follow-up was 14.1 mo. Pts in the NIVO+IPI group were younger, had better ECOG performance status, and a higher likelihood of M1c disease and elevated LDH vs the anti-PD-1 group. ORR was higher for pts treated with NIVO+IPI vs anti-PD-1 (48% vs 33%, P= 0.08). Unadjusted 1-y OS was 78.4% for NIVO+IPI and 73.1% for anti-PD-1. In multivariate Cox model analysis, the hazard ratio for OS for NIVO+IPI vs anti-PD-1 was 0.78 (95% CI, 0.46–1.33; P= 0.36). Grade 3/4 TRAEs occurred in 53% and 22% of pts in the NIVO+IPI and anti-PD-1 groups, respectively ( P˂0.001). QoL changes from baseline were clinically meaningful for EQ-5D VAS and FACT-M in the NIVO+IPI group at 12 mo (Table). After adjusting for baseline covariates, the difference at 12 mo between NIVO+IPI vs anti-PD-1 was 6.7 ( P= 0.04) for EQ-5D VAS and 8.8 ( P= 0.02) for FACT-M. Conclusions: Safety and efficacy outcomes from this prospective real-world study are consistent with those reported in prior clinical trials in treatment-naive aMEL pts. No clinically meaningful deterioration in QoL measures was observed in either group. Clinical trial information: NCT02780089. [Table: see text]
Endocrinopathies associated with immune checkpoint inhibitors: Standard of care at veterans administration medical centers.
Authors: Johnson Brett , Tuck David P. , Ganas Spyridon , Bayless Nicholas , Kotecha Nikesh , Do Nhan
Published: May 2019

e14148

Background: Multiple different immune checkpoint inhibitors (ICI) have now received FDA approval for nearly 70 separate indications covering 14 different tumor types. Patients treated with these agents in clinical trials have an observed incidence of immune related adverse events (irAEs), including endocrinopathies, which may increase morbidity and mortality. Limited information describes the incidence and impact of these events outside of clinical trials. Methods: Retrospective data from the Veterans Health Administration (VA) of patients treated with ICI has been aggregated to understand the impact of these events in a standard of care setting, with a goal of improving patient care through predictive models and contributing to the understanding of the mechanisms and response to treatment. Results: Between October 2015 and December 2018, 10,280 patients were prescribed ICI at VA medical centers, with an average age of 70 years (range 20-99). A total of 11098 ICI orders, allowing for combinations or sequential treatments. Overall, nivolumab was prescribed 6024 times (54.3%), pembrolizumab 3976 (35.8%), ipilimumab 565 (5.1%) and atezolizumab 519 (4.6%). Avelumab (13) and durvalumab (1) had limited use. A candidate set of potential endocrine adverse events was estimated based on selected ICD10 codes recorded for the first time after treatment with ICI (Table). Conclusions: The frequency of endocrine immune related adverse events has been reported to be 5-10%. Here we have identified a cohort of ICI treated patients who may have developed endocrine adverse events. This cohort will be used to evaluate phenotyping, potential biomarkers and models of predictive risk.[Table: see text]
Pembrolizumab versus the standard of care for cancer therapy: A meta-analysis of 12 KEYNOTE trials comparing overall survival.
Authors: Parker Nathaniel , Al-Obaidi Ammar , Truong Quoc Van , Badgett Robert
Published: May 2019

e14159

Background: Pembrolizumab (P) is an antineoplastic agent approved for multiple different tumor origins as well as tumor agnostic based on MSI status. Thus understanding the tumor characteristics most predictive of response is essential. Living meta-analysis provides a method to continuously assimilate emerging trials. In this study, we created a living meta-analysis to compare the effect of P on overall survival (OS). Methods: Meta-analysis was conducted according to the PRISMA guidelines. PubMed and Cochrane databases, and conference abstracts (e.g. ASCO, ESMO), were searched for phase III KEYNOTE RCT’s that reported OS among cancer patients receiving P. Results: 12 phase III trials involving 7,319 patients (3,861 in P arms) treated for 6 different types of cancer were retrieved. Median follow up was 12.9 months [range: 0.1-35.5]. Treatment was P alone, SOC chemo, and P + chemo in 11 (40%), 13 (46%), and 4 (14%) arms, respectively. P significantly improved OS (HR 0.71, 95% CI: 0.59-0.85, p <0.001, I2 = 0%) when used in any cancer type, setting, or therapy for advanced refractory or chemo-naïve cancer patients. The mean median OS was 12.5 vs 11.1 months in the total populations for all P and control arms, respectively (Table). Conclusions: Among all trials, P was associated with improved OS. Additional meta-analysis will be performed with R software (version 3.3.3; R Fdn.). Random-effects models will be used to compare OS. Heterogeneity will be assessed with Cochrane Q -statistic and quantified with I2test via subgroup analyses for cancer type, setting, therapy, and PD-L1%. This meta-analysis is continuously updated at http://openmetaanalysis.github.io/checkpoint-inhibitors. [Table: see text]
Recurrence-free survival (RFS) and objective response rate (ORR) phase 1/2 study of intralesional (IL) neoadjuvant (neo) anti-PD1 agents (aPD1) for stage IIIB-IV melanoma (MEL).
Authors: Samoylenko Igor , Korotkova Olga V. , Shakhray Ekaterina , Zabotina Tatiana , Berdnikov Sergey , Tabakov Dmitry , Zakharova Elena , Petenko Natalia N. , Demidov Lev V.
Published: May 2019

e14171

Background: We previously reported that aPD1 agents could be safely administered IL in patients (pts) with metastatic MEL with superficial lesions, providing local and bystander tumor response (Samoylenko, I., et al. (ASCO-SITC 2018)). We present results from an interim 6 mos analysis of RFS and ORR for IL neo aPD1 therapy. Methods: Pts with unresectable stage IIIC/D/IVM1a-c MEL (safety cohort, N = 7) and resectable stage IIIC/D/IVM1a (expansion cohort, N = 18), with ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm were allocated to 6 doses/12 of nivolumab or pembrolizumab before surgery (surg). aPD1 was given at scale-based dosing regimen reported previously. Tumor sampling for biomarker analysis and pCR confirmation (or core-needle biopsy, CNB) was performed prior to treatment and at week 13-18. The analysis was conducted on the ITT basis to estimate RFS at 6 mos and ORR. An RFS event was defined as disease progression or death due to any cause after surg and assessed in the expansion cohort. ORR for the both cohorts was evaluated. Results: Since Apr 2016 to Dec 2018 25 pts were enrolled. Baseline characteristics are summarized in Table. ORR was 47,6% (10/21 pts assessed), with 5 (24%) clinical CR and 4 pathological CR (19%). Among 18 pts considered for surg 2 refused from surg when CNB confirmed no residual tumor. 89% of pts (16/18 pts) from the expansion cohort remained recurrence free at 6 mos FU. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 20 of 21 pts assessed. Baseline percent of TILs assessed by flow cytometry (FCT) was higher in responders vs non-responders (7.54±7.51% vs 1.51±2.93, p < .05), whereas CD3-CD16+CD56+ and CD4+CD25+ values were lower in responders vs non-responders (0.94±1.45% vs 7.88±6.84, p < .05, and 6.68±3.46% vs 20.50±16.79, p < 0.05, respectively). PD1, PDL-1 and PDL-2 expression in tumor cells and TILs assessed by FCT did not differ significantly between responders and non-responders. Conclusions: We demonstrated the potential clinical efficacy of IL aPD1 in melanoma pts. Further studies are needed to determine if unsuccessful IL administration could predict failure to adjuvant treatment. Primary analysis of RFS at 1-yr is expected. Clinical trial information: NA. [Table: see text]
Quantitative assessment of immune cell populations and associations with clinical outcomes in African-American (AA) versus Caucasian triple-negative breast cancer (TNBC).
Authors: O'Meara Tess , Yaghoobi Vesal , Blenman Kim , Pelekanou Vasiliki , Silber Andrea , Rimm David L. , Pusztai Lajos
Published: May 2019

e14180

Background: Tumor infiltrating lymphocytes (TILs) are powerful prognostic and predictive factors in TNBC. We hypothesized that survival differences in TNBC by race may be caused by differences in the tumor immune microenvironment. We assessed racial differences in the extent and composition of immune infiltration in TNBC and correlated these differences with clinical characteristics and disease-free survival (DFS). Methods: Formalin fixed paraffin embedded TNBC samples and clinical information were collected for n = 43 AA and n = 43 Caucasian cases, matched by diagnosis date and stage. Stromal TILs were assessed on H&E-stained slides. Multiplexed immunofluorescence was performed to quantify CD68 (macrophage), CD8 (cytotoxic T cell) and PD-L1 protein expression in the whole-section, tumor and stromal compartments. Average expression for each marker was calculated over all fields of view. Cox proportional hazards were used to assess associations between DFS, staining markers and clinical variables. Results: Characteristics of AA and Caucasian cases were not significantly different. There were 14 and 8 recurrences in the AA and Caucasian cohorts, respectively (median follow-up 8.7 vs 9.4 yrs). TIL counts (p = 0.031) and overall CD68 expression (p = 0.005) were higher in AA compared to Caucasian patients. 21% percent of AA cases had TIL predominant phenotype versus 3% of Caucasians, but CD8 expression was similar by race. PD-L1 expression was higher in stroma compared to tumor across all patients (median 401 vs 267 au, p = 0.002) and did not differ by race. Higher overall and stromal PD-L1 expression were associated with better DFS in the entire population (median 3501 vs 1895 days, p = 0.0009) and in each race separately. Higher CD68 expression was also associated with better DFS (median 3015 vs 2111 days, p = 0.0004). In multivariate analysis of DFS, stage at presentation remained significant (p = 0.002) in addition to PD-L1 and CD68 expression. Conclusions: AA TNBC had higher TIL counts and CD68 expression but similar CD8 and PD-L1 expression compared to Caucasians. High CD68 and PD-L1 expression were associated with better DFS in both race cohorts.
Effect of gastrointestinal microbiome and its diversity on the expression of tumor-infiltrating lymphocytes in breast cancer.
Authors: Shi Jiajie , Geng Cuizhi
Published: May 2019

e14187

Background: The diversity of gastrointestinal microbiome is closely related to human health. In the present study, we compared gastrointestinal microbiome and tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) patients. Methods: A total of 80 BC patients were divided into three groups based on the expression of TILs as follows: high expression of TILs (TIL-H), medium expression of TILs (TIL-M) and low expression of TILs (TIL-L). DNA of gastrointestinal microbiome was determined by Illumina sequencing and taxonomy of 16S rRNA genes. Kruskal-Wallis test and UniFrac analysis of β-diversity were applied to assess the relationship between patients’ clinical characteristics and diversity of gastrointestinal microbiome. Results: The β-diversity distribution was statistically significant (weighted UniFrac P < 0.01, unweighted UniFac P < 0.01) when comparing between the TIL-L and TIL-H groups or among the three groups (TIL-H vs. TIL-M vs. TIL-L). At the genus level, higher abundances of Mycobacterium, Rhodococcus, Catenibacterium, Bulleidia, Anaerofilum, Sneathia, Devosia and TG5 but lower abundances of Methanosphaera and Anaerobiospirillum ( P < 0.05) were identified in the TIL-L group compared with the TIL-H group . At the species level, the species of stercoris, barnesiae, coprophilus, flavefaciens and C21_c20 displayed a higher abundance in the TIL-L group, while producta and komagatae exhibited a greater abundance in the TIL-H group ( P < 0.05). Conclusions: Collectively, the diversity of gastrointestinal microbiome was related to the expression of TILs in BC patients.