bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of checkpoint inhibition (CI) in cancer patients (pts) with concurrent human immunodeficiency virus (HIV) infection.
Authors: Park Soo , Sacco Assuntina Gesualda , Cohen Ezra E.W. , Daniels Gregory A. 
Published: February 2018

136 Background: There is limited knowledge about the use of CI in cancer pts with HIV. Here we report the safety and efficacy of these agents in this pt population. Methods: We identified cancer pts with HIV at UCSD who received ≥1 dose of ipilimumab, pembrolizumab or nivolumab (anti-PD1), or the combination of ipi+nivo and had ≥1 follow-up visit. Data regarding clinical history, treatment response, and toxicity were collected. Results: Three pts had head and neck squamous cell carcinoma (HNSCC), 2 pts had advanced melanoma, 1 pt had cutaneous SCC, and 1 pt had SCC of unknown primary (suspected lung). Age ranged from 51-73 years. All pts had ECOG PS 0-1 at time of treatment. Six pts received anti-PD1 for a median of 8 cycles (range 2-35); one pt received 4 cycles of ipi+nivo q3wk followed by 4 cycles of anti-PD1. All 7 pts were on anti-retroviral therapy (ART) and had well-controlled HIV (viral load < 400 copies/mL) with varying degrees of immune dysfunction: 4 pts with moderate immune dysfunction (100-199), 1 pt with mild immune dysfunction (200-350), and 2 pts with normal immune function ( > 350). 3/7 pts (43%) had ≥1 clinically significant irAE of grade ≤2 (fatigue and rash); one pt who received ipi+nivo developed grade 3 hepatitis and required systemic steroids though progressive disease likely contributed. No atypical toxicities were seen. Objective responses were seen in 4/7 pts (57%) with 1 complete response and 3 partial responses; two pts had progressive disease and response was not yet evaluable in 1 pt. Four patients died from clinical deterioration unrelated to CI or immunodeficiency. Conclusions: CI demonstrated significant anti-tumor activity in cancer pts with well-controlled HIV. The toxicity profile is consistent with known irAEs. Further study of these agents in this pt population is warranted.
Immune checkpoint inhibition in elderly non-small cell lung cancer patients.
Authors: Marrone Kristen , Zhang Jiajia , Feliciano Josephine Louella , Forde Patrick M. , Hann Christine L. , Kelly Ronan Joseph , Ettinger David S. , Turner Michelle , Rowe Valerie , Bonerigo Sarah , Smith Kellie Nicole , Anagnostou Valsamo , Velculescu Victor E. , Brahmer Julie R. , Naidoo Jarushka 
Published: February 2018

137 Background: Age-related changes in the immune system are dynamic and complex. Use of anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer (NSCLC), with median patient age of 71, has rapidly become standard of care. Understanding how senescent remodeling of the immune system may affect outcomes with anti-PD-1/PD-L1 therapy is poorly understood. Although trends in phase III clinical trials of anti-PD-1/PD-L1 therapy suggest a potential lack of clinical efficacy in patients ≥ 75 years of age, the proportion of treated patients in this age range was low. The use and outcomes of these agents in this population treated in clinical practice has not been reported. Methods: The Johns Hopkins Upper Aerodigestive Diseases Malignancies and Immunotherapy Database was queried for all patients treated with anti-PD-1/PD-L1 agents as part of a clinical trial or as standard of care, from 2007 to 2017. Patients ≥ 75 years old were assessed for demographic, response, toxicity and survival data as of September 2017. Results: Of the 275 patients in our database, 144 NSCLC patients had received an anti-PD-1/PD-L1 agent alone or in combination with another immune checkpoint inhibitor (52%). Of those 144 patients, 20 patients were ≥ 75 years of age at time of anti-PD-1/PD-L1 therapy initiation (14%), with a median age of 81 years (range: 75-90). Of those 20 patients, 19 received anti-PD1 monotherapy (95%); 1 patient received combination anti-PD-1 with an anti-KIR. 14 of the 20 patients (70%) received therapy in second line or beyond; 6 received anti-PD-1 monotherapy as first line therapy. No significant difference in median survival for 1st line or ≥2nd line group was seen (12.7m vs 15.3m; p = 0.92). A median of 5.5 doses were administered (range 1-24). Reasons for off therapy included: progressive NSCLC (9; 45%), consent withdrawal (1; 5%) and adverse events (6; 30%) with 4 patients who remain on therapy (20%). Conclusions: Anti-PD-1/PD-L1 therapy is now standard of care in NSCLC, a malignancy of the elderly. Translational evaluation of how immune system senescent remodeling affects outcome and toxicity is needed. Further analysis of immunologic and genomic data will be presented and compared to the overall population in our database at the time of presentation.
Whole body PD-L1 PET in patients with NSCLC and melanoma.
Authors: Leung David K. , De Langen Joop , Raunig David , Niemeijer Anna-Larissa N. , Smit Egbert F. , Boellaard Ronald , Vallez-Garcia David , Dongen G.a.M.S. van , Windhorst A.D. , Huisman Marc C. , Glaudemans Andor W. J. M. , Hendrikse N. Harry , Smith Ralph Adam , Poot Alex J. , Lipovsek Dasa , Donnelly David J. , Bonacorsi Samuel J. , Velasquez Linda M. , Du Shuyan , Hayes Wendy 
Published: February 2018

139 Background: PD-(L)1 immunotherapy is effective in multiple tumors, including NSCLC and melanoma, but tumor PD-L1 IHC correlates only moderately with treatment outcome. This study aims to assess 1) safety of 18F-BMS-986192 (18F-PD-L1) in human, 2) PD-L1 quantification in tumors using 18F-PD-L1 PET, 3) PD-L1 PET correlation with IHC and treatment outcome, and 4) intra and inter subject tracer uptake variability. Methods: Pts with NSCLC (N = 10) and melanoma (N = 3) were included. At baseline, pts received a static or multiphase dynamic whole body PET scan after injecting 200 MBq 18F-BMS-986192. For NSCLC pts, (1) SUV(max, peak and mean) were measured for each delineable tumor (N = 32, 1-7 tumors/pt), (2) PD-L1 IHC (28.8 assay) was performed on the biopsy, and (3) response to Nivolumab therapy assessed by RECIST 1.1. Intra and inter subject variability and intraclass correlation were calculated using SUVs of all assessed tumors. Equal variance for PD-L1 status was evaluated by a Levene’s test. Four (3 female) pts underwent dosimetry study (ICRP 60). Results: No AEs related to radiotracer was observed. Dosimetry study demonstrated whole body exposure of 30 mGy at dose > 1400 MBq. Biodistribution among pts is comparable. PD-L1 IHC from 13 biopsied lesions were evaluated, 5 < 1%, 4 ≥1%, and 4 ≥50%. Tumor tracer uptake was measured in NSCLC pts and categorized by PDL-1 IHC as ≥50% or < 50%. Clinical trial information: 2015-004760-11. Tumor SUVs did not correlate with RECIST 1.1 assessment. Lesion heterogeneity was reflected in both inter and intra pt variability (CVinter = 41%, CVintra = 53%, ICC = 0.41 for SUVpeak). Levene’s test showed no significance in variability between the two PD-L1 categories. Conclusions: PET-imaging with 18F-BMS-986192 is safe and feasible in pts with NSCLC and melanoma. Pts with higher PD-L1 PET SUV have higher PD-L1 by IHC. Intra pt variability is similar to inter pt variability. With limited number of pts, no clear correlation of PET PD-L1 and tumor response is observed. A prospective study with this tracer is underway to further investigate 18F-BMS-986192 in understanding of PD-L1 expression.[Table: see text]
A single-arm, phase II study assessing the efficacy of pembrolizumab (pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC).
Authors: McArthur Heather L. , Barker Christopher Andrew , Gucalp Ayca , Lebron-Zapata Lizza , Wen Yong Hannah , Phung Anh , Rodine Micaela , Arnold Brittany , Zhang Zhigang , Ho Alice 
Published: February 2018

14 Background: Overall response rates of 13-19% have been reported with checkpoint inhibitor monotherapy in chemotherapy-resistant, PD-L1-positive mTNBC. RT is frequently used to enhance local control in mTNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. In this study, we evaluate the safety and efficacy of RT combined with a programmed cell death protein 1 (PD-1) inhibitor, pembro, in a single-arm, two-stage, phase II study in mTNBC. Methods: Eligible women had biopsy-proven mTNBC, ECOG performance status 0-2, and ≥2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy was delivered in 5 daily fractions. Pembro 200 mg was given intravenously within 3 days of first RT fraction, then every 3 weeks +/-3 days until disease progression. The primary endpoint was overall response rate at week 13 in the non-irradiated lesions by RECIST v1.1. Secondary endpoints included safety and overall survival. Tumor biopsies were obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Of the 17 women enrolled, the median age was 52 y (range 37-73y). and the median number of prior chemotherapies received for metastatic disease was 3 (range 0 to 8). Of the 8 women not evaluable at 13 weeks: 5 died secondary to disease-related complications (at weeks 2, 6, 7, 8, and 9) and 3 came off study due to disease progression prior to week 13. Of the 9 women evaluable at week 13, 3 (33%) had a partial response, 1 (11%) had stable disease and 5 (56%) had disease progression. The 3 partial responses represented 60%, 54%, and 34% decreases in tumor burden by RECIST v1.1 and were durable for 31, 21, and ongoing at 22 weeks, respectively. The stable disease response was durable for 22 weeks. Common toxicities were mild and included fatigue, myalgia and nausea. Conclusions: The combination of pembro and RT is well-tolerated. This is a poor prognosis population with 5/17 (29%) of patients dying within 12 weeks of study entry. However, durable responses were observed outside of the RT field in 3/9 (33%) patients who were unselected for PD-L1 expression and evaluable at 13 weeks. Clinical trial information: NCT02730130.
Baseline circulating myeloid-derived suppressor cells and response to PD-1 inhibitor in non-small cell lung cancer patients.
Authors: Delaunay Myriam , Guibert Nicolas , Lusque Amellie , Farella Magali , Boubekeur Nadia , Gouin Sandrine , Dormoy Inge , Fons Pierre , Esquerre Michael , Favre Gilles , Pradines Anne , Mazieres Julien 
Published: February 2018

145 Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. Methods: Peripheral blood samples regarding 54NSCLC patients treated with nivolumab and 5 healthy donors were prospectively included. Early-MDSC: e-MDSC (LIN-/CD14-/CD15-/HLA-DR-/CD33+), monocytic-MDSC: M-MDSC (HLA-DR low/-/CD14+/CD15-/CD11b+), polymorphonuclear-MDSC: PMN-MDSC (HLA-DR low/-/CD14-/CD15+/CD11b+) were analyzed through flow cytometry. MDSC percentage was calculated from viable peripheral blood mononuclear cells. We assessed if e-MDSC,M-MDSC and PMN-MDSC levels detected before anti-PD-1 therapy correlate with both progression-free survival (PFS) and overall survival (OS). Results: 54 patients were prospectively included: 41 with adenocarcinoma and 13 with squamous NSCLC. When compared to healthy donors, patients had significantly higher levels of circulating e-MDSC(median (range): 0.13% (0-10.9) vs0.02%(0.01-0.14), p = 0.04) and M-MDSC (median (range): 4.55% (0.08-24.18) vs1.36% (0.77-3.76), p = 0.01). Cox proportional hazard regression analysis showed that high level of M-MDSC before anti-PD-1 therapy was associated with OS (HR [CI95%]: 1.08 [1.01; 1.15],p = 0.02) and PFS (HR [CI95%]: 1.07 [1.01;1.14], p = 0.02). No prognostic impact was observed regarding e-MDSC and PMN-MDSC. Conclusions: Our study suggests that a baseline circulating high level of M-MDSC is associated with poor survival. M-MDSC may be a predictive and prognostic biomarker in NSCLC patients treated with anti-PD1. Further studies have been scheduled, including MDSC monitoring during anti-PD1 treatment, in order to confirm our findings. These data would be interesting for the development of combined therapy, targeting the suppressive environment, with ICI.
Correlation of lung cancer mutational profile with immune profile.
Authors: Papanicolau-Sengos Antonios , Pabla Sarabjot , Dy Grace K. , Ernstoff Marc S. , Puzanov Igor , Conroy Jeffrey M. , Nesline Mary , Glenn Sean T. , Burgher Blake , Andreas Jonathan , Giamo Vincent , Qin Maochun , Lenzo Felicia L. , Gardner Mark , Morrison Carl ,   OmniSeq, Inc.
Published: February 2018

146 Background: The association between neoplasm mutational and immune profiles has not been well-characterized. Methods: We collected 26 lung cancer formalin-fixed paraffin embedded (FFPE) samples which had been tested with a comprehensive mutation profile to detect clinically actionable mutations, and a comprehensive immune gene expression profile, which interrogates PD-L1 immunohistochemistry (IHC), PD-L1/2 copy number, CD3/CD8 IHC, microsatellite instability status, mutational burden, and the expression profile of 54 immune-related genes. The ranking of gene expression and 7 immune phenotypes was compared to a reference population. Six cases were positive for an activating KRAS mutation and 2 cases were positive for an activating EGFR mutation. Principal component analysis was performed to determine the association of EGFR/KRAS mutations with the measured immune landscape. Results: The proinflammatory immune phenotype was significantly correlated with KRAS mutation positive samples (first principal component, R squared = 0.53, p < 0.05). Similarly, CD38 expression was correlated with KRAS mutation (R squared = 0.47, p < 0.05). CD137, KLRD1, and DDX58 expression was significantly correlated with EGFR positive samples (second principal component, R squared = 0.47, 0.37, 0.35 respectively, p < 0.05 in all cases). Unsupervised hierarchical clustering of the samples resulted in three distinct clusters, EGFR positive, KRAS positive, and EGFR negative/KRAS negative. In the KRAS positive cluster, high proinflammatory immune phenotype, VISTA moderate expression, presence of CD3/CD8 tumor infiltrating lymphocytes (TILs), and low KLRD1 were overrepresented (p < 0.05), while low VISTA and proinflammatory moderate immune phenotype were significantly underrepresented (p < 0.05). In the EGFR positive cluster DDX58 high, very low TILs, and very low CD8 were significantly (p < 0.05) overrepresented. Conclusions: KRAS mutation positivity is significantly associated with a proinflammatrory immune phenotype and CD3/CD8 infiltration. KRAS positive, EGFR positive, and KRAS/EGFR negative clusters are immunophenotypically distinct. A higher number of specimens is necessary to verify and expand these findings.
Predictive biomarker of response to anti-PD-1 treatment in non-small cell lung cancer patients.
Authors: Zheng Xuan , Hu Yi , Ma Junxun , Zhang Fan , Sun Danyang , Li Lingling 
Published: February 2018

148 Background: PD-1 inhibitors have shown significant clinical activity in different cancer types. However, responses in pts with NSCLC are variable, and insights are needed to identify a predictive biomarker of response with greater diagnostic accuracy. Here we tested the hypothesis tha tserum TNF-a level is predictive of response to anti-PD-1 treatment. Methods: NSCLC patients treated with nivolumab or pembrolizumab were studied. Pts received nivolumab (3mg/kg, q2w) or pembrolizumab ( 2mg/kg, q3w). Pts on anti-PD1 were classified as either responders (R) deriving clinical benefit (with SD, PR, CR) or non-responders (NR) not deriving clinical benefit (PD) based on RECIST criteria.Serum was collected at baseline; at 2-3 weeks after the first dose (early stage); and at the time of response evaluation. Serum TNF-a levels were determined by Luminex kit. Changes in serum TNF-a levels and their strength of association with response were compared with Non-parametric Analysis. Results: Evaluable plasma samples were collected from twenty-one NSCLC patients treated with nivolumab or pembrolizumab. There was no significant difference in baseline serum TNF-a levels in responders (n = 15) vs non-responders (n = 6). Between baseline and early stage ,serum TNF-a levels significantly increased in responders (P = 0.010), while in non-responders, no significant change was found. High early change rate of serum TNF-a levels ( > 50%) was observed only in responders(n = 7).At early stage, responders had significantly higher serum TNF-a levels than non-responders(P = 0.008). We found no significant difference in serum TNF-a levels at the time of response evaluation. Conclusions: Early changes in serum TNF-a levels and high serum TNF-a levels at early stage in non-small cell lung cancer patients correlate to response to anti-PD-1 treatment.
The prognostic significance of PDL1 expression in locally advanced non-small-cell lung cancer (LA-NSCLC) treated with definitive intent.
Authors: Mitra Devarati , Agarwal Vishesh , Chen Yu-Hui , Baldini Elizabeth H. , Barbie David Allen , Chen Aileen B. , Glass Benjamin , Herman Gretchen , Kozono David E. , Schoenfeld Jonathan Daniel , Mak Raymond H. 
Published: February 2018

150 Background: The PACIFIC trial showed an 11-month (mo) improved median (med) progression-free survival after definitive chemoradiation in LA-NSCLC using the PDL1 inhibitor, durvalumab. This study will likely change practice and puts further emphasis on understanding the significance of immune marker expression in this poor-prognosis disease. Methods: From 1999-2012, pathology specimens from 126 patients (pts) with LA-NSCLC who received combined modality therapy at our institution and had sufficient tissue available were selected for tissue microarrays. Immunohistochemistry for PDL1 (E1L3N), PDL2 (9E5), PD1 (NAT105) and CD3 (F7.2.38) was performed and tumor cells and infiltrating immune cells with moderate or high staining intensity were quantified using Definiens Tissue Studio image analysis software. Univariate and multivariate analyses (MVA) were performed using a Cox proportional hazards model. Results: Distribution by stage was: IIA-3%, IIB-3%, IIIA-65%, IIIB-29%. Sixty-three percent of pts had surgery. All patients received fractionated radiation and chemotherapy with 81% receiving concurrent chemoradiation. Med follow-up from start of therapy was 20 mo (rg 2-168 mo). Median overall survival (OS) was 21 mo (2-yr OS 43%). Median progression-free survival (PFS) was 11 mo (2-yr PFS 26%). Immune marker expression was: PDL1-med 3% (rg 0-58%), PDL2-med 0.03% (rg 0-0.5%), PD1-med 0% (rg 0-76%) and CD3-med 21% (rg 0-78%). PDL2, PD1 and CD3 were not associated with outcomes. However, PDL1 > 8% (chosen as the 75th-percentile) was associated with lower risk of distant metastases (DM) (HR 0.57, 95% CI 0.31-0.98, p = 0.04) and a trend towards longer time to disease progression (HR 0.63, 95% CI 0.37-1.02, p = 0.06). There was no association with local-regional recurrence or OS. On MVA including disease stage, PDL1 > 8% was associated with lower risk of DM (HR 0.59, 95% CI 0.35-0.96, p = 0.03) and overall disease progression (HR 0.53, 95% CI 0.29-0.93), p = 0.02). Conclusions: PDL1 > 8% is associated with lower risk of DM and better PFS in LA-NSCLC. This data suggests that even with traditional cancer therapies, the best outcomes may be seen in patients with higher PDL1 expression.
Identification of HLA-A0201 restricted epitope of novel cancer/testis antigens VCX/Y and generation of antigen-specific T-cell receptor engineered T cells for treatment of solid tumor malignancies.
Authors: Pan Ke , Yee Cassian 
Published: February 2018

160 Background: To identify HLA-A0201 restricted epitope of novel cancer/testis antigen VCX/Y, generate antigen specific T cells and T-cell receptor (TCR) engineered T cells for adoptive cell therapy (ACT) of solid cancer patients. Methods: Reverse-immunology method was used to identify HLA-A0201 restricted epitope of VCX/Y. The high binding score peptide or whole length of VCX3A mRNA were pulsed or transfected to mature dendritic cells (mDC) from HLA-A0201+ donor and then stimulated autologous naïve T cells. Tetramer guided sorting were performed to purify the epitope specific T cells and CTL clones were generated with limiting dilution. TCR were cloned out from high activity CTL clone and the recombinant of retrovirus vector were constructed to introduce the TCR to allogeneic PBMC to generate the TCR engineered T cells. Results: One peptide which its sequence was shared with all VCX/Y members was identified. Interesting, only CTL clone generated from simulation of VCX3A mRNA transfected DC can recognize naturally processed VCX/Y presented by HLA-A0201+ tumor cells. Cold target inhibition detection confirmed that this VCX/Y peptide was naturally processed and recognized by HLA-A0201+ CTL clone. After infection of retrovirus containing the TCR from high activity of CTL clone, the TCR engineered T cells can recognize HLA-A2+ tumor cells but not normal lung cells. Moreover, these TCR engineered T cells specifically secreted IFN-γ in response to T2 cells pulsed with peptide, as well as HLA-A0201+ and VCX/Y overexpressed tumor cells. Conclusions: VCX/Y peptide we identified is a novel candidate peptide antigen for vaccine or for endogenous adoptive T cell therapy. The correlated high activity TCR gene can generate TCR engineered T cells from patients with anti-tumor activity and offer an alternative adoptive T cell treatment for patients with VCX/Y expressing solid tumor malignancies.
Updated overall survival and safety profile of durvalumab monotherapy in advanced NSCLC.
Authors: Hellmann Matthew D. , Antonia Scott Joseph , Balmanoukian Ani Sarkis , Brahmer Julie R. , Ou Sai-Hong Ignatius , Kim Sang-We , Ahn Myung-Ju , Kim Dong-Wan , Gutierrez Martin , Liu Stephen V. , Schoffski Patrick , Jaeger Dirk , Jamal Rahima , Leach Joseph W. , Jerusalem Guy Heinrich Maria , Lutzky Jose , Nemunaitis John J. , Gu Yu , Abdullah Shaad Essa , Segal Neil Howard 
Published: February 2018

169 Background: Single-agent durvalumab is being evaluated in patients with advanced squamous and non-squamous NSCLC in an ongoing Phase 1/2 study (NCT01693562). Here we present updated survival and safety data in NSCLC patients. Methods: Treatment-naïve (1L) and previously treated (2L or 3L+) stage IIIB/IV NSCLC patients received durvalumab 10 mg/kg Q2W for up to 12 months. Patients were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 high: ≥25% of tumor cells with membrane staining]), treatment line, and histology. Results: As of 05 September 2017, 304 NSCLC patients received durvalumab monotherapy. Median duration of follow-up was 35.6 (0.3–50.9) months. Investigator-assessed ORR ranged between 23.2% and 30.0% among PD-L1 high patients, and between 3.6% and 8.3% among PD-L1 low/negative patients. Median PFS and median OS were longer in PD-L1 high vs PD-L1 low/negative patients (Table). Any-grade treatment-related AEs (TRAEs) were reported in 57.2% of pts (including fatigue, 17.4%, decreased appetite, 9.2%, diarrhea, 8.9%); in 10.2% of pts these were Grade 3 or 4. TRAEs resulting in treatment discontinuation were reported in 17 patients (5.6%); 1 patient had a Grade 5 TRAE (pneumonia). Conclusions: In this ongoing phase 1 study, OS and safety profile appear encouraging in treatment-naïve and previously treated NSCLC patients, particularly among PD-L1 high patients. Further investigation regarding PD-L1 expression for selection of patients who most likely benefit from durvalumab is needed. Clinical trial information: NCT01693562. [Table: see text]