tbuckley/cabot-search huggingface dataset:
Blocking LILRB and KIR receptors by B57 open conformers induces potent antitumor activity and acts synergistically with checkpoint blockade inhibition.
Authors: Christoph Renner, Michael A. Curran, Julia Kolibaba, Yang Liu, Ulf Petrausch, Alfred Zippelius, Frank Stenner, Anahita Rafiei, Osiris Marroquin Belaunzaran
Journal: Journal of Clinical Oncology (2019)

e14137 Background: HLA open conformers (OC) are defined as HLA class I molecules lacking beta-2-microglobulin (β2m) and peptide. OC can be derived from different HLA I molecules such as HLA-B27, -B57, and –Cw08. OC have a different three dimensional structure when compared to their respective HLA/β2m/peptide counterpart and induce distinct immunological processes by binding to LILRB and KIR molecules, both key receptors of the innate immune system. B57 OC expression is associated with enhanced immunity against viruses and can cause autoimmunity. Its potential anti-tumor activity has not been exploited so far. Methods: B57 OC and control molecules were expressed as IgG4 fusion proteins in CHO cells. The affinity for protein-ligand interaction was measured by surface plasmon resonance (SPR). Human macrophages M1/M2, phagocytosis and NK cytotoxicity were assessed by flow cytometry and cellular assays. Syngeneic pancreatic cancer (Pan02) or colon cancer (MC38) mouse models were used. Mice with tumors of 80mm 3 were treated twice weekly at 5 mg/kg. Tumor and blood samples were analysed. FDA cancer panels were assessed by IHC for LILRB1-5 expression. Results: B57 OC displays distinct protein-ligand interactions with high affinity binding to LILRB2 &amp; 4, KIR2L1-3, and KIR3DL1. Therapeutic efficacy in pancreatic and colon cancer models was observed with monotherapy (p &lt; 0.01), and combo therapy using PD1 and/or 41BB antibodies (p &lt; 0.0001). Ex vivotumor sample analysis revealed a significant reduction of MDSC &amp; Tregs, and an increase of M1 type macrophages. In addition, loss of MDSC functionality and enhanced CD8+ T cell expansion was noticed. IHC of human tissue demonstrated enhanced LILRB2 expression, notably in colon and lung cancer. Conclusions: B57 OC has a unique binding profile to LILRB and KIR receptors. B57 OC induces anti-tumor activity in diverse syngeneic mouse models and acts synergistically with PD1 or 41BB antibodies. Pre-clinical and human in vitroexperiments demonstrate that B57 OC mode of action is established with inhibition of MDSCs, macrophage polarization to M1 phenotype, activation of NK cells and LILRB blockade on tumor cells, which in turn support the adaptive immune system by increasing CD8+ effector T cells and reducing Treg numbers. B57 OC is a first-in-class therapeutic with robust anti-tumor activity.
Impact of tobacco smoking on radiotherapy outcomes in 1875 HPV-positive oropharynx cancer patients.
Authors: Pernille Lassen, Shao Hui Huang, Jie Su, Brian O'Sullivan, John Waldron, Maria Andersen, Hanne Primdahl, Jorgen Johansen, Claus Kristensen, Elo Andersen, Jan Alsner, Jacob Lilja-Fisher, Scott Victor Bratman, Anna Spreafico, John R. de Almeida, Wei Xu, Jens Overgaard
Journal: Journal of Clinical Oncology (2019)

6047 Background: This study investigates the impact of smoking on radiotherapy (RT) outcome and survival in a population based cohort of HPV+ oropharynx cancer (OPC). Methods: We identified all OPC with positive p16 staining from 2007 –2015 who received curative IMRT according to approved guidelines in two oncology groups. Associations between smoking and locoregional control (LRC) and distant control (DC) were estimated by competing risk regression. Disease free survival (DFS) and overall survival (OS) were estimated by proportional-hazards regression model. Multivariable analyses (MVA) adjusted for age, gender, performance status (PS), T- and N-category, and treatment regimen. Results: A total of 1875 patients were included. Median age was 59.2 [31.3-86.8]; 79% (1481) were males; 96% (1651) had PS &lt;2; 71% (1337) received concurrent chemo-radiotherapy (CRT) +/- hypoxic modification (Nimorazole); and 538 (29%) received RT alone +/- Nimorazole. 23% (425) were current smokers (at time of diagnosis) and 46% (853) were ex-smokers. Median smoking pack-years (PY) was 20.1 in the total cohort, and higher in current smokers vs ex-smokers (38 vs 20 PY, p&lt;0.001). 63% of current smokers had &gt;30 PYs. Median follow-up was 4.8 years. Actuarial 5-year univariate analysis showed that current smokers had a reduced probability of LRC (85% vs 92%, p=0.002), DC (88% vs 92%, p=0.046), DFS (69% vs 84%, p&lt;0.001), and OS (73% vs 88%, p=&lt;0.001) compared to never-smokers (n=567). Outcomes for ex-smokers and never-smokers were similar. In MVA current smoking retained strong independent significance for LRC (HR 1.73 [1.18-2.53]), DFS (1.79 [1.35-2.36]) and OS (2.06 [1.49-2.84]). However, DC was not significantly influenced by current smoking status (1.27 [0.83-1.95]). Similar observations were found for &gt;30PY. Conclusions: Heavy lifetime and current smoking negatively impacts LRC and survival in HPV+ OPC. While smoking mediated hypoxia could interfere with RT efficacy, a putative impact on tumor biology remains uncertain in the absence of a detriment to distant metastasis risk. The findings support encouraging smoking cessation to improve therapeutic efficacy of RT and to avoid excess smoking related mortality.
WNT activating pathway mutations confer resistance to first-line antiandrogen therapy in castration-resistant prostate cancer (CRPC).
Authors: Pedro Isaacsson Velho, Nooshin Mirkheshti, Fahad Qazi, Farah Shaukat, Wei Fu, Hao Wang, Michael Anthony Carducci, Mark Christopher Markowski, Samuel R. Denmeade, Catherine Handy Marshall, Tamara L. Lotan, Mario A. Eisenberger, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2019)

5068 Background: Wnt signaling is a cellular pathway responsible for embryogenesis and neoplasm. When activated, in about 10-20% of mCRPC, the WNT signaling pathway may cause androgen-independent growth and consequently antiandrogen resistance. To further characterize the clinical features and biology of this subtype of mCRPC, we studied mutations in genes of this pathway, including APC, CTNNB1, RNF43, ZNRF3 and RSPO2, in patients who received treatment at Johns Hopkins Hospital (JHH). Methods: Patients with CRPC who received first-line antiandrogen (abiraterone or enzalutamide) therapy for CRPC at JHH were retrospectively studied. Pathological staging, extension of primary disease, tumor somatic genomic data by Next Generation Sequencing (NGS) were correlated with clinical outcomes such as time to PSA progression, PSA response and overall survival (OS). Cox regression was used to test associations between variables and clinical outcomes and Kaplan-Meier method was used for time-to-event data. Results: Of 137 pts who received first-line antiandrogen therapy for CRPC, 10.9% (15 pts) had NGS with at least one activating WNT pathway alteration, including mutations in APC (6 pts), CTNNB1 (8 pts) and RNF43 (3 pts). Patients with WNT mutations had fewer T3/T4 tumors (30.8% vs. 51.4%, p = 0.24), but were balanced in other aspects. The median time to PSA progression in WNT activated patients was 6.5 months vs. 9.6 months in WNT negative patients (HR 2.3, 95% CI 1.3 - 4.1, p = 0.003). The presence of WNT mutations (HR 2.3, 95% CI 1.2 - 4.3, p = 0.007) and previous chemotherapy (HR 1.8, 95% CI 1.2 – 2.7, p = 0.003) were independently associated with shorter time to PSA progression. PSA50 response was numerically worse in WNT activated patients (53% vs 75%, p = 0.12). The OS in patients with WNT mutations was 23.6 months vs 27.7 months in patients without WNT mutations (HR 2.2, 95% CI 1.1 - 4.5, p = 0.01). Conclusions: Patients with WNT pathway mutations may have worse outcomes to first-line abi/enza compared to patients without these aberrations. Time to PSA progression and OS were inferior in WNT activated population. Our data reinforce the necessity to develop effective WNT pathway inhibitors to test in clinical trials for WNT activated patients.
Gut microbiota and clinical outcomes treated with nivolumab in Chinese non-small cell lung cancer.
Authors: Shun Lu, Yueping Jing, Liliang Xia, Ziming Li, Chengcheng Yao, Ying Wang
Journal: Journal of Clinical Oncology (2019)

2614 Background: Gut microbiome affecting responses to immune checkpoint inhibitors (ICIs) against non-small cell lung cancer (NSCLC) has been investigated in western population. However, considering genetic variation, this phenomenon remains in vague in east-Asian NSCLC population. The study is designed to explore the relationships between gut microbiome and clinical outcomes treated with anti-PD-1 blockade in Chinese patients. Methods: 37 NSCLC patients received the treatment of Nivolumab were enrolled in the study from the clinical trials CheckMate870 (NCT03195491). Fecal samples were collected at the starting point, every time point performing clinical evaluation and that with disease progression. 16s sequencing was applied to assess the gut microbiota characteristics. Peripheral immune profiles were determined by multi-color flow cytometry in parallel. Results: When subgrouping patients into responders (R) and non-responders (NR) groups according to the clinical response assessed by RECIST1.1, patients in R group harbored higher diversity of gut microbiome at the starting point with consistent composition along the treatment. Analyzing progression-free survival (PFS) according to RECIST 1.1, patients with higher microbiome diversity had significantly prolonged PFS when compared to those with low diversity. Compositional difference was observed between two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium logum, Prevotella corpri in R group whereas Ruminococcus_unclassified in NR group. Analysis of systemic immune responses using multi-color flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had more frequencies of memory CD8+ T cell subset in the periphery in response to anti-PD-1 therapy. Conclusions: Our results report the strong correlation between the gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese NSCLC patients regardless of genetic variation between Western and Chinese population. Patients with a favorable gut microbiome (such as high diversity) have enhanced immune responses mediated by effector T cell function in the periphery. These findings thus provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC.
Feasibility and toxicity of neoadjuvant nivolumab with or without ipilimumab prior to extensive (salvage) surgery in patients with advanced head and neck cancer (the IMCISION trial, NCT03003637).
Authors: Charlotte L. Zuur, Joris B. W. Elbers, Joris L. Vos, Anne van der Leun, Xiaohang Qiao, Baris Karakullukcu, Michiel W. M. van den Brekel, Bing Tan, Bas Jasperse, Wouter V. Vogel, Laura Smit, Stefan M. Willems, Harm van Tinteren, Abrahim Al-Mamgani, Jasper Nijkamp, Ton N. Schumacher, Christian U. Blank, J. P. De Boer, John B. A. G. Haanen
Journal: Journal of Clinical Oncology (2019)

2575 Background: surgery w/wo adjuvant radiotherapy (RT) for (recurrent) advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% 5-year OS, indicating the need for novel treatment options. In recurrent metastatic HNSCC nivolumab nearly tripled the 2-year OS. Aiming at improving clinical outcome in advanced HNSCC in a curative setting, we tested the feasibility of nivolumab ± ipilimumab neoadjuvant to (salvage) surgery w/wo RT. Methods: investigator-initiated phase-IB/II trial to assess feasibility of neoadjuvant nivolumab monotherapy (240 mg in week 1&amp;3: arm-A) or in combination with ipilimumab (1 mg/kg in week 1: arm-B) before surgery (≤ week 5) w/wo RT for advanced HNSCC. Results: 12 patients were included (3+3 design, both arms) in phase-IB of this study; 7/12 (58%) patients had pre-existent moderate-to-severe comorbidities (ACE-27). All patients were HPV negative. All patients received surgery as planned (25-33 days after start of immunotherapy) with no unexpected wound healing problems. In both groups, 4 patients (67%) experienced immune-related toxicity: grade 1-2 (n = 4) and grade 3-4 (n = 1; colitis) in arm-A; grade 1-2 (n = 5) and grade 3-4 (n = 2; colitis and elevated liver enzymes) in arm B. Immune-related toxicity was managed with prednisone (n = 2) and infliximab (n = 1). There was 1/6 (12.5%) pathological response in arm-A (1 near complete response, nCR) and 3/6 (50%) in arm-B (1x partial response and 2x nCR). No patients with nCR had a recurrence at follow-up (median 10 months). Preliminary data (mutational load will be added) show increased H7-B3 gene expression in non-responders before treatment, and increased endothelial cell and NK cell gene expression in responders post-treatment. Overall, in these 12 patients, neoadjuvant ipilimumab + nivolumab resulted in a significant increase in immune-related gene expression when compared to nivolumab only, irrespective of treatment response. Conclusions: neoadjuvant ipilimumab + nivolumab can safely be administered prior to major surgery for advanced HNSCC. Efficacy is promising and will be further evaluated in the phase-II trial continuation. Clinical trial information: NCT03003637.
Immunotherapy with checkpoint inhibitors in mismatch repair deficient (dMMR) cancers: Looking for a needle in a haystack— But, joy on finding one.
Authors: Amit Rauthan, Poonam Patil, Tanvi Sood, Shriniwas Subhash Kulkarni, Nitin Yashas, Gaurav Nigade, S.P. Somashekhar, Shabber Zaveri
Journal: Journal of Clinical Oncology (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.
Phase I study of procaspase activating compound -1 (PAC-1) in combination with temozolomide (TMZ) for the treatment of recurrent malignant glioma.
Authors: Martin Kelly Nicholas, Matthias Holdhoff, Richard A. Peterson, Oana Cristina Danciu, Theodore M. Tarasow, Paul J. Hergenrother, Arkadiusz Z. Dudek
Journal: Journal of Clinical Oncology (2019)

TPS3164 Background: The caspase family of cysteine proteases play key roles in the initiation and execution of apoptosis. The activation of procaspase-3 to caspase-3 is critical in both the intrinsic and extrinsic apoptotic cascades. Procaspase-3 levels are elevated in many cancers, including glioblastoma (GBM). As a result, caspase-3 levels are abnormally low in these tumors; thus they avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 has activity against a wide range of cancer cell lines, and in animal models of cancer. PAC-1 crosses the blood brain barrier and has been shown to synergize with TMZ in both canine malignant glioma and meningioma that arise spontaneously. Methods: This Phase I dose escalation study uses a modified- Fibonacci 3+3 design to determine the MTD of PAC-1 when combined with TMZ in patients with recurrent malignant gliomas: anaplastic astrocytoma (AA) and GBM (open to enrollment). Here, we focus on component 2 of the study. Primary objectives: to establish MTD of PAC-1 when combined with a fixed dose of TMZ, tolerability, and toxicity using CTCAE v.4. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary anti-tumor activity correlation with procaspase-3 expression in tumor tissue, radiographic response using the Response Assessment in Neuro-Oncology (RANO) criteria, and neurocognitive function using a validated test battery. Inclusion criteria: diagnosis of recurrent high grade glioma (AA or GBM), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design, Component 2: PAC-1, orally administered, is dosed at 375-650 mg daily (up to 3 dose levels) on days 1-21 of each 28-day cycle. A fixed dose of TMZ, (150 mg/m2), is administered orally, days 8 -12 of each cycle. The study is currently enrolling patients for Component 2. Clinical trial information: NCT02355535.
Radiomic profiles via machine learning to predict response, overall survival, and KRAS status in metastatic colorectal tumors treated with FOLFOX/bevacizumab/hydroxychloroquine.
Authors: Saima Rathore, Mark H. O'Hara, Thomas Benjamin Karasic, Maryann Redlinger, Mark Alan Rosen, Christos Davatzikos, Peter O'Dwyer
Journal: Journal of Clinical Oncology (2019)

e15125 Background: Autophagy is a resistance mechanism to chemotherapy that is inhibited by hydroxychloroquine (HCQ). We have reported a phase II trial of FOLFOX/bevacizumab/HCQ in 28 evaluable patients with untreated metastatic colorectal cancer (mCRC). Overall response rate was 68%, with 11% complete response (CR) and 57% partial response (PR), while stable disease (SD) was seen in 30%. We hypothesize that analysis of CT imaging features via machine learning (ML) will enhance subtle yet important radiographic characteristics, and reveal imaging signatures determinant of outcome and mutational status. Methods: Baseline CT images were collected and 1265 quantitative imaging (QI) features extracted across all the metastatic sites – liver, lung, and lymph nodes – including descriptors of size, morphology, texture, and intensity. Cross-validated sequential feature selection coupled with support vector machine (SVM) was used to determine the most discriminative QI features for our integrative predictor of response and mutational status, and support vector regression (SVR) was used to derive imaging predictors of overall survival. The model predictions were compared with actual clinical results, including response, survival, and genomic aberrations. Results: Various QI features, primarily descriptive of texture and tumor volume, were determined as most important by the ML predictor. Using this signature, our predictor classified “Responder (PR+CR) vs Non-responder (SD)” with an accuracy of 85% [sensitivity(se) = 0.84, specificity(sp) = 0.71, AUC = 0.85]. The QI features were also able to detect KRAS and TP53 mutational status with an accuracy of 88% [se = 0.92, sp = 0.85, AUC = 0.87] and 86% [se = 0.80, sp = 0.90, AUC = 0.84], respectively. The SVM model predicted overall survival greater than the median (32 mo) with an accuracy of 86% [se = 0.93, sp = 0.79, AUC = 0.87]. The Pearson correlation coefficient between the SVR score and overall survival was estimated to be 0.73 (p &lt; 0.0001). Conclusions: Radiomic analysis of baseline CT imaging features analyzed by ML yielded an imaging signature predictive of response, survival, and KRAS and TP53 mutational status. If validated in a larger clinical data set, machine learning may offer a predictive biomarker to aid clinical decision making for mCRC patients.
Targeting serum response factor as a novel therapeutic approach for triple-negative breast cancer.
Authors: Maria Prencipe, Claudia Aura Gonzalez, Niamh Russell, William M. Gallagher, John Crown
Journal: Journal of Clinical Oncology (2019)

e12560 Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) which lacks estrogen receptor, progesterone receptor and HER2 amplification. Due to the fact that up to 50% of TNBC express AR and that AR expression has been associated with poor prognosis, targeting AR in TNBC is attracting increasing interest. However, although targeting AR in prostate cancer results in initial response, resistance eventually develops, resulting in treatment failure. We previously identified Serum Response Factor (SRF) as an important transcription factor in a cellular model of castrate-resistant prostate cancer. We showed a relationship between SRF and AR which potentially plays a role in the resistance to AR-targeted therapy. Therefore, we hypothesise that AR resistance mechanisms could be bypassed by targeting SRF, singly or in combination with AR-inhibitors. Methods: In this study three TNBC cell lines with different SRF/ AR levels were selected to investigate the effect of SRF inhibition on cell viability, cell migration and cell invasion. Immunohistochemistry was used to assess SRF expression in 3 BC TMAs: TMA1 (n = 144) and TMA2 (n = 512) with different subtypes of BC and TMA3 with 138 TNBC patients. Results: MTT assays showed response to CCG1423 in the two cell lines positive for SRF (MDA-MB-231 and HS578t) with IC50 values of 20 uM, while MDA-MB-453 (SRF negative) did not respond (IC50 &gt; 80uM). In addition, a synergistic effect on cell viability was demonstrated when CCG1423 was used in combination with MDV3100. Scratch assays to assess cell migration showed a slower gap-closure post- CCG1423 treatment compared to controls. In addition, CCG1423 treatment significantly reduced both cell lines’ ability to invade by approximately 50% at 48 hours post-treatment (p &lt; 0.05). Analysis of SRF expression in clinical samples showed higher SRF protein expression in TNBC vs. non-TNBC patients. In addition, one TMA (n = 144) showed that higher SRF expression was associated with shorter overall survival (HR 1.99 [CI (1.02, 3.87)], P value 0.039) and shorter disease specific survival (HR 2.93 [CI (1.19, 7.21)], P value 0.014). Conclusions: Our data support the rationale for using SRF as an alternative target to AR, alone or in combination with AR-antagonists.