bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI).
Authors: Thapa Bicky , Roopkumar Joanna , Kim Ann S , Gervaso Lorenzo , Patil Pradnya Dinkar , Calabrese Cassandra , Khorana Alok A. , Funchain Pauline 
Published: May 2019

e14151 Background: ICIs have revolutionized outcomes in many advanced malignancies, however their use is associated with irAEs. Methods: An IRB-approved, retrospective chart review was done using the Cleveland Clinic pharmacy database. Patients were included who received six FDA approved (nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, or durvalumab) ICIs from July 2015 to December 2017. irAEs were identified from review of electronic medical records. Descriptive analysis was done to evaluate the incidence, pattern, and severity of irAEs. Results: A total of 1091 patients received ICI therapy, 651 (59.7%) were male, 958 (87.4%) white, 95 (8.7%) black. Lung cancer (540, 49.5%) comprised the majority of the cohort, followed by melanoma (152, 13.9%), and renal cell carcinoma (121, 11.1%). About 996 (91.3%) received treatment with only one ICI, 85 (7.8%) with 2 ICIs, and only 10 patients received 3 ICIs. A total of 487 (44.63%) patients encountered irAEs, 128 (11.73%) resulting in treatment cessation. Fatigue (152, 13.9%) was the most common, followed by dermatologic irAEs (131, 12%). Endocrine irAEs occurred in 108 (9.89%), GI toxicities, namely diarrhea and colitis, were seen in 92 (8.4%) and hepatotoxicity in 54 (4.94%). Other irAEs including rheumatologic, pneumonitis, renal, and neurological adverse effects were documented in 6.5%, 5.1%, 2.56%, and 2.01% respectively. Rare irAEs such as ocular toxicity, cardiac toxicity, and vasculitis were seen in 0.8%, 0.73%, and 0.54%, respectively. Compared with a pooled analysis from clinical trials (De Velasco G et al. Comprehensive Meta-analysis of Key irAEs from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients) dermatologic irAEs and fatigue were less frequent; diarrhea/colitis, pneumonitis and rheumatologic irAEs were more frequent. Conclusions: irAEs on ICI therapy are very common. Awareness of the relative frequencies of various irAEs, particularly severe and rare irAEs, in a real-world setting can help improve quality of care for cancer patients receiving ICI. [Table: see text]
Phase Ib study of pembrolizumab and trebananib (angiopoietin-2 inhibitor [Ang-2]): Preliminary analysis of the colorectal cancer (CRC) cohort.
Authors: Rahma Osama E. , Cleary James M. , Schlechter Benjamin L. , Ng Kimmie , Eno Jessica , Stroiney Amanda , Giobbie-Hurder Anita , McDermott David F. , Hodi F. Stephen 
Published: May 2019

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.
Characterization of a patient-specific T-cell and tumor cell coculture model of immuno-cytotoxicity in colorectal cancer.
Authors: Li Yanhui , Gunn Nicole Ann , Kua Lindsay , Lee Fiona Yi Xin , Koo Si-Lin , Chua Clarinda Wei Ling , Tan Emile , Toh Ee-Lin , Mathew Ronnie , Lee Ser Yee , Tan Wah Siew , Dasgupta Ramanuj , Tan Iain B. 
Published: May 2019

e14178 Background: Colorectal Cancer (CRC) is the third most commonly diagnosed cancer in the world. Yet, CRC has been difficult to treat with immunotherapy, as majority (85%) of CRC are Microsatellite stable (MSS), lowly immunogenic and do not respond well. To investigate immuno-cytotoxicity in MSS cancers, we set up an ex vivo co-culture model using patient-derived tumor epithelial cells and autologous tumor-infiltrating lymphocytes (TILs). Aims: To perform phenotypic and functional characterisation of the model, and show we are able to modulate immuno-cytotoxicity. Methods: Fresh tumor, adjacent normal and/or liver metastasis samples were collected and freshly dissociated from 29 colorectal cancer patients undergoing surgery. TILs and tumor epithelial cells were grown in culture. Weekly immunophenotyping of TILs was performed via flow cytometry and data was analysed to identify temporal changes in proportions of cell types. To modulate cytotoxicity, epithelial cell lines were co-cultured with autologous and allogeneic TILs at various effector:target ratios with and without anti-PD1 (Pembrolizumab). Caspase dye was used to detect apoptosis and measure cell death. Results: TILs from most patients were successfully expanded, with a theoretical potential of up to 10,000 times. CD4+ T cells were selectively expanded, while CD8+ T cells decreased in proportion over time. A select group of patients showed an opposite trend. Cell type proportions in metastases mirrored those of the primary tumour while NK cells expanded more in tumour samples than normal samples. Selection proceeded up to 3 weeks then decreased. In the cytotoxicity experiment, we show that cell death is increased at higher effector:target ratios in the presence of autologous TILs. Addition of Pembrolizumab further modulates cytotoxicity in vitro. Conclusions: We have developed and characterised an autologous T cell and epithelial cell co-culture system to evaluate immuno-cytotoxicity in colorectal cancer. This will allow screening of perturbations for improved immuno-cytotoxicity in colorectal cancer.
Prognostic significance of NLR kinetics in operable triple negative breast cancer.
Authors: Ganta Ranga Raman , Nasaka Srividya 
Published: May 2019

e14201 Background: Inflammatory response exacerbates mechanisms linked to tumor growth and dissemination. As an index of systemic inflammatory marker, neutrophil lymphocyte ratio (NLR) may be a predictive biomarker of both prognosis and outcome in several malignancies. However very few reports have addressed the association of change in NLR and outcome in operable breast cancer. We evaluated preoperative NLR and postoperative NLR to assess which one would be predictive of disease outcome in triple negative breast cancer patients. Methods: This study included 67 stage I-III triple negative breast cancer patients diagnosed at HCG Cancer center, between 2013 to 2015. Those patients who underwent upfront surgery were included in the study. Patients who received neoadjuvant chemotherapy and those without adequate medical records were excluded. The NLR was calculated from the differential count by dividing neutrophil percentage with lymphocyte percentage. All preoperative NLRs were calculated from medical records, at the first visit. Postoperative NLR was obtained before first cycle chemotherapy. The NLR was divided into high if ratio is > 3 and low if it is ≤ 3. We evaluated prognostic value of NLR on 3 year DFS. Results: The median preoperative NLR was 2.52 (Range 0.77-8.6). The pre op NLR was high in 19 patients (28%) and low in 48 patients (72%). There was no significant difference between two groups in baseline characteristics. Among the preoperative High and low NLR groups, 3 year DFS is statistically significant. The median postoperative NLR was 2.23 (Range 0.89-8.1). The post operative NLR was high in 7 patients (11%) and low in 60 patients (89%). Among the postoperative High and low NLR groups, 3 year DFS is statistically not significant. The 12 (63%) patients in the high preoperative NLR patients were converted to of the low NLR after surgery. Conclusions: Preoperative NLR correlated with outcome in operable triple negative breast cancer than postoperative NLR. The NLR kinetics might be an index of response to the treatment which needs to be evaluated in prospective studies. Drawbacks of the study: single centre, retrospective study and small sample size.[Table: see text][Table: see text]
Identification of immune microenvironment subtypes of breast cancer in TCGA set: Implications for immunotherapy.
Authors: Liu Chang , Xiao Yi , Tao Zhonghua , Hu Xi-Chun 
Published: May 2019

e14205 Background: Checkpoint blockade immunotherapy has been reported to show promising responses in breast cancer. However, only a small quantity of patients benefited from immunotherapy. To understand the underlying molecular mechanisms of immunotherapy and distinguish appropriate patients, we profiled the immune microenvironment landscape of breast cancer. Methods: We analyzed 1092 breast cancer samples from the Cancer Genome Atlas (TCGA) profiled by RNA sequencing. Using 141 immune-related genes, the cohort was divided into 2 subtypes (Immune and non-Immune) by k-means cluster analysis. Immune-related gene signatures representing different immune statuses or immune cells were used to profile Immune Class by k-means cluster analysis, and we further classified them into Active and Exhausted Immune Classes. Results: We identified 40% of breast cancer in TCGA set (433/1092) as Immune Class and further classified them into 2 distinct subtypes, Active and Exhausted Immune Classes (17% and 23%, respectively). Compared with non-Active Immune Class, Active Immune Class was associated with black people and negative hormone receptor (all, P < 0.01). We detected higher proportions of basal-like and HER2-enriched cases within Active Immune Class compared to Exhausted and non-Immune Class (basal-like, 41.0% vs. 11.3% and 12.6%; HER2-enriched, 14.1% vs. 7.1% and 6.5%). In survival analyses, Active Immune Class was significantly correlated with favorable disease-free survival ( P = 0.019) and overall survival ( P = 0.041). Multivariate analyses further identified Active Immune Class as an independent prognostic factor for overall survival ( P = 0.024). Conclusions: Our work classified breast cancer into 3 immune microenvironment subtypes. This novel classification can indicate the prognosis of patients, reveal the underlying immunological mechanisms of tumor progression and may assist immunotherapy decision-making for breast cancer patient. [Table: see text]
Immunotherapy clinical trials suggest predictive immune-related biomarkers are tissue specific.
Authors: Jones Wendell , Ganapathi Ram N. , Ganapathi Mahrukh K 
Published: May 2019

e14206 Background: RNA-based immune landscape signatures (RILS) portray the breadth of immune and stromal cell activity in the tumor microenvironment (TME). Their predictive and prognostic capability for patients with solid tumors and treated with various therapies has been reported. Methods: Single and multi-variable survival analysis, multi-variable linear models, publicly available data on clinical trials NCT00796445, NCT01621490, NCT02108652. Results: Using publicly available data, RILS were compared to each other and to tumor mutational burden (TMB) to determine their relative ability to identify responders/non-responders and estimate patient survival in a series of immunotherapy clinical trials. These immunotherapy trials include patients treated with a PD1 inhibitor, PD-L1 inhibitor or MAGE-A3 tumor antigen combined with immunostimulant (MAGE-A3). Although no single RILS/TMB biomarker emerged as a clear indicator of immunotherapy response and survival for all cases, there were certain immune-related signatures that recurred as significant (p < .05) or had near-significance (p < .10) related to a specific cancer or therapy. Immune signatures for T cell trafficking, ratios of PD1 to PD-L1 expression, cytotoxic lymphocytes and B cells were consistently predictive and prognostic in melanoma patients treated with the PD1 inhibitor, nivolumab or MAGE-A3. However, while these same signatures were not predictive/prognostic in bladder and kidney/ureter cancer patients treated with the PD-L1 inhibitor, atezolizumab, biomarkers significantly associated with outcome included TMB, TGFB1, and the ratio of T cell trafficking to M2 tumor associated macrophage activity. Since TMB and various immune signatures generally worked better together than individually in predicting outcome, there is potential for utilization of a combination of biomarkers and immune signatures in the design of effective immunotherapy clinical trials. Conclusions: In summary, our results suggest effective immunotherapy trials may require tissue-specific biomarker development. Further, a combination of immune signatures and biomarkers such as TMB shows markedly increased utility compared to single factor such as TMB, PD-1 or PD-L1 expression alone.
Novel monoclonal antibody therapeutics for metastatic castration resistant prostate cancer.
Authors: Ghosh Maloy , Rodrigues Kavitha Iyer , Maity Sunit , Bhattacharjee Sanghamitra , Manjunath Yogendra , Chakrabarty Subhra Prakash , Dubey Ashvini Kumar , Tiwari Anurag , Murugesan Sathyabalan , Halan Vivek 
Published: May 2019

e14222 Background: Therapeutic potential of innate immunity comprising Natural killer cell based targets are beginning to unravel the complexity of immune responses. NK cells recognize and induce cytotoxicity of wide range of target cells, such as, tumor cells without prior antigen sensitization. In this study, we have studied Lectin-like transcript 1 (LLT1), a member of the C-type lectin super family, is expressed on target cells and various immune cells. LLT1 isoform 1, is known to interact with CD161, a critical receptor on NK cells. CD161 is expressed on most of human NK cells, NK-T cells, γδ T cells and so on. Tumors exploit the CD161- LLT1 interaction to evade host defense mechanism (“DO NOT KILL” signal); indicating LLT1 as an attractive immunotherapeutic strategy. Methods: Prostate cancer cell lines and other tumor cell lines were used to evaluate novel anti LLT1 antibodies for therapeutic potential - IFNγ production assays and tumor cell death assays were carried out. In vivo efficacy of these antibodies were established using PC3 xenograft in humanized mouse model (HuNOG-EXL). Results: Human androgen independent prostate cancer cell line, PC3 was studied for LLT1 expression and interactions with immune cells, to understand role of LLT1 in metastatic castration resistant prostate cancer (mCRPC). Overexpression of LLT1 on tumor cells was influenced by cytokines and various TLRs. Inhibition of CD161-LLT1 interaction with novel anti LLT1 antibodies leads to IFNγ production and consequent NK cell mediated cytotoxicity – hall mark of anti-tumor responses. Disruption of LLT1 - CD161 innate immunity axis with anti LLT1 antibody releases the break on NK cell cytotoxicity and hence, established a new therapeutic option. PC3 xenograft on HuNOG mouse revealed in vivo efficacy of LLT1 antibody. Significant tumor growth reduction was observed with specific anti LLT1 antibodies alone and in combination with check point antibodies. Thus, synergistic tumor growth reduction was established by combinatorial application of anti LLT1 antibody and PD1/PDL1 axis inhibitors. Conclusions: PC3 xenograft study and other results point to therapeutic opportunities in metastatic castration resistant prostate cancer, a disease condition which needs improved patient outcomes. The ligation of CD161/LLT1 will serve as a new immuno-oncology pair regulating innate and adaptive immune responses; novel human antibodies against LLT1 described here will bring therapeutic benefit to patients in need.
An innovative combined immunization platform for personalized cancer immunotherapy.
Authors: Matta Jessica , Matta Célia , Thiebault Peter Emilie , Moulaert David , Drillien Robert , Petit-Demouliere Benoit , Sorg Tania , Bou about Ghina , Limacher Jean-Marc 
Published: May 2019

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.
Occupational health risk of pressurized intra-peritoneal aerosol chemotherapy (PIPAC) via endoscopical microcatheter system.
Authors: Khosrawipour Tanja , Pigazzi Alessio , Chaudhry Haris , Mikolajczyk Agata , Schubert Justyna , Khosrawipour Veria 
Published: May 2019

e14231 Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is becoming an increasingly widespread approach for delivering intra-peritoneal chemotherapy (IPC) by means of a chemoaerosol. In current studies, a flexible and easy-to-handle endoscopic microcatheter (MC) approach has been introduced to replace the conventional micropump used in PIPAC. While this new method has many advantages such as wide availability, cost effectiveness and improved drug distribution, its possible occupational health risks remain unknown. Methods: PIPAC was performed on three post mortem swine using the MC device. According to standard protocol in patients, solutions of doxorubicin and oxaliplatin were aerosolized in a standardized procedure room with laminar flow. Multiple probes of all surgical material including instruments and sutures, surrounding area surfaces and the operating personals’ items such as gloves and gowns were collected. Moreover, the air filter of the operating room was examined for doxorubicin and oxaliplatin concentrations. Results: The majority of probes showed no measurable doxorubicin or oxaliplatin concentrations. No exposure was detected on the operating personals’ gowns as well as the surrounding area surfaces. While a few of the surgical materials as well as the personals’ gloves and the main part of the application system showed low drug exposure, no drug exposure was measurable in the room filter. Conclusions: Our ex-vivo data suggest that PIPAC delivered via MC is safe and does not exhibit any major occupational hazards if the safety protocol is followed. MC offers an improved, easy-to-handle and cost-effective alternative to the micropump used in conventional PIPAC. Furthermore, the MC offers the great advantage of flexibility which allows access even in anatomically difficult situations and reduces the surgical point of entry to only one abdominal trocar placement.
Targeting KDM1A with iadademstat in combination with immunotherapy in an in vivo model of melanoma.
Authors: Maes Tamara , Mascaró Cristina , Sacilotto Natalia , Lufino Michele MP , Ciceri Filippo 
Published: May 2019

e14248 Background: By recruiting the immune system against cancer cells, immunotherapy holds promise to achieve long-lasting responses in several malignant conditions. However, a therapeutic response is observed only in a subset of patients. The low mutational burden of “cold” tumors enables them to stay undetected from the host inflammatory response (innate resistance). Also, cancer cells develop a number of coping strategies in response to the selective pressure applied by the treatment with checkpoint inhibitors (recruitment of regulatory cells, defective antigen presentation, immunosuppressant mediators, reduced costimulation, and T cell apoptosis). Hence combinatorial treatments are being considered to tackle the problem of resistances and responsiveness. Iadademstat (ORY-1001) is a selective, orally-available KDM1A inhibitor with low nanomolar potency (Maes et al., 2018). KDM1A is a histone demethylase involved in transcription regulation and key to tumorigenicity in different hematological and solid malignancies. The tolerability and safety of iadademstat has been evaluated in Phase I studies in AML and SCLC and the drug is currently being investigated in combination with SoC in phase II clinical trials in AML and in SCLC. Methods: The combined efficacy of iadademstat administered orally at 10 µg/kg, a dose that does not provoke weight loss or thrombocytopenia, and an anti-Pd1 antibody was evaluated in the mice syngeneic B16F10 melanoma model. Results: Treatment with iadademstat and the checkpoint inhibitor anti-Pd1 monoclonal antibody was well tolerated. By Day 15, treatment with the anti-Pd1 antibody alone or in combo with iadademstat reduced tumor growth by 45% and 65% relative to vehicle controls. Control animals were sacrificed by day 19 due to progression. By day 22, 54% reduction was achieved in the animals treated with the combination compared to the animals treated with the anti-Pd1 antibody alone. Conclusions: This proof-of-concept in vivo experiment highlights the potential of iadademstat in combination with checkpoint inhibitors, prompting further investigation in other oncological indications, characterized by low or no response to the currently approved immune-oncology treatments.