bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of CD19-targeted chimeric antigen receptor T cells in the treatment of relapsed extramedullary B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL).
Authors: Hu Yongxian , Wu Zhao , Yu Jian , Wang Jiasheng , Wei Guoqing , Wu Wenjun , Luo Yi , Shi Jimin , Xiao Lei , Huang He 
Published: September 2018

e14549 Background: Chimeric antigen receptor T cells directed at CD19 (CART19) have shown promising results in the treatment of refractory/relapsed acute lymphoblastic leukemia and chronic lymphocytic leukemia. Evidence of efficacy on mass lesions such as extramedullary ALL and non-Hodgkin’s lymphoma is still emerging. Methods: Patient-derived T cells were transfected ex vivo with lentiviral vector encoding anti-CD19 scFv, human 4-1BB, and CD3ζ signaling domains. 2 patients with relapsed extramedullary ALL and 2 patients with relapsed DLBCL were enrolled (median age 25.5, range 17~35). Lymphodepletion regimens were fludarabine 50mg/m2 infused over 3 days, and cyclophosphamide 750mg/m2 infused over 3 days in DLBCL patients or over 2 days in ALL patients. CART19 were infused one time or fractionated over 3 days with dose from 1×106/kg to 1×107/kg. Results: The 2 ALL patients received prior allogenic HSCT; one relapsed with isolated testicular ALL, the other with mammary/axillary lymph node ALL with 15% blast cells in the bone marrow. The other two patients relapsed with DLBCL. After CART19 therapy, all patients achieved complete remission (CR) within a median of 30d (range 29~52d). With a median follow up of 53.5d (range 52~153d), the 2 DLBCL patients remained in CR; the testicular B-LBL patient relapsed with isolated testicular involvement on +153d and received a second CART19; the other B-LBL patient relapsed with isolated bilateral mammary glands involvement on +52d and remained in stable disease. Grade 2 cytokine release syndrome (CRS) were observed in the 2 DLBCL patients (50%). CRS self-resolved within 10d without treatment. Conclusions: CART19 was effective and safe against mass lesions such as relapsed extramedullary ALL and DLBCL with high CR rate. CART19 can induce rapid remission in lymphoma patients around one month.
Evaluation of safety and efficacy of ipilimumab and nivolumab (ipi+nivo) combination in patients (pts) previously treated with anti-PD-1 antibodies (PD1): A single-center experience.
Authors: Park Soo , Daniels Gregory A. 
Published: September 2018

e14556 Background: All clinical trials studying ipi+nivo have involved treatment-naive pts. Knowledge about the safety and efficacy of ipi+nivo is limited for pts previously treated with PD1. Methods: Nine pts were retrospectively evaluated and treated with ipi (3 mg/kg) and nivo (1 mg/kg) q3wk for 4 doses followed by maintenance nivo q2wk after progression on PD1 from 10/2014 to 11/2016. Data regarding clinical history, treatment response, and toxicity were collected. Results: Six pts had advanced melanoma, 2 pts had metastatic HNSCC (mHNSCC), and 1 pt had recurrent parotid myoepithelial carcinoma. Age ranged from 44 to 86. Eight pts had ECOG PS 0-1; 1 pt had ECOG PS 2. Three melanoma pts were BRAF+; 1 was BRAF WT and 2 were NRAS+. Both mHNSCC pts were p16+. Pts received a median of 3 prior lines of treatment including chemotherapy and immune treatments encompassing ipi, PD1, 4-1BB agonist, autologous TILs, high-dose IL2, IFN, T-VEC, and TLR8 agonist. All 9 pts received pembro prior to ipi+nivo; 1 pt received both pembro and nivo separately. Median number of PD1 doses prior to ipi+nivo was 10 (range 3-13). All 9 pts received all 4 doses of ipi+nivo without delay. Seven pts received nivo maintenance for median number of 11 cycles (range 1-22). Two pts were unable to receive nivo maintenance due to progressive disease (PD) and instead were treated with ipi+T-VEC and BRAF/MEK inhibition. Objective responses were seen in 6/9 pts (67%) with 2 radiological CRs and 4 radiological PRs. PD was seen in 3/9 pts (33%) including in the 1 pt with ECOG PS 2; all 3 pts died from clinical deterioration unrelated to ipi+nivo treatment. CRs were observed in 1 BRAF+ and 1 NRAS+. 7/9 pts (78%) had ≥1 clinically significant irAE and 3 of these pts required systemic steroids. Five pts are still receiving maintenance nivo with clinical benefit. One pt with CR was taken off nivo maintenance, remains disease-free, and is now on surveillance. Conclusions: Ipi+nivo demonstrated significant anti-tumor activity in pts previously treated with PD1. The toxicity profile is consistent with known irAEs. While this is a small series, these data support the use of ipi+nivo after PD1 failure.
A quantum biochemistry investigation of cancer immunotherapy.
Authors: Albuquerque E.L. , Tavares Ana Beatriz M.L.A. , da Silva L.R. , Lima-Neto J.X. , Fulco U.L. 
Published: September 2018

e14558 Background: Immunotherapy is a procedure to boost the patient's own immune system to fight diseases such as cancer. In some types of cancer, it has been found that the programmed cell death receptor PD-1 impedes the body's immune defenses from functioning at full strength. Therefore drugs, like pembrolizumab, which prevent the interaction between this protein and the T-cells, may be a key tool to avoid the onset of cancer tumors. Methods: The aim of this work is to describe the interaction energies between the protein PD-1 and its drug inhibitor pembrolizumab by using a quantum biochemistry calculations, taking advantage of the X-ray crystal structure of the protein PD-1 in complex with its inhibitor. The protonation state of the drug was obtained using the Marvin Sketch code (Marvin Beans Suite). The optimization procedure was performed using the parametrization tool for organic molecules CHARMM (Chemistry at Harvard Macromolecular Mechanics). Afterwards, simulations within the density functional theory (DFT) framework were carried out by using the Gaussian code to provide a detailed energy profile of the interactions between the inhibitor and the receptor. Results: The interaction energy between each PD-1 molecule and the drug was calculated considering any significant attractive and repulsive drug’s amino acid residues. A searchfor an optimal binding pocket radius was done, looking for no significantvariation in the total binding energy. The converged binding pocket radius was found to be 1.5 nm, comprising a total of 145 amino acids residues displayed in a BIRD (Binding site, Interaction energy and Residues Domain) graphic panel. Although it was observed few repulsive interactions, the attractive ones were predominant, pointing out to a strong inhibition of the programmed cell death receptor. Conclusions: Immunotherapy is ranked nowadays as an important alternative to treat cancer. Among the drugs been tested, those blocking the protein PD-1 and its ligands have been considered an efficient way to trigger the T-cells. In this context, the computational method used in this work is a low cost efficient first step to unveil the drug’s amino-acids residues that play the most important role on the binding affinity of the receptor-ligand complex.
Some patients who achieved CR due to accelerator+brake therapy that was performed in the form of activated autologous lymphocytes with the concomitant use of low-dose immune checkpoint inhibitors.
Authors: Abe Yoshinobu , Aikawa Yoshiyuki 
Published: September 2018

e14561 Background: Otsuka et al. from Kyoto University reported in Oncoimmunology (October 24, 2016) that a group responding to Opdivo showed an increase in the number of “Type-9 helper T (Th9) cells”, which are a type of lymphocyte. On the basis of this clinical study, in September 2015, our clinic introduced immunotherapy that is performed in the form of activated autologous lymphocytes with the concomitant use of low-dose Opdivo and Yervoy. This therapy was named Accelerator+Brake therapy, and obtained a registered trademark in Japan. Methods: Accelerator+Brake therapy was performed for 359 patients between September 2015 and September 2016. These patients had lung cancer (n = 84), breast cancer (n = 45), colorectal cancer (n = 32), etc. The therapy was also performed for patients with sarcoma, which is a rare type of cancer. The patients underwent 5 courses of Accelerator+Brake therapy with 2-week intervals (overall treatment period: two and a half months), and the numbers of NK and T cells increased to approximately two billion through culture activation. In every course, Opdivo and Yervoy were administered at doses of 20 and 10-25 mg, respectively. Although not all patients have been followed up on a long-term basis, we encountered some patients who achieved CR after one or two courses. Results: I present 6 cases of CR. First case is 65 y.o. male, renal pelvis cancer has spread to his mediastinal lymph nodes. Second case is 57 y.o. male, intrahepatic cholangiocarcinoma has spread to his bilateral lungs. Third case is 64 y.o. female, breast cancer has spread to her lumbar vertebra. 4th case is 53 y.o. male, renal cancer has spread to his lung. 5th case is 55 y.o. female, breast cancer has spread to her lung. Last case is 39 y.o. male, renal cancer has spread to his pleural lesion. All 6 cases result in CR. I also present several cases of PR. Conclusions: Activated autologous lymphocytes with the concomitant use of low-dose Opdivo and Yervoy named Accelerator+Brake therapy is may become a breakthrough treatment to solid cancer.
Inflammatory arthritis: An under-recognized immune-relate adverse effect.
Authors: Mooradian Meghan , Cohen Justine Vanessa , Giobbie-Hurder Anita , Fadden Riley , Rubin Krista M. , Flaherty Keith , Lawrence Don P. , Sullivan Ryan J. 
Published: September 2018

e14565 Background: Checkpoint inhibition (CPI) has significant and durable effectiveness against a broadening range of cancers and currently is FDA approved for more than 10 different malignancies. With increasing use of CPI, there is a need to understand the range and extent of immune-related adverse effects (irAE). Though certain irAEs, such as colitis and pneumonitis have been well studied, CPI- induced arthritis (CA) has not been widely recognized nor well characterized with data on the subject largely comprised of case reports and small case series. Methods: We retrospectively reviewed 125 patients (pts) with advanced melanoma treated with CPI to define the incidence and clinical features of CA. We identified 20 pts who developed CA during the course of CPI treatment. Cases were included only if active rheumatic signs or symptoms developed after receiving therapy. Demographic data (gender, age), type of CPI, number of CPI cycles, treatment of CA and other irAE manifestations were extracted from the medical chart. Results: 16% of patients treated with CPI developed CA. Among the 20 pts, the average age at CA onset was 70.3 (43, 84) with 75% of pts male. 80% had received anti-PD-1 monotherapy, 15% combination anti-PD-1 + anti-CTLA-4 and 5% monotherapy with CTLA-4 inhibition. The average number of infusions prior to symptom onset was 13.5 (1-48) after a median time point of 6.6mths on therapy. Basic rheumatologic testing (RF, CCP, ANA) was only positive in 10% of cases. 20% of pts were treated with non-steroidal anti-inflammatory drugs alone, whereas 40% required corticosteroids (systemic or injection). The remaining 40% necessitated treatment with disease modifying anti-rheumatic drugs. Conclusions: CA is a debilitating irAE with a higher incidence (16%) than most other irAEs and a negative impact on the quality of life of pts affected. Based on our retrospective review, this irAE tends to delayed in onset and often requires systemic immune suppressants for effective treatment. We posit that this is an under recognized and undertreated irAE. Further work is needed to better define the clinical factors that may affect or predict its development.
Isolation and expansion of OCT4/Sox2 specific cytotoxic T lymphocytes in vitro.
Authors: Zhang Xueyan , Lou Yuqing , Zheng Xiaoxuan , Zhang Yanwei , Xu Jianlin , Gu Ping , Wang Huiming , Han Baohui 
Published: September 2018

e14578 Background: The main reason for tumor MDR (multidrug resistance ,MDR) is the presence of CSC(cancer stem cells,CSC). In the CSC of lung cancer, OCT4 and Sox2 are closely related to the tumor MDR. Therefore, in the current study, we introduced a method for the generation of OCT4+/Sox2+ CSC specific CTL(cytotoxic T lymphocytes,CTL) through co-culture with CD154+ feeder layer cells. Methods: Lenti/CD154 was constructed. The NIH3T3 cells were incubated with Lenti/CD154 (103 vp per cell) for 24 h at 37 °C and 5% CO2. Then the NIH3T3 cells were subsequently maintained in fresh complete DMEM medium. Lenti/GFP was used as a control. On the 6th day post infection, the infection rate was determined by flow cytometry after incubation with CD154-PE antibody. The feeder layer cells were co-cultured with CD40B cells and the biomarkers of CD40B cells were determined by flow cytometry. The CTL were treated with OCT4 plus Sox2 antigen and then the biomarkers of CTL were examined by flow cytometry and IL-2 and IFNγ were determined by ELISA. Results: The rate of CD154+ NIH3T3 cells was 99.7%, which was higher than that of uninfected-cells (14.8%). After co-culture with CD154+ NIH3T3 cells, the rates of CD40B expressing CD80, CD86 and HLA-A were significantly increased. OCT4 plus Sox2 treatment further increased the CD3, CD4 and CD8 expression and elevated the secretion of IL-2 and IFNγ. After co-culture of CTL with MDR PC9-drived cancer stem cells (CSC) and parental PC9 cells at different ratio, CTL significantly killed the tumor cells compared with control. Conclusions: The generation and expansion of OCT/Sox2 specific CTL is a feasible method for the treatment of lung cancer.
Identification of DNA repair/replication genes mutations in determining response to immune checkpoint inhibitors in non-small cell lung cancer patients.
Authors: Li Meng-Xia , Wang Guan , Yang Xiao , Lu Xianfeng , Zhang Shiheng , Xu Jiayue , Wang Dong , Xu Qiang 
Published: September 2018

e14582 Background: Tumor mutational burden (TMB) is considered a promising predictive biomarker for immune checkpoint blockade (ICB) therapy response . However, the measurement of TMB relies on the whole-exome sequencing (WES), which is technically limited by sample volume and freshness, thus restricts its use in clinical practice. Since TMB is controlled by the balance between DNA damage and the repair, it is a rational approach to identify a subset of DNA repair/replication gene mutations associated with increased TMB as a surrogate, which could be monitored in clinic to predict ICB efficacy even busing limited archived tissues. Methods: The mutation status of 471 genes associated with DNA repair and replication were analyzed for the correlation with TMB and/or ICB therapeutic responses in three cohorts of NSCLC patients, which are: Cohort A, WES data of 100 Chinese NSCLC patients; Cohort B, WES data of NSCLC patients from TCGA database; Cohort C, WES data and therapeutic response to PD-1 mAb from a Science paper (Rizvi et al. 2015, Science). Results: We identified somatic mutations in 32 DNA repair/replication genes associated with high TMB in both Cohort A and Cohort B. In Cohort C, mutations were found in 20 out of these 32 genes, and the mutation status of 17/20 genes were associated with the clinical benefit of ICB therapy. Noteworthy, mutations of TP53, POLQ, MMS22L, HERC2, CEP164, BRCA1/2, FANCM and MSH4 were mostly common mutations associated with TMB in all 3 cohorts, and ERCC2 and ERCC6 were uniquely high mutated and associated with high TMB in Chinese Han people from Cohort A. Interestingly, EGFR activating mutations were inversely correlated with both high TMB and good ICB response. Conclusions: This retrospective study identified 17 DNA repair/replication-related genes, whose mutation status was associated with high TMB and/or ICB response. Mutational patterns of DNA repair genes are likely different between western and Chinese NSCLC patient population. The data also suggested that NSCLC patients carrying EGFR activating mutations are not preferential population for ICB therapy. Further data is needed to verify the validity of these observations.
Adoption of immunotherapy into real-world practice: Insights from the use of checkpoint inhibitors.
Authors: O'Connor Jeremy , Seidl-Rathkopf Kathi , You Paul , Nussbaum Nathan C. , Torres Aracelis Z. , Fessele Kristen L. , Darius Katie , Adelson Kerin B. , Yin Emily , Presley Carolyn Jean , Chiang Anne C. , Ross Joseph S. , Abernethy Amy Pickar , Gross Cary Philip 
Published: September 2018

e14583 Background: Cancer research has been criticized regarding the generalizability of trials to older persons, as well as the timeliness of the impact of new trials on real-world practice. Despite growing enthusiasm about programmed death 1 checkpoint inhibitors (anti-PD1s), little is known about the speed with which these drugs are adopted into real-world practice, or whether anti-PD1 treated patients in real-world practice are older than patients treated in trials. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced melanoma (n=1,670), advanced non-small cell lung cancer (aNSCLC; n=19,536), or metastatic renal cell carcinoma (mRCC; n=2,018). Then, we determined the proportion treated with anti-PD1s in the 2nd line or later following US Food and Drug Administration (FDA) approval. Therapy lines containing study drugs were excluded. Chi-square tests were used to compare age distributions of patients treated in real-world practice to patients treated in trials that support FDA approval. Results: At 6 months following FDA approval, 71.9% of patients with melanoma undergoing treatment were receiving anti-PD1s, versus 33.0% of patients with aNSCLC and 46.0% of patients with mRCC. Within 1 year, more than half of all treated patients with these 3 cancers were receiving anti-PD1s (71.0% in melanoma; 51.4% in aNSCLC; and 51.8% in mRCC). The median ages at first receipt of anti-PD1s were ≥65 years (65.1 years in melanoma; 67.9 years in aNSCLC; 66.0 years in mRCC). Anti-PD1 treated patients were significantly older in real-world practice than patients treated in trials (Table: all p<0.001). Conclusions: In a large national sample of patients with cancer, anti-PD1s were adopted rapidly into real-world practice. Compared to patients treated in real-world practice, older patients were underrepresented in clinical trials. [Table: see text]
Digital image analysis as an aid in the assessment of the combined positive score in ovarian carcinoma.
Authors: Kulangara Karina , Calcagno David , Boyer Scott , Hanks Debra Ann , Yamada Holly 
Published: September 2018

e14584 Background: Developing scoring methods for PD-L1 to identify patients who will respond effectively to anti-PD1 therapy is key in the development of companion and complementary diagnostic assays. The Combined Positive Score (CPS) is an elegant method for the evaluation of PD-L1 expression in solid tumors. CPS includes the number of PD-L1 positive cells (tumor, lymphocytes and macrophages) in relation to total tumor cells. The accurate manual capturing of total number of tumor cells can be a challenge to pathologists. Methods: Image analysis was used to evaluate possibledifferences in tumor density for well, moderately, and poorly differentiated ovarian epithelial serious carcinomas. Multiple regions of interest of 158 hematoxylin-stained specimens were analyzed. Algorithm parameters were systematically adjusted to minimize mean differences in tumor count relative to manually counted scores in small, user-selected regions of 33 representative specimens. Results: The average nuclei count ranged between 2000 and 7000 with ~50% falling between 4.0-5.5 x 103. Conclusions: Digital image analysis of nuclear quantification has been shown to be a useful tool to aid the pathologist with the correct assessment of the CPS score.
Clinical outcomes of patients on check point inhibitor therapy who receive routine vaccinations.
Authors: Schenk Erin Lynn 
Published: September 2018

e14597 Background: Routine vaccination reduces preventable illness and infection in cancer patients even while undergoing therapy. Increasingly, patients with advanced malignancies receive check point inhibitors (CPI) and, with tumor response, can remain on therapy for extended periods of time. These agents promote tumor clearance by impeding a normal route of immune regulation which can result in autoimmunity. To the best of our knowledge, clinical outcomes for patients on CPI therapy who receive routine vaccinations have not been studied. Methods: The medical records of patients who received CPI therapy at Mayo Clinic in Rochester, Minnesota from March 25, 2011 to August 25, 2015 were reviewed for type and date of immunizations, CPI duration, adverse events (AE) at least possibly related to therapy, and survival from start of CPI. Patients who received > 1 dose of pembrolizumab or nivolumab were included in analysis. Patients were excluded if no follow up was done at our institution. Results: One hundred and eight patients were included in the analysis. Most patients received CPI therapy for metastatic melanoma (n = 71) or non-small cell lung cancer (n = 23). A total of 53 routine vaccinations were administered to 30 patients while on CPI therapy. Eighteen patients received a single vaccination. Annual influenza vaccination was most frequently administered (n = 38) followed by pneumococcal vaccines (n = 9). AEs were reported in 17/30 vaccinated patients and in 22/78 non-vaccinated patients (p = 0.004). In the vaccinated cohort, 11 patients experienced AEs after immunization and was not significantly different from the non-vaccinated patients (p = 0.265). For both cohorts, thyroid, rash, and pneumonitis were the most common AEs. Grade 3 AEs occurred with similar frequency between the 2 groups. Patients in the vaccinated cohort received more cycles of therapy (median 20.5 vs 6 cycles, p < 0.001). Median survival of patients who were not vaccinated was 503 days and median survival was not reached in the vaccinated group (p = 0.005). Conclusions: Routine vaccination of patients receiving CPI therapy did not significantly increase number or severity of adverse events. Routine vaccination did not reduce patient benefit from CPIs.