bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCR-engineered T-cell therapy through personalized identification of CDR3 clonotypes.
Authors: Zhou Zishan , Pu Yue , Xiao Shanshan , Wang Ping , Yu Yang , Lin Rui , Wang Tao , Jiao Shun Chang 
Published: May 2020

e15021 Background: T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancers. Unlike many shared tumor-specific antigens, such as melanoma-associated antigen (MAGE)-A3, MAGE-A4, and New York esophageal squamous cell carcinoma (NY-ESO)-1, neoantigen has garnered much attention as a potential precision immunotherapy. Personalized neoantigen selection serves a broader and more precision future for cancer patients. Methods: Dendritic cells (DCs) derived from adherent monocytes were pulsed with mixed peptides during the maturation phase. CD8+ cells positively selected from PBMCs were incubated with washed DCs. After 21day culture in X-VIVO medium with IL-7 and IL-15, cells were harvested and stimulated with peptides for 6 h. CD137+ cells were sorted by flow cytometric and immediately processed using the 10x Genomic Chromium Single Cell 5' Library & Gel Bead Kit and Chromium Single Cell V(D)J Enrichment Kit. The T-cell TCR libraries were constructed and sequenced on the Illumina HiSeq X Ten platform. The sequencing reads were aligned to the hg38 human reference genome and analyzed using the 10x Genomics Cell Ranger pipeline. The paired TCR α and β chain sequence of each cell was demonstrated with V(D)J analysis. TCR-T cells were constructed using the information of neoantigen specific TCR, and infused to patients. Results: Two patients were treated with the personalized TCR-T treatment. At the first stage, specialized immune cells were harvested and proceeded to single-cell TCR profiling. Then, the single cell sequencing of the first patient's sample revealed the top five neoantigen specific TCR CDR3 clonotypes with the proportion of 25%, 7.67%, 4.81%, 2.79%, and 2.54%, respectively. Similarly, the other patient had the top five TCR CDR3 sequenced with the proportion of 13.38%, 7.04%, 4.21%, 2.83%, and 1.94%, respectively. The results demonstrated that both patients had one or two dominant CDR3 clonotypes, which might reflect the strength of neoantigen in vivo. At the third stage, TCR-T cells were constructed, and infused to the patients. The clinical outcome will be evaluated in the near future. Conclusions: We have generated a pipeline for a highly personalized cancer therapy using TCR-engineered T cells. Although some questions remain to be answered, this novel approach may result in better clinical responses in future treatment.
Targeting non-engrafting IL-2 activated intentionally mismatched donor lymphocytes with monoclonal or bispecific antibodies for treatment of otherwise incurable cancer.
Authors: Slavin Shimon 
Published: May 2020

e15033 Background: Cure of certain resistant cancers by donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (SCT) suggests that alloreactive lymphocytes can eliminate otherwise resistant cancer. First patient with resistant relapse following supra-lethal chemoradiotherapy treated with DLI is alive & well > 34 years; > 400 patients with hematological malignancies confirmed DLI efficacy for prevention & treatment of relapse. Using murine leukemia (BCL1) & metastatic breast cancer (4T1), IL-2 activated mismatched lymphocytes with no prior SCT eliminated otherwise lethal minimal residual disease (MRD). Using anti-EpCAM x anti-CD3 bispecific antibody (BSA) lethal melanoma was eliminated, also resulted in long-lasting immunity against lethal tumor challenge. Graft-vs-host disease (GVHD) was prevented by consistent rejection of mismatched lymphocytes. Accordingly, our goal was to develop effective immunotherapy of cancer using non-engrafting intentionally mismatched Allogeneic Targeted Activated Cancer Killer cells (ATACK) using relevant monoclonal antibodies (MoAb) or BSA. Methods: Patients with multiple myeloma & lymphoma and advanced solid tumors were treated with haploidentical or unrelated donor lymphocytes pre-activated 5 days with IL-2, following non-myeloablative conditioning with endoxan or fludarabine and IL-2 injection x5 days for in vivo lymphocyte activation. ATACK with no MoAb was investigated in 40 patients with different cancers. Safety of ATACK with MoAb was investigated in 16 patients with resistant NHL, metastatic breast, lung & colorectal cancer, using commercial MoAbs against CD20, Her-2, EGFR or VEGF, respectively, or using anti-EpCAM BSA. Results: Protocols were well-tolerated with mild transient toxicity following ATACK and BSA. No patient developed GVHD. Disease-free survival > 15 years was documented in 2/2 patient with multiple myeloma and 2/2 patients with lymphoma. Longterm progression-free survival was observed in 5/31 evaluable patients with advanced metastatic solid tumors treated with no MoAbs. Minor toxicity in targeted ATACK recipients was manageable in outpatient clinic. Conclusions: Intentionally mismatched IL-2 activated killer cells guided by MoAbs or BSA represents a promissing approach for treatment, possibly even cure, of cancer patients with MRD while avoiding GVHD.
Novel CoupledCAR technology for treating colorectal cancer.
Authors: Xiao Lei , Li Song , Pu Chengfei , Cao Zhiyuan , Lu Cheng , Hang Yang , Huang Xi , Shen Xiaogang , Wang Xiuwen , Wu Zhao 
Published: May 2020

e15035 Background: Conventional CAR-T cell therapy has thus far shown weak cell expansion in solid tumor patients and achieved little or no therapeutic responses. Methods: We developed CAR T cells based on a novel CoupledCAR technology to treat solid tumors. We engineered CoupledCAR-T cells with lentiviral vectors encoding an anti- colorectal cancer specific protein CAR molecule, and anti- colorectal cancer specific protein (CRCSP) CAR-T cells showed anti-tumor activities in vitro and in vivo experiments. Further, we conducted several clinical trials for various solid tumors, including two patients with colorectal cancer. After the infusion of CoupledCAR T cells, these two patients showed rapid expansion of CoupledCAR T cells and the killing of tumor cells. Specifically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites. Results: Both patients achieved PR (Partial Response). Patient Profile: Patient 1: Male, 55Y, Colon Adenocarcinoma. In May 2016, 8 cycles of XELOX chemotherapy and 1 dose of radiotherapy were performed. In Step 2016, “radical rectal resection and terminal ileum double ileostomy” was performed. After surgery, gemcitabine chemotherapy was performed for 2 cycles. In January 2018, relapse and metastasis of prostate and left lung were observed. In April 2019, relapse and metastasis were observed. Patient 2: Female, 57Y, Colon Adenocarcinoma. In December 2014, DT46Gy/2Gy/23 radiotherapy was performed. In December 2014 and January 2015, the single drug chemotherapy of Xeloda was taken orally. In February 2015, laparoscopic radical resection of rectal cancer was performed. In April, May, June, and July 2015, mFOLFOX6 chemotherapy was performed. In June 2019, CT showed tumor metastasis. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR; most of the target lesions were significantly reduced by more than 50%, and the primary tumor volume was reduced by ~45%. Patient 2: M1, the patient was also evaluated as PR; the tumor in the left upper lobe tip posterior segment was reduced by approximately 75%. Conclusions: The clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-CRCSP CoupledCAR T cells. Further, since our CoupledCAR technology is a platform technology, we are developing it to treat other solid tumors using different target markers.
Aristotle: A single blood test for pan-cancer screening.
Authors: Dempsey Adam A , Tripp James Howard , Chao Samuel , Stamatiou Dimitri , Pilcz Tanya , Ying Jay , Burakoff Robert 
Published: May 2020

e15037 Background: Blood participates in physiological and pathological changes throughout the body which are reflected as changes in cellular gene expression. The involvement of the immune system in cancer suppression and promotion through immunoediting exemplifies this. These characteristics make blood a promising non-invasive surrogate tissue for cancer diagnosis and monitoring. Methods: A multi-class cancer classification model, Aristotle, was developed with logistic regression using Affymetrix gene expression profiles generated from 2,845 unique human whole peripheral blood samples. The model was evaluated through 100 iterations of 2-fold cross-validation. Results: The 1,013 cancer patient samples (age 61±13, 40.6% ♀), include cancer of the bladder (n = 87, age 65±11, 23.3% ♀), breast (n = 94, age 54±10, 98.4% ♀), colon (n = 205, age 64±13, 39.5% ♀)/colon polyps (n = 226, age 61±11, 36.0% ♀), cervix (n = 36, age 55±13), endometrium (n = 25, age 49±12), liver (n = 16, age 57±11, 12.5% ♀), nasopharynx (n = 78, age 51±13, 26.9% ♀), ovaries (n = 64, age 55±12), prostate (n = 160, age 68±9) or stomach (n = 22, age 59±11, 28.6% ♀); and 1,832 control samples (age 53±16, 38.9% ♀), including healthy subjects (n = 1,042, age 55±16, 37.0 ♀) and subjects with ankylosing spondylitis (n = 59, age 39±12, 18.6% ♀), heart failure (n = 193, age 67±12, 40.0% ♀), inflammatory bowel disease (n = 51, age 37±9, 40.0% ♀), osteoarthritis (n = 248, age 53±15, 45.6% ♀), rheumatoid arthritis (n = 40, age 57±17, 84.6% ♀), schizophrenia (n = 110, age 36±13, 43.6% ♀) or other (n = 89, age 50±14, 41.1% ♀). Aristotle classified cancer profiles with sensitivities from 55.6-100% and positive predictive values from 5.6-77.7% at a specificity of 99.0% (Table). The mean false positive rate for the 11 cancer classes ranged from 0.3- 6.8%. Conclusions: Our study demonstrates the clinical viability of using whole peripheral blood for multi-class cancer classification. Aristotle was capable of classifying patients with different types of cancer with clinically relevant accuracy. We are confident that Aristotle holds great promise to help address the need for practical and non-invasive early-stage cancer diagnostics. [Table: see text]
Baseline circulating myeloid-derived suppressor cells subpopulations, neutrophils/lymphocytes ratio, and response to PD-1/PD-L1 inhibitor in non-small cell lung cancer patients.
Authors: GarcIa SAnchez JosE , Benet Gimenez Marta , Cordón Lourdes , De Julian Maria , Piqueras Marta , Ruiz Veronica , Garde Javier , Piera Nuria , Sanchez Alfredo , Lorente David , Carretero Julian , Juan-Vidal Oscar , Lahoz Agustin 
Published: May 2020

e15042 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. We aimed to assess the role of pretreatment circulating MDSC subpopulations on ICI outcomes in NSCLC patients. Methods: 86 NSCLC patients treated with ICI and 10 healthy donors in 3 centers between 02/2018 and 10/2019 were eligible. Pretreatment immunophenotyping of monocytes, early-MDSC (e-MDSC: CD14-/CD15-/HLA-DR-/CD33+/CD11b+), monocytic-MDSC (M-MDSC: CD14+/CD15-/HLA-DR-/CD33+/CD11b+) and polymorphonuclear-MDSC (PMN-MDSC: CD14-/CD15+/HLA-DR-/CD33+/CD11b+) was prospectively performed by flow cytometry in fresh whole blood. Correlation between baseline circulating MDSC subpopulations and Neutrophils/Lymphocytes Ratio (NLR) was evaluated as well as their impact on outcomes. Results: 86 patients who received at least one previous platinum based combination chemotherapy for stage III-IV NSCLC were prospectively included; 82 (95%) smokers, median age 62 years; 52 (60%) non-squamous; 69 (93%) ECOG PS 0-1; 43 (50%) PDL1 ≥ 1% and 65 (76%) were treated in a second line setting. Median PFS (mPFS) was 2.79 months (m) [95% CI, 1.3-4.2] and mOS 11.6 m [9.3-13.9]. Overall, 3m-death rate was 18.6%. Pretreatment high-NLR (NLR > 3) (62/86; 72%) was correlated with poor PFS (p = 0.03), OS (p = 0.01) and a 3m-death rate of 22.6%. High level of global MDSC before anti-PD-1/PD-L1 therapy, defined by the median value as a cut-off ( > 6.3%), was associated with poor OS (p = 0.03). Pretreatment low e-MDSC ( < 21.7%), were also associated with poor PFS (p = 0.01), OS (p = 0.006) and a 3m-death rate of 23.8%. There was not correlation between M-MDSC and PMN-MDSC and clinical outcomes. Conclusions: Our study suggests that a baseline circulating low level of e-MDSC and high-NLR are associated with early failure to ICI and poorer survival. The role of e-MDSC appears interesting as a potential predictive and prognostic biomarker in NSCLC patients treated with anti-PD1/PD-L1. Dynamic assessment of MDSC levels over time and further validation with longer follow up in larger cohorts are needed.
Leukocytes with bound platelets as a predictive biomarker for immune-related adverse events (irAEs) in advanced non-small cell lung cancer (NSCLC) patients (pts) receiving anti-PD-(L)1 agents.
Authors: Riudavets Mariona , Zamora Carlos , Sullivan Ivana , Alserawan Leticia , Barba Andrés , Gallardo Pablo , Gavira Javier , Serra Jorgina , Anguera Georgia , Barnadas Agusti , Vidal Sílvia , Majem Margarita 
Published: May 2020

e15047 Background: Anti-PD-(L)1 blocking agents can induce irAEs, compromising treatment continuation and patient safety. Since complexes of leukocyte-platelet have been shown to play a role in inflammation by reducing cytokine production, we hypothesize that the percentage of these complexes could be used as a predictor of irAEs in pts receiving anti-PD-(L)1 agents. Methods: From May 2015 to January 2019, 87 advanced NSCLC pts treated with anti-PD-(L)1 agents at our institution were prospectively included. Percentages of circulating CD4+T lymphocytes and monocytes with bound platelets (CD4+PLT+ and CD14+PLT+, respectively) were obtained by flow cytometry and compared between NSCLC pts and healthy donors (HD, n = 26). The association of leukocyte-platelet complexes with the presence of irAEs was analyzed. According to CD4+PLT+ and CD14+PLT+ levels, NSCLC pts were grouped as CD4+PLT+ high (n = 29), CD4+PLT+ low (n = 58) and as CD14+PLT+ high (n = 36) and CD14+PLT+ low (n = 51). Frequencies and grade of irAEs were compared between groups using Chi-square test. Results: NSCLC pts showed significant higher percentages of circulating CD4+PLT+ and CD14+PLT+ than HD (9.41±0.54% vs. 6.01±0.45% and 57.44±2.42 vs. 35.43±2.22, respectively; p< 0.001). No significant differences in CD4+PLT+ and CD14+PLT+ were found according to the presence of irAEs. CD4+PLT+ high group presented a higher rate of dermatological irAEs while CD4+PLT+ low group showed higher rate of non-dermatological irAEs (dermatological: 44.85% vs. 8.6%; non-dermatological: 10.3% vs. 39.7%, respectively; p< 0.001). Lower percentage of grade ≥2 irAEs was observed in the CD4+PLT+ high group than in the CD4+PLT+ low group (17.3% vs. 41.4%; p< 0.05). No significant differences in the type of irAEs were observed between CD14+ PLT+ high and low groups. Pts with CD4+PLT+ high and CD14+PLT+ low levels showed the lowest rate of irAEs, presenting only grade ≤1 irAEs (53.8% dermatological, 7.7% dermatological + non-dermatological, 38.5% no-irAEs). In contrast, pts with CD4+PLT+ low and CD14+PLT+ high levels presented higher rate of grade ≥3 irAEs (50% grade 0-1, 20% grade 2, 30% grade ≥3; p< 0.05) and predominantly developed non-dermatological irAEs (45% non-dermatological, 30% dermatological + non-dermatological, 25% no-irAEs; p< 0.01). Conclusions: Combining CD4+ PLT+ and CD14+ PLT+ levels may be used as predictive of development and severity of irAEs in advanced NSCLC pts receiving anti-PD-(L)1 agents.
Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer.
Authors: Uba Richie , Raez Luis E. , Dumais Katerine , Gentile Frank , Powery Herman W. , Domingo Gelenis Calzadilla , Izquierdo Paola , Hunis Brian 
Published: May 2020

e15055 Background: There is immune evasion and resistance to checkpoint inhibitors (CPI). Programmed death-ligand 1 (PD-L1) and Tumor mutational burden (TMB) might help us predict response, but we have not yet validated biomarkers that can predict resistance. Mutations (mut) in STK11 can induce epigenetic changes that confer proliferative advantages to cancer cells and preliminary reports have suggested that they can confer resistance to CPI. We investigated the role of STK11 and KRAS mut as markers of poor response to CPI in patients (pts) with non-small cell lung cancer (NSCLC). Methods: Clinical outcomes of 127 pts with stage IIIB-IV NSCLC who were tested for KRAS and STK11 mut and received CPI were evaluated for progression free survival (PFS) and overall survival (OS). For statistical analysis log-rank tests were used to compare OS and PFS, chi-squared tests were used to compare 1-year survivals and proportions among different variables, and Kaplan-Meier survival curves were used to report OS and PFS. Results: Of the 127 pts: 31 had STK11 mut, 14 had STK11+KRAS mut (SKM group), and 10 pts were in the SKMP group (STK11+KRAS mut+PD-L1 (-)). Median age was 65y (27-88y). Males were 54% of the total and 30 pts (24%) were Hispanic (H). STK11 mut patients had an inferior PFS and OS as shown in table. Pts in SKM and SKMP groups had worse outcomes; however, not all the P values were significant. The difference in OS and 1-year OS were very impressive and significant when compared between the SKMP group (4m and 30%) and the wild type group (15m and 73%). There were no significant differences in clinical outcomes for H vs. non-H White pts. Conclusions: The presence of STK11 mut were associated with shorter OS/PFS in NSCLC pts treated with CPIs, proving its utility as a negative predictive marker. This can be enhanced combining STK11 and KRAS mut and possibly adding PD-L1 (-). These findings are consistent with recent studies that have reported STK11 mut as a genomic driver of primary resistance. Due to the small sample size further studies will be needed to validate these findings. [Table: see text]
Predictive factors for combined anti-PD-1 and anti-angiogenic therapy in multiline treatment of advanced non-small cell lung cancer.
Authors: Wang Yina , Li Xiaobin , Chen Yao , Xu Mingyan , Song Lele 
Published: May 2020

e15059 Background: Immune checkpoint inhibitors (ICIs), such as PD-1/ PD-L1 inhibitors, have made a significant breakthrough in lung cancer first-line treatment. However, there are few reports on stratification, therapeutic response and prognosis prediction of NSCLC patients treated with immunotherapy combined with anti-angiogenic therapy in multiline therapy. The aim of this study was to investigate the clinical efficacy of anti-PD-1 plus anti-angiogenic therapy in the second-line or multiline treatment of NSCLC, and to explore potential predictive biomarkers for response and prognosis in this combined therapy. Methods: A total of 22 advanced NSCLC patients were recruited in this study, in which 14 patients received this combined immunotherapy as second-line therapy, and 8 patients as multiline therapy. Genomic profiles were determined with blood by a 451-gene next-generation sequencing panel. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: All patients were followed up until progression or the end of this study. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) time for all patients was 5.25 months. Surprisingly, the pre-therapeutic blood tumor mutation burden (bTMB) could not discriminate clinical benefit from non-benefit group in this combined therapy (P = 0.167). However, we found that the concentration of pre-therapeutic blood circulating free DNA (cfDNA) was an independent predictor of PFS (HR = 27.75, P = 0.003), in which higher cfDNA concentration correlated with poorer outcomes. Meanwhile, patients harboring MIKI67 gene mutations or gene variations related to hyper-progressive disease showed significantly shorter PFS time (p < 0.05). In addition, patients with negative ctDNA before therapy might benefit more from this combined immunotherapy (P = 0.068). Conclusions: Our study suggested that the combined strategies may improve clinical efficacy of ICIs in second and multiline therapy. The pre-therapeutic bTMB was not predictive for clinical benefit in multiline combined therapy. Patients with pre-therapeutic high concentration of cfDNA, MIKI67 mutations or gene variations related to hyper-progressive disease may be less likely to benefit from the combined therapy. Our findings may improve the prediction of therapeutic effect and prognosis in future combined treatment involving immunotherapy.
The effect of concomitant cannabinoids during immune checkpoint inhibitor treatment of advanced stage malignancy.
Authors: Biedny Adam , Szpunar Susan , Abdalla Ahmed , Kafri Zyad , Hadid Tarik H. 
Published: May 2020

e15064 Background: Immune checkpoint inhibitors are used in treatment of advanced neoplasms. Immunotherapy agents create a potent pro-inflammatory effect in cancer. The efficacy of immunotherapy may negatively be impacted by the use of anti-inflammatory agents. An anti-inflammatory effect of cannabinoids has been described in literature in several models. Recent data suggests a negative impact of cannabis on tumor response to immunotherapy. Methods: We retrospectively reviewed medical records of all patients with metastatic cancer who received at least 2 months of immune checkpoint inhibitors between August 2014 and August 2018. The patients were stratified by use of cannabis (cannabis vs non-cannabis users). Baseline patients’ characteristics were compared. Overall survival was estimated and compared between the two groups. An analysis was performed using analysis of variance, Student's t-test, correlation, chi-squared test, and logrank test. All data were analyzed with SPSS v. 26.0 and a p-value less than 0.05 was set to indicate statistical significance. Results: A total of 104 patients with advanced-stage malignancy met the inclusion criteria. The median age was 63.9±10.5 years, 48.1% males and 81.7% Caucasians. 41.3% of patients has lung adenocarcinoma, 20.3% has squamous cell carcinoma of the lung, 11.5% has squamous cell carcinoma of the head and neck and 26.9% have other tumor types. Twenty patients (19.2%) had brain metastasis and twenty-three patients (22.1%) had bone metastasis. Seventy patients (66.8%) received Nivolumab, and twenty-seven patients (26%) received Pembrolizumab. The mean duration of immunotherapy use was 10.2 months. Characteristics of patients were similar between the groups except for a higher prevalence of tobacco use in the cannabis group. Twenty-eight patients (26.9%) reported concomitant cannabis use during immunotherapy treatment, 23 were prescribed (dronabinol) and 5 used it recreationally (smoking marijuana/cannabis oil). Non-cannabis users had significantly longer overall survival (OS) compared to cannabis users (40 months vs 16 months, p = 0.004). Conclusions: This study shows significant association between the use of cannabis during immunotherapy treatment and worse OS. This can be explained by an anti-inflammatory effect of cannabis, which may decrease response to immune checkpoint inhibitors. This observation should be further investigated in randomized trials. Health care professionals should be aware of the potentially harmful effect of cannabis on cancer care.