bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vivo reprogramming macrophages and dendritic cells with Allocetra-OTS: Successful mono- and combination-antitumor therapy.
Authors: Mevorach Dror , Shabat Yehudit , Regev Eshchar , Yalon Eran , Karbian Netanel , Reicher Barak 
Published: June 2022

2532 Background: Chimeric antigen receptor (CAR) T cells can activate an immune response to a cancer-specific antigen but is less effective in solid tumors. Immune check point inhibitors (ICI) revolutionized the treatment of solid tumors, however, in many tumors only partial response is achieved. Here we questioned the role of synergistic effect of Allocetra-OTS (cellular therapy for in-vivo reprogramming macrophages and dendritic cells, Enlivex Therap.) on solid tumor progression. Methods: To follow tumor growth in vivo, HeLa-CD19 cells were stably transduced with pLenti-PGK-V5-Luc-Neo. For CAR preparation, fresh mononuclear cells (MNC) were transfected with CD19-CAR plasmids. For the intraperitoneal solid tumor model, SCID-Bg mice were injected intraperitoneally (IP) with human HeLa-CD19 or HeLa-CD19-luciferase cells, 10×106 allocetra-OTS or vehicle, and 10×106 CD19-CAR T cells or mock T cells. In an immune-competent model, Balb/c mice were treated IP with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti-CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical signs and peritoneal fluid accumulation and weekly for tumor growth. Kaplan-Meier log rank test was done for survival. Peritoneal cells were evaluated using single cell analysis and flow cytometry. Tumors were examined for bacterial presence by immunohistochemistry staining with antilipoteichoic acid (LTA) and antilipopolysaccharide (LPS). For allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis. Results: SCID mice survived 30±5 days (range 27–37) and were sacrificed or died from solid tumor in the peritoneal cavity after accumulation of bloody peritoneal fluid and clinical deterioration. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly ameliorated survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further ameliorated survival to 75±10 (p < 0.001) with 20-40% complete remission. In AB12 model, anti CTLA4 therapy significantly ameliorated survival from 26±5 to 38 ±9 days (p < 0.05). However, Allocetra-OTS monotherapy ameliorated survival to 45 ±12 days (p < 0.02) and combinational therapy to 75±9 days (p < 0.0001) with complete remission in 60-75% of mice. Single cell analysis revealed that restoration of large peritoneal macrophages (LPM), were associated with antitumor activity. Conclusions: During intraperitoneal tumor progression, allocetra-OTS as monotherapy or combinational therapy with CAR or anti-CTLA4 significantly reduced tumor size and enable complete remission in up to 75% treated mice. Based on excellent safety profile in > 30 patients treated for sepsis and Covid19, human phase I/II of allocetra-OTS plus ICI, for peritoneal metastases, is planned for 2022.
Efficacy and safety of autologous expanded tumor infiltrating lymphocytes (TILs) in multiple solid tumors.
Authors: Amaria Rodabe Navroze , Vining David J. , Kopetz Scott , Overman Michael J. , Javle Milind M. , Antonoff Mara , Tzeng Ching-Wei D. , Wolff Robert A. , Pant Shubham , Lito Kathryn , Rangel Kelly M. , Wilson Louis , Fellman Bryan M. , Haymaker Cara L. , Yuan Ying , Forget Marie-Andree , Hwu Patrick , Bernatchez Chantale , Jazaeri Amir A. 
Published: June 2022

2536 Background: TIL therapy has been used extensively in metastatic melanoma patients for many years, now with ongoing efforts to commercialize treatment. The efficacy of TIL outside of melanoma is largely unknown thus we designed and implemented a trial using TIL manufactured at a single academic center for treatment refractory metastatic colorectal (CRC), pancreas (PDAC) and ovarian (OVA) cancers. Methods: Patients with CRC, PDAC and OVA refractory to standard therapies with ECOG PS 0-1 and normal organ function were eligible for TIL harvest. Ex vivo TIL expansion and manufacturing was conducted at the MD Anderson TIL lab under conditions that included IL2 and 41BB stimulation (using urelumab). All patients received a lymphodepletion regimen consisting of cyclophosphamide 60mg/kg days -7 and -6 and fludarabine 25mg/m2 days -5 through day -1, followed by infusion of pooled ex-vivo expanded TIL. Patients received up to 6 doses of high dose IL-2 (600,000 IU/kg) after TIL infusion. The primary endpoint was evaluation of the objective response rate (ORR) using RECIST 1.1 criteria with secondary endpoints including disease control rate, duration of response, PFS, OS and safety. Results: A total of 17 patients underwent TIL harvest and 16 were treated on protocol; including 8 CRC, 5 PDAC and 3 OVA. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). Median number of TIL infused was 76 X 109 (range 20.3 x 109-150 x 109). Median doses of cyclophosphamide and fludarabine administered were 2 (range, 2-2) and 3 (range, 1-5), respectively. Median doses of IL-2 administered was 6 (range, 1-6). There were no responders. Best response included prolonged SD in a patient with PDAC lasting until 18 months. Grade 3 or higher toxicities attributable to therapy was seen in 14 subjects (87.5%; 95% CI: 61.7 – 98.4) with the majority of toxicities representing expected pancytopenia from lymphodepletion. Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type. Early on-treatment biopsy of PDAC patient with prolonged SD showed presence of proliferating (KI67+) CD4+ and CD8+ TIL. Conclusions: Generation of TIL at a single academic center for CRC, PDAC and OVA is feasible and treatment is associated with no new safety signals. For these tumor types, further research is required to identify host factors associated with resistance to TIL therapy and optimize manufacturing processes to create more effective TIL cell therapy. Clinical trial information: NCT03610490.
The addition of fludarabine to cyclophosphamide for lymphodepleting chemotherapy enhances the persistence of infused NY-ESO-1 TCR anticancer therapy TBI-1301.
Authors: Butler Marcus O. , Saibil Samuel , Sotov Valentin , Boross-Harmer Sarah , Scheid Elizabeth , Gray Diana , Van As Brendan , Trang Aileen , Ross Kendra , Ohashi Pamela S. , Tanaka Shinya , Takahashi Shuichi , Hirano Naoto 
Published: June 2022

2539 Background: Adoptive transfer of T cell receptor (TCR) gene-engineered T cells can induce durable anti-cancer responses. TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector that encodes siRNA to silence endogenous TCR. In this study, we examined a repeat infusion of TBI-1301 and the addition of fludarabine to cyclophosphamide for pre-infusion lymphodepletion. Methods: Eligibility included informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by IHC. Eligible patients underwent harvest of PBMC which were processed at the treating site to generate engineered TBI-1301 cells. The study design infused 5x109 cells on day 0 and day 14 to patients following lymphodepletion with cyclophosphamide (CY; 750 mg/m2 on day -7 and -6) plus fludarabine (FLU; 30 mg/m2 on day -7 and -6). Repeat infusions were performed in two cohorts: Cohort B - patients who had previously received NY-ESO-1 TCR-transduced cells and Cohort C - NY-ESO-1 TCR treatment naïve patients. Endpoints included safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Ten patients were enrolled in cohorts B and C. Nine patients in total are evaluable for response and toxicity, and no DLTs have been observed. In cohort B, 5 patients (5 synovial sarcoma) were treated, and 5 have received the target dose. In cohort C, 5 patients (3 synovial sarcoma, 2 melanoma) were treated, and 4 have received the target dose. One patient received a single infusion due to bacteremia on week 2. One of 5 patients in cohort B was previously treated with TBI-1301 cells in cohort C. In each cohort, 4 patients experienced grade 1-2 cytokine release syndrome. Best overall response by RECIST v1.1 was 3 stable disease, and 2 progressive disease in cohort B; and 2 stable disease and 2 progressive disease in cohort C. When compared to the earlier cohort, biomarker analysis demonstrated substantially longer persistence of transferred TBI-1301 cells in infused patients who received fludarabine (up to 372+ and 460+ days), and the cells displayed a less differentiated phenotype. Conclusions: Repeat infusions of TBI-1301 following lymphodepletion appears to be safe and to possess anti-tumor activity. Addition of FLU to the lymphodepletion regimen may contribute to longer persistence of gene-engineered T cells. Clinical trial information: NCT02869217.
Study to evaluate intraperitoneal (IP) ONCOS-102 with systemic durvalumab in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Phase 2 results.
Authors: Zamarin Dmitriy , Odunsi Kunle , Zsiros Emese , Slomovitz Brian M. , Pimentel Agustin , Duska Linda R. , Reilley Matthew , Nemunaitis John J. , Hamouda Danae M. , Patel Hitendra , Segal Neil Howard , Pesci Giulio , Holland Aliya , Shohara Lisa , Schwarzenberger Paul Otto , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Jaderberg Magnus Erik , Venhaus Ralph Rudolph 
Published: June 2022

2600 Background: Locoregional treatment with oncolytic viruses may be used to improve the efficacy of immune checkpoint inhibitors at both treated and distant tumor sites. This study evaluated the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GM-CSF), with systemic durvalumab (durva) in patients (pts) with advanced OC or CRC who have failed prior chemotherapy. Methods: This open-label study (NCT02963831) evaluated ONCOS-102 (IP 3 x 1011 VP in 500ml saline [recommended phase 2 dose] weekly x 6) + durva (IV 1500 mg every 4 weeks x 12). One dose of cyclophosphamide was given prior to first ONCOS-102 dose. Phase 2 evaluated the activity of the combination using Simon’s 2-stage MINIMAX design. In MINIMAX stage 1, if ≥ 5 of 18 OC pts or ≥ 1 of 13 CRC pts met the efficacy criteria (progression free at end of week 24), 15 additional OC pts or 14 additional CRC pts were to be enrolled in stage 2. The efficacy endpoint would be met if ≥ 11 OC pts or ≥ 4 CRC pts remained progression free at 24 weeks. Safety, response rate and progression-free survival (PFS) by RECIST 1.1, overall survival (OS), and immunologic effects in tumors were evaluated. ITT population = all pts who received at least one dose of durva or ONCOS-102; per protocol (PP) population = all pts who received at least 60% of ONCOS-102 doses and at least 1 durva dose in the first 2 cycles. Results: In MINIMAX stage 1, the OC cohort did not meet the efficacy criteria and was closed. For CRC, stage 1 efficacy criteria were achieved and the cohort was opened for stage 2. As of the 14 Dec 2021 cutoff, CRC enrollment was complete, and all pts were followed for 24 weeks or until progression or off study. Two pts were progression free at 24 weeks (see table). Treatment-related adverse events (TRAEs) occurring in > 30% pts were vomiting, nausea, fatigue, chills, and pyrexia. There were no grade 4 or 5 TRAEs. Grade 3 TRAEs were reported in 8 pts, 2 in the OC cohort and 6 in CRC. All grade 3 TRAEs occurred in no more than 1 pt for each AE except abdominal pain, which occurred in 2 pts. Conclusions: The combination of IP ONCOS-102 and durva was well tolerated. The study did not meet its efficacy endpoint. Evaluation of pre- and on-therapy translational parameters is ongoing. Clinical trial information: NCT02963831. [Table: see text]
First-line PD-1 inhibitors immunotherapy and chemotherapy combined with or without radiotherapy for patients with advanced non-small cell lung cancer.
Authors: Ding Peng , Huang Yu , Tong Fan , Chen Lingjuan , Wen Lu , Zhang Ruiguang , Cheng Shishi , Dong Xiaorong 
Published: June 2022

2606 Background: Immunochemotherapy has become a standard first-line regimen for advanced non-small-cell lung cancer (NSCLC). Several studies showed the synergistic effects of immunotherapy and radiotherapy on local and abscopal tumour control. But the data of first-line immunochemotherapy combined with radiotherapy for the advanced NSCLC is still scarce. Methods: Patients with advanced NSCLC receiving first-line PD-1 inhibitors immunotherapy plus chemotherapy in a single center were retrospectively analyzed in this study. They were divided into two groups according to whether they had received radiotherapy. The efficacy and safety of first-line immunochemotherapy combined with radiotherapy (ICRT group) and immunochemotherapy alone (ICT group) were investigated. Results: A total of 135 patients were included; 65 patients received PD-1 inhibitors plus chemotherapy and radiotherapy, while other 70 patients were treated with immunochemotherapy alone. The median interval time between radiotherapy and PD-1 inhibitors immunotherapy was 5 days (range, 0-96 days). The overall response rate (ORR) was 50.8% in the ICRT group and 40.0% in the ICT group, respectively. Patients in the ICRT group achieved significant longer progression-free survival (PFS, median 16.5 vs 10.4 months, P= 0.043) and overall survival (OS, median not reached vs 21.0 months, P= 0.030) compared with those in the ICT group. The addition of radiotherapy was the only prognostic factor for PFS (HR = 0.617, 95%CI: 0.385-0.989, P= 0.045) and OS (HR = 0.512, 95%CI: 0.277-0.947, P= 0.033) by univariate Cox regression analysis. Patients were well tolerated and the overall incidence of adverse events was similar between the ICRT group and ICT group. One patient in ICRT group stopped immunotherapy because of severe immune-associated pneumonia. 3.1% of grade 3-4 radiation-related adverse events were observed. Conclusions: Adding radiotherapy to first-line PD-1 inhibitors immunotherapy and chemotherapy improved outcomes of patients with advanced NSCLC and showed acceptable toxicity. Additional prospective studies exploring the first-line combination of immunochemotherapy and radiotherapy are warranted.
Pan-cancer analysis of YAP1 expression as a predictive biomarker for cancer immunotherapy.
Authors: Owonikoko Taofeek K. , Elliott Andrew , Ivanov Andrey , Dwivedi Bhakti , Walker Phillip , Vanderwalde Ari M. , Puri Sonam , Dacic Sanja , Morgensztern Daniel , Liu Stephen V , Borghaei Hossein , Sica Gabriel 
Published: June 2022

2629 Background: High YAP1 expression correlates with the ‘T-cell inflamed’ expression phenotype in small cell lung cancer (SCLC), but its association with other biomarkers of immune checkpoint vulnerability and in tumor types beyond SCLC is not known. We examined whether YAP1 expression correlates with other established markers of immune checkpoint blockade (ICB) efficacy (PDL1 expression and TMB) in a tumor agnostic manner to determine clinical relevance. Methods: Next-generation sequencing of DNA (592 gene panel or whole exome) and RNA (whole transcriptome) was performed for patient samples (n = 57,134), representing 13 cancer types, submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). The ‘T-cell inflamed’ signature (TIS) score was calculated as an 18-gene weighted coefficient composite value (Cristescu, 2018). PDL1 expression was assessed by immunohistochemistry (IHC) with cancer type-specific antibodies and thresholds, and high tumor mutational burden was defined as ≥10 mut/Mb. Patients were stratified into subgroups based on median YAP1 expression (YAP1-High/YAP-Low) within each cancer type. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: YAP1-High tumors were associated with significantly increased TIS scores compared to YAP1-Low across all 13 cancer types examined, with the largest fold increase observed in SCLC (1.33-fold, p < 0.0001), followed by pancreatic cancer (1.28-fold, p < 0.0001), while the smallest occurred in melanoma (1.13-fold, p < 0.0001). Spearman correlation strength (range 0.23-0.57) between YAP expression and TIS scores was consistent with increased TIS scores in YAP1-High samples. TMB-High rates were similar in YAP-High and YAP1-Low subgroups for most cancer types, with slightly lower rates in YAP1-High tumors observed for endometrial (23.0 vs 26.6%, p < 0.001) and esophageal (7.0 vs 9.5%, p < 0.05) cancers. YAP1 expression was not significantly increased in PDL1+ (IHC) tumors for most cancer types. However, significantly decreased YAP1 expression was associated with PDL1+ samples in RCC (Renal Cell Carcinoma) (0.91-fold change, P < 0.05), MM (0.90-fold change, P < 0.001), and ENCA (0.80-fold change, P < 0.0001) Conclusions: Our analyses provide confirmation that YAP1 expression positively correlates with the ‘T-cell inflamed’ phenotype across many cancer types, including those with approvals for (ICB) therapy. YAP1 expression was independent of established markers of ICB response, including TMB and PDL1. Further analysis of YAP1 expression as an additional tumor agnostic predictive biomarker is warranted.
Comparing rate of immunotherapy treatment change due to toxicity by gender.
Authors: Chua Kevin Joseph , Sterling Joshua , Doppalapudi Sai Krishnaraya , Kaldany Alain , Kronstedt Shane , Srivastava Arnav , Liu Hao , Singer Eric A. 
Published: June 2022

2656 Background: Immunotherapy (IO) is associated with a variety of treatment related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females Methods: The Oncology Research Information Exchange Network (ORIEN) Avatar Database collects clinical data from ten different United States cancer centers, where patients receive IO. Of 1,035 patients receiving IO, 447 patients were analyzed, excluding those (N = 573) who did not have documentation noting if a patient changed treatment. 15 additional patients with an unknown or gender-specific cancer were excluded. All cancer types and stages were included. Primary endpoint was documented treatment change due to toxicity. Significance was calculated with logistic regression, linear regression, chi-squared test for categorical variables and Mann-Whitney U test for continuous nonparametric variables. Results: 447 patients (281 males and 166 females) received IO treatment for cancer. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course compared to males on Mann-Whitney U test (median 3.7 vs 5.1 months, respectively, p=0.02) and multivariable linear regression (Beta -3.87, 95% CI -6.591, -1.149, p=0.005). 54 patients changed IO treatment due to toxicity. There was no significant difference in the rate of treatment change due to toxicity between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and logistic regression (Table). Pembrolizumab, Nivolumab, Ipilimumab/Nivolumab, Ipilimumab, Durvalumab, Avelumab, and Atezolizumab were given to 16, 14, 9, 9, 3, 2 and 1 patients who changed treatment due to toxicity, respectively. The median length of time for IO treatment prior to change for toxicity was 3 months (IQR 1.4 – 5.9 months). Significantly more patients with COPD changed treatment due to toxicity (Table). Conclusions: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity related treatment change was associated with COPD. Studies with larger sample sizes with more granular data (i.e., type of adverse effects) are needed to truly characterize if a difference between genders and IO toxicity exists. [Table: see text]
Association between germ-line HLA and immune-related adverse events.
Authors: Jiang Ning , Yu Yue , Wu Dawei , Wang Shuhang , Ma Peiwen , Miao Huilei , Tang Yu , Li Ning 
Published: June 2022

2658 Background: In recent years, great progress has been made in immune checkpoint inhibitors (ICIs), opening a new chapter for cancer treatment. However, accompanied by remarkable efficacy, immune-related adverse events (irAEs) also arose. Though some pilot studies have explored the possible factors that may influence the development of irAEs, the mechanism of irAEs remains unclear. Previous studies indicated a positive association between certain HLA types and irAEs. To uncover the relationship between irAEs and divergent HLA types, we initiated a large cohort study. Methods: We screened 626 patients who have been treated in the clinical research ward, Cancer Hospital of Chinese Academy of Medical Sciences. All participants included should be diagnosed with malignant tumors and have received at least 2 cycles of ICIs with complete security follow-up data in the original electronic medical records. The blood samples were collected before the first cycle of treatment. Sequencing libraries were generated using a customized panel. Six digit formatted HLA alleles were extracted from HLA-HD (v1.4.0) results for further analysis. Fisher-exact test was used to perform association analysis between HLA and different irAEs. To control the type I error, we introduce two external reference groups as well as the non-irAE control group. In addition, false discovery rate (FDR) correction was performed with the resulting p-values when comparing the HLA allele frequency between patients with irAEs and the MHC-han Chinese reference cohort. We also explored the relationship between zygosity of HLA genes, evolutionary divergence of HLA class I genotype (HED) and irAEs. Results: Of the 626 participants, 530 received at least 2 doses of ICIs. The median follow-up time was 10.3 months. 97% patients received anti-PD-1/PD-L1 treatment. Of all participants, 78% reported irAEs of any grade, with 10.2% reporting grade 3 and above irAEs. The occurrence of overall irAEs showed no significant difference between homozygous group and heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs, including the significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/ hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037) as well as anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). Conclusions: IrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity have no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs, and potential therapies targeting irAE-inducing HLA types without influencing the anticancer effect may be considered to benefit the patients.