bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulatory effects of a dipeptidyl peptidase inhibitor, ARI-4175, and NK cell activation in a colon cancer model.
Authors: Macfarlane Alexander , Bagnyukova Tetyana V , Campbell Kerry , Jones Barry , Bachovchin William , Borghaei Hossein 
Published: March 2020

3058 Background: A possible mechanism of the antitumor effect of therapeutic antibodies is antibody-dependent cellular cytotoxicity (ADCC). We reported that an inhibitor of dipeptidyl peptidase (DPP)4-like serine proteases, Ari-4175, significantly slowed the growth of KRAS-mutated HCT-116 xenografts in nude mice, either as a single agent or with cetuximab (Ctx). Ari-4175 is not cytotoxic in vitro, and since it was able to overcome the resistance to Ctx due to the KRAS mutation in the HCT-116 line, we hypothesized that the antitumor activity involves the activation of NK cells and enhancement of ADCC. Methods: Ari-4175 was administered orally to nude mice at 200 µg q.d. x5 days/week. Peripheral blood or spleens were assayed for immune parameters, ex vivo, at various time points. Expression of surface markers on myeloid and NK cells were monitored by flow. Natural cytotoxicity and ADCC were assayed using HCT116 cells and Ctx using a flow based assay. Cytokines were measured using Luminex assays. Results: Ari-4175 induced upregulation of CD69 on NK cells on day 2, followed by upregulation of CD16 on day 7. Coordinate with these changes in peripheral blood, splenocytes from treated mice exhibited significantly increased in vitro cytotoxicity toward the HCT116 cells. Increased serum levels of inflammatory cytokines, including IL-1b, IL-6, MCP-1, GCSF, and IL-2 were seen. A significant expansion of a distinct CD45+CD14+Gr-1+MHC-II-CDllb+CD11cvariable myeloid cell population in both peripheral blood and spleens of mice was also seen after one week of treatment. Conclusions: Ari-4175 showed dramatic anti-tumor effect in KRAS-mutant CRC xengrafts when given alone or in combination with Ctx. In vitro data suggest that the therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevated expression of CD16 on NK cells. In addition, Ari-4175 appears, in vivo, to expand a unique myeloid cell population, which may be responsible for an inflammatory cytokine response and subsequent activation of NK cells. Our study provides a mechanistic rationale for testing Ari-4175 in a clinical trial and possible biomarker endpoints for evaluation in peripheral blood samples.
Circulating myeloid-derived suppressor cells (MDSC) and correlation to poor prognosis, Th2-polarization, inflammation, and nutritional damages in patients with gastric cancer.
Authors: Gonda Kenji , Shibata Masahiko , Kanke Yasuyuki , Yazawa Takashi , Monma Tomoyuki , Suzuki Satoshi , Nakamura Izumi , Ohki Shinji , Shimura Tatsuo , Ohto Hitoshi , Takenoshita Seiichi 
Published: March 2020

3063 Background: Recent studies have shown that myeloid-derived suppressor cells (MDSC), which have been identified in most patients, are potent suppressors of T cell activation. MDSC have been reported to be correlated with tumorigenesis and the progression of tumors. We have previously reported significant correlations of MDSC with nutritional damage and inflammation in many types of cancer. In this study the quantitative detection of MDSC in peripheral blood was analyzed in the prognosis in patients with gastric cancer. Methods: We tested PBMCs from 29 preoperative patients with gastric cancer and 18 healthy volunteers using flow cytometric analysis (CD14-CD11b+CD33+). Markers for nutritional status (serum levels of total protein), inflammation (NLR: neurphil/lymphocyte ratio, serum levels of vascular endothelial growth factor: VEGF) and Th2-polarization (PBMC’s production of IL-6 and IL-10) were measured in this study. The prognosis of the patients was assessed by Kaplan-Meier tests for correlation with levels of MDSC. Results: MDSC levels in 29 preoperative patients with gastric cancer were significantly higher than in normal volunteers. These levels were not associated with pathological characteristics. However they were significantly correlated with the production of IL-6 and IL-10, VEGF levels and NLR. A significant inverse correlation with levels of total protein was obtained. MDSCs were increased in stage IV patients compared with healthy volunteer and 2-year survival rate of the patients with higher levels of MDSC (> 1.104%PBMC) was significantly poorer (median OS, 498 vs 473 days; p = 0.048), while there was no significant difference in patients with stages I, II, and III. Conclusions: These data suggest that increased MDSC is an effective biomarker for immunosuppression due to Th2-polarization, nutritional impairment, systemic inflammation and poor prognosis in advanced patients with gastric cancer.
Biologic meshes in cancer patients: A double-edged sword—Differences in production of IL6 and IL12 caused by acellular dermal matrices in human immune cells.
Authors: Guenthner-Biller Maria Margarete , Enders Sabine , Knabl Julia , Engelstaedter Verena , Duewell Peter , Rack Brigitte Kathrin , Mayr Doris , Jeschke Udo , Dian Darius 
Published: March 2020

3064 Background: Acellular dermal matrices (ADM) have been used in different fields of surgery for almost 20 years. In 2005 Breuing et al first described its use in breast cancer patients. It is assumed that it is safe to use in an oncologic setting, but data from controlled studies are still missing. Because of its lack of cells ADM are considered not to cause an immune reaction. With increasing knowledge about the importance of immunology in breast cancer more information about ADM on different immune cell populations is needed. IL6 and IL12 are two central cytokines and key regulators of immune supression and activation. Methods: Strattice (ST; LifeCell) CollaMend (CM; Bard Davol), Biodesign (BD; Cook Biotec) as well as TiLoop a synthetic mesh (TL; pfm medical) were used in this study. We isolated myeloid dendritic cells (MDC), untouched plasmacytoid dendritic cells (PDC), naïve B-cells and CD8+ T-cells using the MACS System and co-cultered them with the biologic meshes or TL. For positive controls, we used CpG ODN 2216 3 µg/ml and LPS in a concentration of 100 ng/ml. Cytokine concentration of IL12p70 and IL6 were determined after seven days by using sandwich Elisa sets. Statistical significance was determined by the nonparametric Friedman-Test. The single hypothesis was calculated with a paired Wilcoxon Test. Results: There was a highly significant difference between the different ADM and TL in the immunologic response. The statistical difference for IL 6 was p= 0.0006131 for B cells and p= 0.00418 for T cells between TL and ADM. ST also caused significantly more IL6 than CM and BD. We found similar differences in IL 12 with p= 0.00194 for B cells and p= 0.003636 in T cells in regard to the difference between TL and ADM. For IL 12 there was no statistical difference between the ADM. We didn´t see any significant differences in the cytokine profile between the various ADM/TL in the MDC and PDC subpopulations. Conclusions: Despite the assumed lack of immune answer to ADM, immune cells reacted in our study with significantly different cytokine profiles. These findings can have implications regarding the activation or suppression of effector cells in a cancer patient.
Multicenter trial for assessing tolerability of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage small-cell lung cancer: RNCLC-01 study.
Authors: Kashii Tatsuhiko , Miwa Toshiro , Kajiura Shinya , Kinoshita Ichiro , Oizumi Satoshi , Nakagawa Ken , Nagase Seisuke , Akashi Yusaku , Takada Minoru , Iwamoto Yasuo , Tsuboi Masahiro ,   Research Network for Chemotherapy of Lung Cancer
Published: March 2020

3072 Background: Polysaccharide-K (PSK, Krestin) is a protein-bound polysaccharide, extracted from cultured mycelium of Coriplus versicolor, and is associated with immunostimulatory activity. Although combination use of PSK with chemotherapy has been shown to prolong the response period in patients with small-cell lung cancer (SCLC), the efficacy of PSK in combination chemotherapy including cisplatin has been less examined. We examined safety and efficacy of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage (ED) SCLC. Methods: Eligible pts included: histologically confirmed ED-SCLC without prior chemotherapy, age under 75 years, ECOG performance status ≤ 1, with evaluable disease and adequate organ function. Treatment: irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 every 4 weeks for 4 to 6 courses, and oral PSK 3,000 mg/body daily. The treatment with PSK was continued after the end of cisplatin and irinotecan administrations, and was combined as a part of second-line therapy after exacerbations. Results: Between January 2008 and July 2010, 17 patients were enrolled, and the efficacy and prognosis were evaluated in 15 of 17 patients. Response rate was 66.6%, one-year survival rate was 66.6%, and two-year survival rate was 33.2%. The major toxicities were diarrhea and myelosuppression, and the common toxicity of PSK-containing combination chemotherapy was not observed. Conclusions: The combination chemotherapy with cisplatin, irinotecan, and PSK was effective and well tolerated in ED-SCLC. Clinical trial information: NCT00546130.
VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group.
Authors: Monk Bradley J. , Brady William E. , Lankes Heather A. , Facciabene Andrea , Manjarrez Kristi , Hershberg Robert Mark , Fracasso Paula M. , Bell-McGuinn Katherine M. , Walker Joan L. , McCourt Carolyn K. , Aghajanian Carol , Coukos George 
Published: March 2020

3077 Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 + pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N=13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N=13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N=7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8+ T cell responses were also induced. In humans, treatment with PLD + VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNF-α). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N=6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel + VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD + VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.
Targeting myeloid-derived suppressor cells and the PD-1/PD-L1 axis to enhance immunotherapy with anti-CEA designer T cells for the treatment of colorectal liver metastases.
Authors: Burga Rachel A. , Thorn Mitchell , Nguyen Cang T. , Licata Lauren , Espat N. Joseph , Junghans Richard Paul , Katz Steven C. 
Published: March 2020

3079 Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed death ligand-1 (PD-L1, CD274) on MDSC binding to programmed death-1 (PD-1, CD279) on T cells. We hypothesize blocking PD-L1 will improve adoptive cellular therapy efficacy for CRCLM through inhibition of MDSC-mediated T cell suppression. Methods: “Designer” T cells (dTc) were produced from activated murine splenocytes transduced with chimeric antigen receptor (CAR) specific for CEA. C57BL/6 mice were injected with CEA+ MC38 tumor cells via spleen, and liver MDSC (CD11b+Gr1+) were purified with immunomagnetic beads after two weeks. MDSC were co-cultured with stimulated dTc with or without in vitro PD-L1 blockade. Results: MDSC expanded 2.4-fold in response to CRCLM, and expressed high levels of PD-L1 (63.8% PD-L1+). PD-L1 was equally expressed on both monocytic (CD11b+Ly6G-Ly6C+) and granulocytic (CD11b+Ly6G+) MDSC subsets (43.6% PD-L1+ and 27.9% PD-L1+, respectively). Expression of related ligand, PD-L2 was found to be negligible in both subsets. The cognate inhibitory receptor, PD-1, was expressed on dTc (23.8% PD-1+) and native T cells (37.3% PD-1+). Increasing endogenous T cell expression of PD-1 significantly correlated with MDSC expansion (r=0.9774, p<0.0001) in response to CRCLM. Co-culture of dTc with MDSC demonstrated the suppressive effect of MDSC on dTc proliferation which was abrogated with in vitro targeting of PD-L1. The percentage of dTc proliferating in the presence of CEA+ tumor decreased from 72.2% to 29.3% (p<0.001) with the addition of MDSC, and immunosuppression was reversed with blockade of PD-L1, which resulted in a 1.6-fold increase in dTc proliferation (p=0.01 ). Conclusions: Liver MDSC expand in the presence of CRCLM and mediate suppression of anti-CEA dTc via PD-L1. Our results indicate that blockade of PD-L1:PD-1 engagement is a viable strategy for enhancing the efficacy of adoptive cell therapy for liver metastases.
Phase I clinical study of NK105, paclitaxel-encapsulating micelles, on a weekly schedule, in patients with malignant tumors (dose-escalation phase).
Authors: Kato Ken , Mukai Hirofumi , Esaki Taito , Ohsumi Shozo , Hozumi Yasuo 
Published: March 2020

3082 Background: NK105 is the formulation of a novel drug delivery system that encapsulates paclitaxel (PTX) in polymeric micelles and possibly resolves the safety issues associated with the additives contained in the conventional PTX formulation. In the phase II study of NK105 administered to gastric cancer patients on a 150Emg/m2 triweekly schedule, peripheral sensory neuropathy was mitigated compared to prior data for conventional PTX, without any reduction in efficacy. Based on the dose-density theory, we conducted a phase I study of NK105 on a weekly schedule to determine the dose-limiting toxicity (DLT) and recommended dosage (RD), and to evaluate the pharmacokinetic profile. Methods: Patients with advanced solid tumors refractory to standard therapy received NK105 at dosage levels of 50-100 mg/m2 as a 30-min infusion without premedication, once a week for three weeks, followed by one week of rest. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Sixteen patients were enrolled in the study. In the 100Emg/m2 cohort (n=7), one patient experienced DLT (grade 4 neutropenia lasting 5 days), and dose reduction or delay was necessary in 4 of the 7 patients during the first course due to neutropenia. It was decided that 100 mg/m2 was the maximum tolerated dosage, and the RD was set at 80 mg/m2. Grade 3 or more severe adverse drug reactions reported for the 80Emg/m2 cohort were neutropenia, anemia, fatigue, hearing impaired and ataxia. Comparison of the pharmacokinetic parameters of NK105 with those of PTX at the same dosage (100 mg/m2) showed that the AUC0-inf. and Vdss of NK105 were approximately 50-fold and 1/15 of the reported PTX values, respectively. A refractory gastric cancer patient and an esophageal cancer patient each showed a partial response, at dosages of 80 mg/m2 and 100 mg/m2, respectively. Conclusions: 80Emg/m2 weekly administration of NK105 was well tolerated and showed anti-tumor activity, including partial responses and several occurrences of stable disease. The expansion phase of the study is ongoing at the RD of 80 mg/m2. Clinical trial information: JapicCTI-101233.
Active immunotherapy in patients with progressive disease (PD) after first-line therapy: Racotumomab experience.
Authors: Gomez Roberto E , Alfonso Saily , Santiesteban Eduardo Rafael , Neninger Elia , Ardigo Maria Laura , Vazquez Ana Maria , Crombet Tania , Perez Rolando , Lage Agustin , Macias Amparo 
Published: March 2020

3086 Background: Racotumomab is a therapeutic vaccine that induces a cellular and humoral immune response against NeuGc-containing gangliosides expressed in several tumors but not in normal human tissues. A previous randomized, double blinded, placebo-controlled trial has demonstrated low toxicity of racotumomab and a statistically significant benefit in overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) who had achieved partial or complete response or disease stabilization after first line therapy. Methods: An open, non-randomized study was performed to evaluate if racotumomab could also be beneficial in patients with progressive disease. Patients with recurrent and advanced stages (IIIB/IV) of NSCLC, in progression after completion of first-line onco-specific treatment as per the NCCN Oncology Therapeutic Guidelines (surgery, chemotherapy and/or radiotherapy) were included in the study. Most of them had received 4 to 6 cycles of cisplatin/vinblastin. Vaccination consisted of 5 intradermic doses of racotumomab (1 every 14 days), followed by 1 dose every 28 days until patient refusal or worsening of ECOG status. The patients did not receive second-line therapy. Results: 180 patients were included in an intent to treat (ITT) survival analysis (Kaplan Meier estimate), after at least 10 months of follow-up. Median survival was 8.06 months. OS rate (%) at 24 months was 21%. A control group of 85 consecutive patients treated at the same institution by the same investigators, who did not receive second-line therapy or racotumomab showed a median survival of 6.26 months (log rank test p= 0.011). OS rate (%) at 24 months was only 7%. A per protocol survival analysis including only the 124 patients (68.8%) who received ≥ 5 doses of racotumomab showed a median survival of 12 months. OS rate (%) at 24 months was 30%. Conclusions: Patients with PD after first-line treatment show favorable results in survival when vaccinated with racotumomab. This result is similar to previous clinical trials where racotumomab was administered to patients with objective response (partial or complete) or stable disease after first line therapy.
A phase II study of intratumoral administration of the autologous immature dendritic cell (DC) vaccine used after lesion photodynamic therapy (PhDT) and immunomodulation with cyclophosphamide (Cy) in pretreated patients with disseminated malignant melanoma.
Authors: Novik Alexey Viktorovich , Baldueva Irina Alexandrovma , Gelfond Mark Lvovich , Protsenko Svetlana , Nehaeva Tatyana Leonidovna , Waal Andrei Ivanovich , Vorobeychikov Eugene Vladimirovich , Danilova Anna Borisovna , Danilov Alexey Olegovich , Semenova Anna Igorevna , Teletaeva Gulfiya Midhatovna , Moiseyenko Vladimir 
Published: March 2020

3088 Background: Immature DC can be loaded in vivo with tumor-specific antigens after tissue destruction and induce specific immune response even in pretreated patients with unfavorable prognosis. We assess clinical efficacy of this approach in melanoma patients after at least 1 line of drug therapy in metastatic setting. Methods: Totally, 14 pts were enrolled: 11 men, 3 women. Stage M1a in 4 (28%) pts, M1b in 1 (7%) and M1c was in 9 (64%) pts. Patient received Cy 300 mg IM at D0, photoditasine (PH) at D3, PhDT therapy on injectable lesion 2 hrs after PH (662 nm, 300 J). The immature DC derived from peripheral blood stem-cells were injected in irradiated lesion 6 hrs after photodynamic therapy at D3 and daily until D7 of the 21-day cycle. Vaccine dose was 60-100*10^6 cells. Toxicity was measured by CTC AE v4, efficacy by RECIST 1.0. Primary endpoint was clinical benefit rate (CBR), secondary – overall survival (OS), response rate (RR), time to progression (TTP) and toxicity. Results: 14 pts were evaluable for toxicity, 13 for response. 37 cycles of therapy were performed. 2 patients achieved PR lasting 393 and 218+ days. 5 patients were stable for 33+, 108, 113, 168 and 239 days. RR was 15 (95% CI 2-39)%, CBR – 54 (95% CI 27-81)%. Median OS was 334 days, TTP – 113 days. RR was well correlated with OS (p=0,014). No SAE or AE of 4th degree occurred. The only grade 3 toxicity was fever. All grade 1-2 AEs were immune-related: fever (the most frequent AE), pain in the lesions, flu-like reactions, myalgia as well as high serum ALT, AST and bilirubin in patients with liver metastases. Conclusions: Thus, using the described approach for immunotherapy of melanoma has clinical efficacy and worth further developing.
A phase I study of an MVA vaccine targeting p53 in cancer.
Authors: Chung Vincent M. , Hardwick Nicola , Ellenhorn Joshua D.I. , Espenschied Jonathan R. , Lim Dean , Chu Peiguo , Qian Dajun , Kim Joseph , Chao Joseph , Fakih Marwan , Yen Yun , Diamond Don J. 
Published: March 2020

3089 Background: Despite chemotherapy, survival for most patients with metastatic gastrointestinal cancer is <2 years. These dismal statistics reflect lack of effective therapy. We are conducting a first-in-human trial of modified vaccinia Ankara (MVA), an attenuated viral vaccine that targets wild-type (wt) p53. This approach applies to the majority of p53-involved tumors, since the bulk of the p53 sequence is identical, except for individual point mutations. Our phase I study evaluates the safety and tolerability of the vaccine. Methods: Patients with metastatic colon, gastric and pancreas cancer that failed standard treatment were eligible for vaccination if >10% of the cells stained strongly positive for p53. A standard 3+3 design was employed and patients were accrued to either the 108 pfu or 5.6 x 108pfu dose levels. A total of 3 injections were given, each spaced apart by 3 weeks and patients were evaluated for dose limiting toxicities. Results: Three patients were accrued to the 108 pfu dose level; 2 patients with colon cancer and 1 patient with pancreatic cancer. There were no dose limiting toxicities and the injection was well tolerated and only local irritation at the injection site was seen. The dose was escalated to 5.6 x 108 pfu; 3 patients were accrued, 1 with colon cancer and 2 with pancreatic cancer. There were no dose limiting toxicities observed in the 3 patients. Grade 2 toxicities that were at least possibly related to the vaccine include injection site reaction and fatigue seen in one patient each. One patient with pancreatic cancer had stable disease on CT after completion of the 3 injections. This dose level is being expanded to accrue an additional 6 patients to evaluate safety and immunogenicity using cytokine flow cytometry to characterize p53-specific CD4+ and CD8+ T cell response. Of the cell-surface markers employed, PD1 showed extraordinary strong expression prior to vaccine injection. All patients had a humoral response to the MVA backbone. Conclusions: Our MVA p53 vaccine is well tolerated with minimal grade 1-2 toxicities. The highest dose tested is 5.6 x 108 pfu and additional patients are being accrued to evaluate immunogenicity. Since many cancers have mutant p53, this is an attractive target and may potentially be used with many other cancers. Clinical trial information: NCT01191684.