scholarly journals CD8-dependent Tumor Growth Inhibition by Tumor Cells Genetically Modified with 4-1BBL

2021 ◽  
Vol 27 (4) ◽  
pp. 329-333
Author(s):  
Hong Sung Kim
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Genetically Modified ◽  
Tumor Growth Inhibition

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

scholarly journals The Role and Mechanism of Upregulation of HO-1 Expression By Activating of Adenosine-2a Receptor in the Tumor Immune Microenvironment with Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2948-2948
Author(s):  
Chanjuan Wang ◽  
Jishi Wang
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Receptor Activation ◽  
Tumor Growth Inhibition ◽  
Immune Microenvironment ◽  
Positive Correlation ◽  
Tumor Immune Microenvironment

Abstract Objective: In the previous study, we found a high proportion expression of HO-1 and Foxp3 in tumor tissues of patients with DLBCL result in a poor prognosis, and there is a positive correlation between HO-1 and Foxp3. Activation of A2aR not only increases the number of Treg cells but also directly enhances their immunosuppression to tumor cells. on the other hand, A2aR on the surface of tumor cells was also induced, considering a positive correlation between HO-1 and Foxp3, it is hypothesized that activation of A2aR in tumor cells results in upregulated HO-1 expression. And HO-1 play a crucial role in the maintenance and survival of tumor cells in the tumor immune microenvironment, so this study aimed to prove that adenosine activates the A2aR receptor of tumor cells to upregulate the expression of HO-1. Further investigating the regulation and mechanism of the interaction between A2aR and HO-1, elucidating the role of A2aR receptor activation in the immune microenvironment of patients with DLBCL. Methods: Multi-color immunohistochemical staining (mIHC) was performed on paraffin sections of clinical cases with DLBCL to make a quantitative analysis the expression of biomarkers of the immune microenvironment, K-M survival curve and Log-Rank test were used for statistical analysis. Oci-ly10 and Oci-ly19 cell lines were used as the DLBCL cell model, were treated with A2aR receptor agonist, adenosine and NECA. NECA-pretreated cells were treated by anticancer drugs Cisplatin and Vincristine (VCR). Western blot, CCK8 test and FACS were performed on measure the expression of HO-1, cell viability and apoptosis, respectively. NOD-SCID mouse bearing Oci-ly10 cells were established in to investigate the effect of induced HO-1 by A2aR activation on tumor growth inhibition and drug-resistance in vivo. Results: The results of multicolor immunohistochemistry showed that lower expression of HO-1, Foxp3 and PD-L1 and higher expression of CD8 obtained a higher overall survival(p<0.05). There was no significant difference in the OS with CD4 and CD68 (p>0.05). There was a positive correlation between the HO-1 and Foxp3 cells among the tumor microenvironment markers (p<0.05). Western blotting results showed that both NECA and adenosine induced the upregulation expression of HO-1 through the activation of A2aR receptors in Oci-ly10 and Oci-ly19 cell lines in a concentration- and time-dependent manner (p<0.05). 0.5μmol of the inhibitor preladenant inhibited the activation of HO-1 expression mediated by A2aR receptor activation (p<0.05). The knockdown A2aR expression by si-A2aR resulted in the above induction. siRNA rescue experiments showed that the cells regained the ability of NECA to induce HO-1 upregulation by reset the A2aR expression. Pretreatment with NECA reduced the sensitivity of cells to cisplatin or VCR, and the concentration of IC50 increased significantly (p<0.05). However, the above changes were not significant after preladenant-pretreatment. FACS results showed that NECA significantly increased anti-apoptotic ability of cisplatin in Oci-ly10 cells, but preladenant-pretreatment blocked the enhancement of anti-apoptotic effect (p<0.05). When HO-1 was knockdown, NECA activation of A2aR receptor could not induce HO-1 up-regulation, and the apoptosis rate was not significantly different from that of cisplatin-treated group (p>0.05) NECA further phosphorylated p38 MAPK through activation of A2aR. Downstream transcription factors regulate the induction of HO-1 expression. The results showed that the tumor growth of cisplatin and preladenant combination group was the most significantly inhibited (p<0.05), while cisplatin had limited effects in inhibiting tumor growth. In addition, tumor growth inhibition was significantly reduced (p<0.05) by NECA-pretreatment. The positive rates of HO-1 and Foxp3 cells in the cisplatin plus NECA group were significantly higher than those in the cisplatin group after NECA stimulation of the A2aR receptor (p<0.05). In contrast, after the inhibition of A2aR receptor activation, the positive rate of HO-1 cells in the cisplatin plus preladenant group was lower than that in the cisplatin group (p<0.05). Conclusion: It is essential for the maintenance and survival of tumor cells in the tumor immune microenvironment. Upregulation of HO-1 by A2aR receptor activation plays an important role in the immune microenvironment of DLBCL tumors. Disclosures No relevant conflicts of interest to declare.

Intratumoral exposure levels of pentaglutamated pemetrexed following treatment with LEAF-1401 and pemetrexed.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3524-3524
Author(s):  
Gwangseong Kim ◽  
Angelique Nyinawabera ◽  
Zhenghong (Hannah) Xu ◽  
Jason DeFuria ◽  
Alvin Sezibera ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Xenograft Model ◽  
Fold Increase ◽  
Drug Candidate ◽  
Tumor Growth Inhibition ◽  
Intracellular Enzyme ◽  
Exposure Levels

3524 Background: The activity of pemetrexed is highly dependent on the intracellular enzyme folypolyglutamate synthase (FPGS) which adds glutamates to pemetrexed and yields very potent pemetrexed polyglutamates. Pemetrexed pentaglutamate (tetraglutamated pemetrexed) is 80-fold more potent than pemetrexed in inhibiting thymidylate synthase. Yet it is a poor drug candidate because it cannot readily cross the negatively charged cell membrane due to its own negative charge. We are developing LEAF-1401, a novel nanoliposomal encapsulation of gamma L-pentaglutamated pemetrexed. Because liposomes can readily be taken up by tumor cells, for its anti-tumor effect, LEAF-1401 can directly deliver pentaglutamated pemetrexed into tumor cells, bypassing the need for transmembrane folate carriers and FPGS which are both downregulated in resistant tumors. Methods: To measure drug levels in tumor, blood and various tissues (biodistribution), in vivo testing of LEAF-1401 and pemetrexed was conducted in a CT-26 murine colorectal carcinoma xenograft model. Animals were treated with a single dose of either LEAF-1401 (80mg/kg; equivalent to 32 mg/kg pemetrexed) or pemetrexed (118mg/kg). Tumor growth inhibition and clinical assessments were conducted. Animals were sacrificed: 5 mice per timepoint in each group and tumor, blood, liver, spleen and other tissues were harvested. Pentaglutamated pemetrexed levels were quantitatively analyzed by LC/MS/MS. Results: Compared to pemetrexed, LEAF-1401 treatment resulted in a 19-fold increase in exposure levels of pentaglutamated pemetrexed in the tumor and significant tumor growth inhibition. Plasma levels of pentaglutamated pemetrexed were high with LEAF-1401, but undetectable with pemetrexed. Like other liposomes, LEAF-1401 also resulted in accumulation of pentaglutamated pemetrexed in the liver and spleen (See Table below). Treatment appeared to be generally well tolerated. Conclusions: LEAF-1401, given at approximately a quarter of the equivalent pemetrexed dose, resulted in a 19-fold increase in pentaglutamate pemetrexed in tumor tissue compared to regular pemetrexed. LEAF-1401 represents a promising new class of novel nanoliposomal antifolates, that enhance the intratumoral delivery of potent polyglutamate antifolates, and improve antitumor activity while retaining an acceptable safety profile. [Table: see text]

scholarly journals Close Interactions between Mesenchymal Stem Cells and Neuroblastoma Cell Lines Lead to Tumor Growth Inhibition

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48654 ◽  
Author(s):  
Giovanna Bianchi ◽  
Fabio Morandi ◽  
Michele Cilli ◽  
Antonio Daga ◽  
Chiara Bocelli-Tyndall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Tumor Growth Inhibition ◽  
Neuroblastoma Cell Lines

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

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