scholarly journals 797 A novel anti-PD-1/IL15 bi-functional antibody with robust anti-tumor activity in multiple solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A832-A832
Author(s):  
Dan Lu ◽  
Tzu-Pei Chang ◽  
Zhanna Polonskaya ◽  
Stella Martomo ◽  
Xenia Luna ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Solid Tumors ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Novel Mutation ◽  
Systemic Toxicity ◽  
Tumor Rejection ◽  
Clinical Activity ◽  
List Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICI) such as PD-1/PD-L1 have revolutionized cancer therapy, but only a fraction of patients responded to approved ICIs; the majority are either resistant or quickly become refractory. IL-15 is a key cytokine promoting CD8+ T, NK, and NKT cell proliferation and has demonstrated clinical activity. Kadmon has established a cytokine fusion protein platform to extend the IL-15 serum half-life and direct its action to tumors and/or T cells in tumor microenvironment (TME).1–3 An important asset of this platform is KD050, an anti-PD1/IL15 bi-functional antibody with a novel mutation on the IL15 to lower the systemic toxicity of IL-15. Previous studies showed that KD0501 and its mouse surrogate2 were cis-presented to PD-1 and IL2/15Rß? co-expressed TILs. The simultaneous binding to both PD-1 and IL2Rß potentially maximized KD050 bi-functionality of PD-1 blockade and IL-15 stimulation, resulting in robust anti-tumor activity in a PD-1/PD-L1 resistant human PD-1/PD-L1 transgenic colon carcinoma model (hPD-1/PD-L1 CT26) and murine lung cancer model (LL/2), respectively. Here, we continue to evaluate KD050 surrogate anti-tumor activity in multiple murine solid tumor models.MethodsKD050 mouse surrogate, mPD-1 antibody m3A7 and anti-PD-1/ non-mutated IL15 fusion (wtKD050) were generated and characterized in vitro as done previously.1 2 Single-dose efficacy of KD050 mouse surrogate was evaluated in 12 syngeneic murine models (MC38, CT26, H22, LL/2, Pan02, A20, B16-F10, B16-BL6, Renca, Hepa1-6, RM-1 and EMT6), and anti-tumor efficacy was further evaluated in Pan02 model in different dose levels and frequencies. Briefly, tumor cells were subcutaneously transplanted to the mice and the treatment was started when tumors reached 100 mm3.ResultsKD050 surrogate showed similar potencies as the mPD-1 antibody m3A7 in binding to the soluble and cell expressed human PD-1 and blocking of the PD-L1 binding to PD-1. Comparing to wtKD050 (anti-PD-1/ non-mutated IL15 fusion), mutated IL15 fusion KD050 surrogate showed lower CD8 T cell stimulation in the CTLL2 and mouse spleen cell proliferation. In vivo, different levels of tumor regression were observed in all 12 models with no significant systemic toxicity. Furthermore, tumor rejection in some mice was achieved in the MC38, CT26, A20, H22, Pan02 and EMT6 models, and dose response anti-tumor efficacy was observed in Pan02 model.ConclusionsWe demonstrated that KD050 surrogate had very robust anti-tumor activity and low systemic toxicity in mice bearing multiple solid tumors. These findings suggest that the bi-functional antibody KD050 has encouraging therapeutic potential.ReferencesMartomo S. etc. Mol Cancer Ther February 1 2021;20(2):347–356; DOI: 10.1158/1535-7163.MCT-20-0457.Polonskaya Z. etc. AACR 2020 #2263.Polonskaya Z. etc. SITC 2020 #573Ethics ApprovalAll studies were conducted following an approved IACUC protocol. Although this study was not conducted in accordance with the FDA Good Laboratory Practice regulations, 21 CFR Part 58, all experimental data management and reporting procedures were in strict accordance with applicable Crown Bioscience, Inc. Guidelines and Standard Operating Procedures. The methods and results in the Final Study Report accurately reflect the raw data generated during the execution of the study.

CX-4945, An Orally Bioavailable Selective Inhibitor of Casein Kinase 2 (CK2), Exhibits Anti-Tumor Activity in Hematologic Malignancies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3512-3512
Author(s):  
Renee C Prins ◽  
Stephen Spurgeon ◽  
Jeffrey W Tyner ◽  
Luke B Fletcher ◽  
Abdusebur Jemal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Solid Tumors ◽  
Therapeutic Potential ◽  
Wide Spectrum ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Orally Bioavailable ◽  
Anti Tumor Activity

Abstract Abstract 3512 Background: CK2 is a highly conserved and constitutively active serine-threonine protein kinase that plays a fundamental role in maintaining cell survival through pro-proliferative, anti-apoptotic and pro-angiogenic signaling. It is comprised of two catalytic (α and α') and two regulatory (β) subunits. Overexpression and hyperactivation of CK2 has been well described in a variety of human solid tumors, and more recently, in hematologic malignancies including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphocytic leukemia (T-ALL), and multiple myeloma (MM). CK2 is known to support the viability of cancer cells through increased activation of the downstream PI3K/AKT signaling pathway, which results in cell-cycle progression, and suppression of apoptosis. Inhibition of CK2 has been shown to lead to preferential apoptosis of CLL, AML and myeloma cells. Studies have also demonstrated that CK2 inhibition in MM enhances the cytotoxic effect of chemotherapeutic drugs. Therefore, CK2 appears to be a rational target for novel therapies to treat hematologic malignancies. CX-4945 is a potent and orally bioavailable inhibitor of both isoforms of the CK2 catalytic subunits, and is the first small molecule inhibitor of CK2 to progress to human clinical trials. CX-4945 has been found to be highly selective for CK2 and has also been shown to inhibit phosphorylation of the CK2-specific S129 site of AKT and inhibit activation of the AKT pathway. Anti-tumor activity of CX-4945 has been validated in cancer cell lines and murine xenograft models, and biological activity was observed in early clinical trials with solid tumors and multiple myeloma. However, little is known about its possible effects in leukemias and lymphomas. Therefore, we explored the therapeutic potential of CX-4945 in 224 adult and pediatric patient samples across a wide spectrum of hematologic malignancies including AML, ALL, CLL, CML, CMML and leukemic phase lymphomas. Methods: Fresh primary cells from 224 patients were purified using a Ficoll gradient. Purified cells were then added to wells (5 × 104 per well) containing 10% serum containing media and four serial dilutions of CX-4945 (ranging from 10 nM to 10 μM). Three days after culturing cells in the presence or absence of each drug concentration, we performed a tetrazolium-based cell viability assay (MTS) to evaluate the effect of CX-4945 across a broad spectrum of primary hematologic malignancy samples. The viability data were normalized to untreated controls and used to calculate IC50 values. Results: Of the 7 categories of hematologic malignancies evaluated, all except for 2 (CMML and CML) demonstrated a subset of patients with significantly decreased viability (IC50 < 1 μM) in response to CX-4945 (Table 1). Investigations evaluating the effect of CK2 on downstream targets such as AKT and other cellular protein kinases, as well as studies exploring CK2 expression in AML are ongoing and will be presented. Conclusions: Our data confirms that CX-4945 demonstrates significant pre-clinical activity across a broad range of hematologic malignancies, and also confirms previous findings that CK2 may play a significant role in the tumorigenesis of certain hematologic malignancies. CX-4945 may be an attractive compound for clinical development, particularly in lymphoid malignancies such as CLL. Future studies will focus on the identification of highly sensitive subsets of cells, further defining the mechanistic details of the CK2 pathway in hematologic malignancies, and exploring the specific features that drive response to CK2 inhibition. Disclosures: Druker: Cylene Pharmaceuticals: Consultancy. Loriaux:Cylene Pharmaceuticals: Research Funding.

Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15068-e15068
Author(s):  
Vaibhav G. Patel ◽  
Qian Qin ◽  
Bo Wang ◽  
Mahalya Gogerly-Moragoda ◽  
George Mellgard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Model Systems ◽  
Beta Blockade ◽  
Clinical Activity ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Adrenergic Signaling

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.

scholarly journals The role of miR-31-5p in the development of intervertebral disk degeneration and its therapeutic potential

2020 ◽  
Author(s):  
Yong Zhou ◽  
Jiqing Su ◽  
Mingsi Deng ◽  
Wei Zhang ◽  
Dongbiao Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intervertebral Disc ◽  
Therapeutic Potential ◽  
Cell Structure ◽  
Methylation Status ◽  
Intervertebral Disk ◽  
Luciferase Assay ◽  
List Type ◽  
In Vitro Experiments

AbstractIntervertebral disc degeneration (IDD) refers to the abnormal response of cell-mediated progressive structural failure. In order to understand the molecular mechanism of the maintenance and destruction of the intervertebral disc, new IDD treatment methods are developed. Here, we first analyzed the key regulators of IDD through miRNA microarrays. The cell structure and morphology were discovered by Histological and radiographic. Then, the level of miR-31-5p was disclosed by qRT-PCR. The association between miR-31-5p and SDF-1/CXCR7 axis was discovered by 3’-Untranslated region (UTR) cloning and luciferase assay. The apoptosis of cells under different treatments was disclosed by Flow cytometer. The cell proliferation was discovered by EdU assay. Finally, the protein levels of SDF-1, CXCR7, ADAMTS-5, Col II, Aggrecan and MMP13 were discovered by Western blot. The results show that miR-31-5p is a key regulator of IDD and its level is down-regulated in IDD. Overexpression of miR-31-5p facilitates NP cell proliferation, inhibits apoptosis, facilitates ECM formation and inhibits the level of matrix degrading enzymes in NP cells. The SDF-1/CXCR7 axis is the direct target of miR-31-5p. miR-31-5p acts on IDD by regulating SDF-1/CXCR7. In vitro experiments further verified that the up-regulation of miR-31-5p prevented the development of IDD. In conclusion, overexpression of miR-31-5p can inhibit IDD by regulating SDF-1/CXCR7.HighlightsThe level of miR-31-5p decreased in NP;The increase in methylation status is consistent with the decrease in miR-31-5p levels;Upregulation of miR-31-5p stimulated NP cell proliferation, restrained apoptosis, promoted ECM;SDF-1/CXCR7 axis is the target of miR-31-5p;Overexpression of miR-31-5p inhibits IDD through SDF-1/CXCR7;In vitro experiments proved up-regulation of miR-31-5p prevented the development of IDD.

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Phase II trial of Voyager-V1 (vesicular stomatitis virus expressing human IFNβ and NIS, VV1), in combination with cemiplimab (C) in patients with NSCLC, melanoma, HCC or endometrial carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Mario Sznol ◽  
Jose Lutzky ◽  
Alex A. Adjei ◽  
Steven Francis Powell ◽  
Aiwu Ruth He ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Solid Tumors ◽  
Vesicular Stomatitis Virus ◽  
Checkpoint Inhibitors ◽  
Oncolytic Viruses ◽  
Type I ◽  
Sodium Iodide Symporter ◽  
Term Survival ◽  
Vesicular Stomatitis ◽  
Anti Tumor Activity

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

573 A novel human anti-PD1/IL15 bi-functional protein with robust anti-tumor activity and low systemic toxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A607-A607
Author(s):  
Dan Lu ◽  
Zhanna Polonskaya ◽  
Tzu-Pei Chang ◽  
Stella Martomo ◽  
Xenia Luna ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Weight Loss ◽  
Body Weight ◽  
Fusion Protein ◽  
Body Weight Loss ◽  
Systemic Toxicity ◽  
Wild Type ◽  
Functional Protein ◽  
Bifunctional Protein ◽  
Anti Tumor Activity

BackgroundIL-15 is a key cytokine promoting CD8+ T, NK, and NKT cell proliferation and has demonstrated clinical activity in cancer patients without evidence of any Treg stimulation.1 2 However, its short half-life and systemic toxicity limit its clinical utility. Kadmon has established an IL-15 fusion protein platform to extend the IL-15 serum half-life and direct its action to the tumor microenvironment.3 A major asset of this platform is anti-PD1/IL15 bifunctional protein. To test the bifunctionality hypothesis of this fusion protein in murine models, four different formats of the surrogate bi-functional proteins were engineered by fusing mouse IL-15 to a mouse-human chimeric anti-mouse PD1 antibody (m3A7). We presented earlier that the single IL-15 N-terminal fusion to anti-PD1 antibody (1N-IL-15/m3A7) showed significantly stronger anti-tumor activity in vivo mainly due to the cis-presentation to the PD1 and IL2Rβγ co-expressed on TILs. The cis-presentation potentially maximizes the bi-functionality of PD1 blockade and IL-15 stimulation.4 Here, the therapeutic single IL-15 N-terminal fusion antibodies containing a novel human PD1 antagonist antibody (38B2) and either wild-type IL15 (1N-IL-15/38B2) or mutated 65S-IL15 (65S-1N-IL-15/38B2) have been constructed; their anti-PD1 functions, IL15 stimulation and anti-tumor activities were evaluated.MethodsPurified 1N-IL-15/38B2 and 65S-1N-IL-15/38B2 were generated and characterized in vitro.4 The anti-tumor activities were examined in the human-PD-1/PD-L1 transgenic BALB/c mice subcutaneously transplanted with the human-PD-L1 positive CT26 colon carcinoma. The treatment was started when tumors reached 100 mm3 (IP, QW).ResultsAll 1N-IL-15/anti-PD1 fusions showed similar potencies in binding to the soluble and cell expressed human PD1 and blocking the hPDL-1 binding to hPD1. Comparing to wild-type 1N-IL-15/38B2, mutated 65S-1N-IL-15/38B2 showed lower stimulation (>150 folds) in the M07e, CTLL2, mouse spleen cells and hPBMC (mainly CD8T+ T cell) proliferation. When we treated hPDL1-CT26 tumor transplanted hPDL1-hPD1 transgenic mice with 65S-1N-IL-15/38B2 at 6 mg/kg, 80% of tumor growth inhibition (TGI) was achieved with no body-weight loss. Although wild-type 1N-IL-15/38B2 at 3 mg/kg demonstrated similar efficacy, a significant mouse body-weight loss was observed and 1/3 mice died after second injection. No anti-tumor activity was observed for 65S-1N-IL-15 non-target fusion in 6 mg/kg.ConclusionsThe previous observation of robust anti-tumor activity of surrogate 1N-IL-15/m3A7 in PD1 resistant LL2 model was replicated with the therapeutic bifunctional protein in this study. We also found that lower stimulation 65S-1N-IL-15/38B2 showed strong anti-tumor activity with significant low systemic toxicity; suggesting that the 65S mutation increased the therapeutic window of this bi-functional proteinReferencesGoldrath, AW etc. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med 2002; 195:1515–1522.Waldmann TA. Cytokines in Cancer Immunotherapy. Cold Spring Harb Perspect Biol 2018;103. Martomo, S. etc. ESMO 2019 1221P; SITC 2019 P#4854. Polonskaya Z. etc. AACR 2020 #2263

scholarly journals 260 CD47 antibody, AO-176 demonstrates potent anti-tumor activity in pre-clinical solid tumor xenografts as a single agent and in combination with multiple classes of therapeutics

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A282-A282
Author(s):  
Gabriela Andrejeva ◽  
Benjamin Capoccia ◽  
Rachel Delston ◽  
Michael Donio ◽  
Ronald Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
In Vivo Efficacy ◽  
Acidic Conditions ◽  
Anti Tumor Activity

BackgroundCD47 is a cell surface protein expressed on tumors that binds SIRPα on macrophages and dendritic cells resulting in a ”don’t eat me” signal that allows tumors to evade phagocytosis. The highly differentiated monoclonal antibody, AO-176 directly targets CD47 and blocks this signal. AO-176 is currently being tested in phase 1 clinical trials in solid tumors and multiple myeloma. The purpose of this study was to assess in vivo efficacy of AO-176 in solid tumor models as a single agent and in combination with multiple classes of therapeutics including chemotherapeutics, monoclonal antibodies and T-cell checkpoint inhibitors.MethodsCD47 expression levels on solid tumor types were assessed by immunohistochemistry using a tumor tissue microarray. Cell-based binding was performed using flow cytometry under acidic and physiologic pH conditions to characterize the functional activity of AO-176 in the two pH environments representing tumor and normal physiologic environments. In vivo studies were performed using models of solid cancers.ResultsAll 12 solid tumor indications assessed were positive for cell membrane localized CD47 (3.3–98.6 H-scores). Cell-based binding of AO-176 to solid cancer cell lines was significantly greater (1.6–25-fold decrease in EC50, 11–39% increase in Bmax) in acidic conditions as compared to a neutral pH environment, demonstrating improved binding in the lower pH environments associated with solid tumors. AO-176 treatment in solid tumor xenograft models resulted in potent anti-tumor activity as a monotherapy (40–58% TGI) and in combination with paclitaxel in an ovarian model (99% TGI), cisplatin in an ovarian model (84% TGI), cisplatin in a gastric model (76% TGI), and an anti-VEGFR-2 in a gastric model (86% TGI). In vivo efficacy of CD47 blockade alone (~33% TGI) and in combination with anti-PD-1 (74% TGI) and anti-PD-L1 (80% TGI) T-cell checkpoint inhibitors was observed in a syngeneic model of colon cancer using a surrogate anti-CD47 blocking antibody.ConclusionsAO-176 is a differentiated anti-CD47 agent that in addition to blocking the don’t eat me signal, directly kills cancer cells, shows lower binding to normal cells such as RBCs and demonstrates increased binding activity in acidic conditions as found in the microenvironment of solid tumors. AO-176 also elicits potent anti-tumor activity in xenograft and syngeneic models as a single agent and in combination with chemotherapies, monoclonal antibodies and T-cell checkpoint inhibitors. AO-176 is currently in clinical trials as a single agent and in combination in patients with select solid cancers (NCT03834948) and in multiple myeloma (NCT04445701).

A phase I study of AK119, an anti-CD73 monoclonal antibody, in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, in patients with advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2675-TPS2675
Author(s):  
Ben Markman ◽  
Amy Hsin-Chieh Hsieh ◽  
Jermaine Coward ◽  
Matteo S. Carlino ◽  
Sophia Frentzas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Open Label ◽  
Tumor Types ◽  
Anti Tumor Activity

TPS2675 Background: AK119 is a humanized IgG1 monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73, a cell surface enzyme that converts adenosine monophosphate (AMP) into adenosine. Adenosine has been shown to facilitate tumor-mediated evasion. CD73 inhibition may therefore reduce adenosine accumulation and promote anti-tumor immunity. AK104 is a recombinant humanized IgG1 bispecific antibody that simultaneously binds to programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte-associated antigen protein 4 (CTLA-4). Preliminary data from phase I and II studies suggest that AK104 has encouraging anti-tumor activity in selected tumor types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 mAbs. Preclinical studies show that CD73 inhibition synergistically increases the anti-tumor activity of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs). Published early clinical data suggests that anti-CD73 therapy in combination with ICIs produces improved clinical outcomes. Thus, AK119 plus AK104 is postulated to have synergistically enhanced anti-tumor activity compared to the administration of anti-CD73 monotherapy or ICIs alone. Methods: This is a phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced solid tumors that are refractory to standard therapies. The primary objective is to assess safety, tolerability and dose limiting toxicity; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of AK119 in combination with AK104. Secondary objectives are to evaluate antitumor activity, PK and AK119 immunogenicity. The dose-escalation phase will evaluate 5 dose levels of AK119 (1mg/kg to 40 mg/kg Q2W IV) in combination with 6mg/kg AK104 Q2W IV using a 3+3+3 study design. Eligible pts will receive a single dose of AK119 on C0D1 of a 14-day “lead-in” period. Thereafter, from C1D1 pts will receive AK119 in combination with AK104 on a 28-day cycle, until unacceptable toxicity, confirmed progressive disease, subject withdrawal, or for a maximum of 24 months. The “lead-in” period is only applicable for dose-escalation cohorts. Any dose-escalation cohort not exceeding the MTD may be expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, PK/ PD, immunogenicity, and preliminary anti-tumor activity. Cohort 1 is currently in progress with the first patient enrolled in January 2021. For the dose-expansion phase, cohorts of pts with advanced/metastatic pancreatic cancer or MSS/pMMR colorectal cancer will be enrolled. Cohorts of other tumor types may be added based on emerging pharmacodynamic and anti-tumor response data. Clinical trial information: NCT04572152.

Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3004-3004 ◽  
Author(s):  
Lawrence Fong ◽  
Patrick M. Forde ◽  
John D. Powderly ◽  
Jonathan Wade Goldman ◽  
John J. Nemunaitis ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adaptive Design ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
Dose Schedule ◽  
Clinical Activity ◽  
Specific Expansion ◽  
Anti Tumor Activity

3004 Background: Adenosine production in the tumor leads to immunosuppression through A2aR on infiltrating immune cells. CPI-444 is an oral A2aR antagonist with single agent(SA) anti-tumor activity in pre-clinical models. This phase 1/1b clinical trial uses a 2-step adaptive design to evaluate CPI-444 as a SA and in combination (combo) with the anti-PDL1 antibody, atezolizumab (atezo). We report results of RCC and NSCLC cohorts. Methods: Primary objectives: safety, efficacy and to identify optimal dose/schedule. Step 1 utilized 3 SA and 1 combo cohort to select dose/schedule. Step 2 included disease-specific expansion cohorts including RCC and NSCLC. Eligible pts had selected advanced cancers and failed standard therapies including checkpoint inhibitors. Results: 34 pts have enrolled and 25 pts were evaluable for response (Table 1). Median prior regimens: 3 (range,1-5) and most pts were resistant/refractory to anti PD1/PDL1 therapy (R/R). Most common AEs were Gr 1 nausea (n = 3) and pyrexia (n = 3); Gr 3 tachycardia was the only possibly related SAE. The selected Step 2 doses were CPI-444 100mg BID as a SA and in combo with atezo 840mg IV q2 weeks. The disease control rate (DCR, CR+PR+SD; duration 2 mo to > 8 mo) for pts with RCC and NSCLC cohorts were 86% and 50%, (100% and 43% for R/R pts), respectively. DCRs were similar in the SA and combo cohorts. Of 7 evaluable RCC pts, 1 pt has an ongoing PR (SA cohort, > 4 mo) and 5 have ongoing SD, duration 3 mo to > 8 mo (2 SA, 3 combo). Biopsy of the PR pt showed no detectable tumor and infiltration with CD8+ lymphocytes. In 18 evaluable NSCLC pts, 1 PR (PDL1 negative pt) and 8 SD were seen. PRs and SDs were seen in R/R pts and in PDL1 negative pts in both diseases. Conclusions: CPI-444 is well tolerated and shows anti-tumor activity in RCC and NSCLC pts as a SA and in combo. Pts who are R/R to anti PD1/PDL1 therapy and who are PDL1 negative can also benefit. Clinical trial information: NCT02655822. [Table: see text]

Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5013-5013 ◽  
Author(s):  
Sumanta K. Pal ◽  
Neeraj Agarwal ◽  
Yohann Loriot ◽  
Cristina Suarez Rodriguez ◽  
Parminder Singh ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Mucosal Inflammation ◽  
Clinical Activity ◽  
Mri Scans ◽  
Metastatic Sites ◽  
Ecog Ps

5013 Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences < 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received ≥2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960 .

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