P2, N=11, Not yet recruiting, Henan Cancer Hospital

We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.

Ex-vivo studies confirmed higher efficacy of BTX-A51 on RUNX1 -mutated myeloblasts and demonstrate synergy with azacitidine and venetoclax. Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches.

P2, N=29, Active, not recruiting, City of Hope Medical Center | Trial completion date: Aug 2024 --> Dec 2024

P1/2, N=70, Not yet recruiting, Lamassu Bio Inc

Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors...Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.

Here, we show the therapeutic potential of chemotherapeutic drugs (doxorubicin, cisplatin) and telomerase-specific oncolytic adenoviruses (OBP-301, p53-armed OBP-702) to induce ICD in human OS cells (U2OS, MNNG/HOS, SaOS-2) and murine OS cells (NHOS). Subcutaneous NHOS tumor models demonstrated that intratumoral injection of OBP-702 significantly increased the tumor infiltration of cytotoxic CD8+ T cells and induced the abscopal effect against non-treated tumors compared with OBP-301. Our results suggest that OBP-702 is a promising antitumor reagent to induce ICD with secretion of ATP and HMGB1 and the abscopal effect against OS.

Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

The patient is in a general good condition now without any relapse of abdominal lymph node for over a year. On this basis, we propose that the combination therapy of oncolytic virus and capecitabine could be a promising clinical therapeutic strategy for unresectable recurrent lymph node metastasis in CRC patients.

Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.

Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

P1, N=12, Not yet recruiting, Michael Wagner

P2, N=29, Active, not recruiting, City of Hope Medical Center | Trial completion date: Mar 2024 --> Aug 2024 | Trial primary completion date: Mar 2024 --> Aug 2024

We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

Patients with up-regulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A+ DCs and GZMK+CD8+ T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provided insights into the relevant cellular processes following oncolytic virotherapy.

P1, N=7, Terminated, Roswell Park Cancer Institute | N=36 --> 7 | Trial completion date: Aug 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2024 --> Jan 2024; low accrual

P2, N=30, Not yet recruiting, Fudan University | Initiation date: Jan 2024 --> Dec 2024

P1, N=12, Suspended, Fox Chase Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Mar 2025

P1, N=11, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

P4, N=66, Recruiting, Beijing Tsinghua Chang Gung Hospital | Not yet recruiting --> Recruiting | Trial completion date: Apr 2024 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2026

P2, N=32, Not yet recruiting, First Affiliated Hospital Bengbu Medical College

This study demonstrates the potential efficacy of combining H101 with nivolumab in treating refractory advanced HCC, with well-tolerated toxicities.

OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.

PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.

P2, N=30, Not yet recruiting, Fudan University

P2, N=29, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

We conducted an unprecedented work via a WES-based approach and provided preliminary insights into H101 treatment-induced genetic aberrations in which some genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) could be considered potential therapeutic targets of H101-containing treatment in cervical carcinoma. Moreover, the therapy-associated characteristics such as clonal evolution and a mutational signature may warrant further evaluation of H101 in clinical settings for treating cervical carcinoma.

We have developed tumor suppressor gene p53-armed oncolytic adenovirus(OBP-702), and have clarified therapeutic effects on PDAC cells. In this study, we investigate the therapeutic effect of OBP-702 on PDAC CAF.

The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.

In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.

P1/2, N=95, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting | N=38 --> 95

Before, 10 mg dexamethasone was intravenously administered...Exploratory endpoints are the changes from baseline in CD4+, CD8+, Treg, Th1 and Th2. The adverse events will be monitored.

H101 injection may enhance primary tumor regression for locally advanced cervical cancer, with an acceptable safety profile. This treatment regimen should undergo further prospective randomized controlled studies.ChiCTR-OPC-15006142.

P2, N=25, Recruiting, Fudan University | Not yet recruiting --> Recruiting

P1, N=12, Recruiting, Fox Chase Cancer Center | Trial primary completion date: Nov 2024 --> Mar 2024

Proteasome-mediated degradation was determined using the proteasome, inhibitor MG-132, while MYC half-life was measured using pulse chase experiments in the presence of cycloheximide. Co-treatment with COTI-2 and the MYC inhibitor, MYCi975 resulted in synergistic growth inhibition in all 4 mutant p53 cell lines investigated. The dual ability of COTI-2 to reactivate mutant p53 and degrade MYC should enable this compound to have broad application as an anticancer drug.

P2, N=38, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

P2, N=14, Terminated, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2023 --> May 2022 | Active, not recruiting --> Terminated; Sponsor closed study

COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.

P1, N=11, Active, not recruiting, City of Hope Medical Center | N=19 --> 11 | Trial completion date: Dec 2022 --> Dec 2023