A poliovirus and method for treating human glioma

Abstract

This application provides a poliovirus and method for treating human glioma, comprising a composition of oncolytic poliovirus and an Ommaya capsule, a delivery method, and uses.

Description

Technical Field

[0001] This application relates to the field of biomedicine, specifically to a poliovirus and method for the treatment of human glioma. Background Technology

[0002] Glioblastoma (GBM) is the most malignant, aggressive, and has the worst survival rate among brain tumors. GBM accounts for 14.5% of all primary central nervous system tumors and 48.6% of all malignant primary central nervous system tumors. US registry data from 2011-2015 shows an age-corrected mean annual incidence rate of 3.21 per 100,000. GBM incidence is influenced by age and sex. The average age of diagnosis is 65 years, with a peak incidence between 75 and 84 years, and it is more common in men than women. According to statistics from the National Cancer Center of China, in 2016, there were 109,000 new cases of malignant brain and central nervous system tumors in my country, approximately 7.88 per 100,000 people, with an age-standardized incidence rate (ASIRW) of 5.57 per 100,000 people, of which GBM accounted for about 30%.

[0003] GBM has a poor prognosis, with a 5-year survival rate of less than 5%. It has been reported that the median overall survival (OS) for GBM patients undergoing maximum safe resection is 15.5 months, compared to 11.7 months for those undergoing subtotal resection and 5.9 months for those without resection. A large single-center study conducted between 2010 and 2017 collected follow-up data from 967 newly diagnosed glioblastoma (nGBM) patients who underwent surgery at Huashan Hospital affiliated with Fudan University, showing a median OS of 16.3 months (95% confidence interval [CI], 15.4–17.2). Despite decades of research, the survival rate of GBM patients has not significantly improved, and almost all GBM patients experience recurrence post-surgery. Recurrent tumors are even more aggressive, with a median OS of only about 6 months. Recurrence typically signifies a rapid deterioration in survival and is a leading cause of death. Therefore, GBM recurrence has become a significant clinical problem, urgently requiring effective treatments to improve patient survival.

[0004] GBM treatment primarily involves surgical resection, combined with radiotherapy, chemotherapy, and other comprehensive therapies. Currently, lomustine (CCNU), carmustine, carmustine implantable wafers, temozolomide (TMZ), bevacizumab (BEV), and therapeutic electric fields (TTF) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of GBM, but they only offer limited improvements in patient survival. Most trials show that the median progression-free survival (PFS) and median overall survival (OS) for GBM are 6.2–7.5 months and 14.6–16.7 months, respectively. Most patients typically experience disease progression and corresponding symptom worsening within 6 months of diagnosis.

[0005] For example, a single-arm phase I / II study of G47Δ in patients with recurrent glioblastoma (rGBM) enrolled 13 patients, allowing two intratumoral injections. Results showed a median overall survival (mOS) of 7.3 months (95% CI, 6.2–15.2) and a 1-year survival rate of 38.5%. The median progression-free survival (PFS) was 8 days (95% CI, 7–34). Three patients survived for more than 46 months. At 2-year evaluation, one patient achieved a complete response (CR) and one patient achieved a confirmed partial response (PR). Another phase II repeated-dose (6-dose) clinical study of G47Δ in patients with rGBM showed a 1-year survival rate of 84.2% (95% CI, 60.4–96.6%) after initiation of G47Δ treatment, with an mOS of 20.2 months (95% CI, 16.8–23.6).

[0006] For example, the results of a Phase I clinical trial in the United States of PVSRIPO, an oncolytic virus product modified from the Sabin I attenuated strain of poliovirus, showed that 61 patients who received a single dose of PVSRIPO (with a dose range of 10) were able to recover. 7 ~10 10 TCID 50 The 2-year and 3-year survival rates for rGBM patients treated with (between) were 21% (95% CI, 11-33%), while the survival rate in the historical control group was lower and continued to decline, with a 24-month survival rate of 14% (95% CI, 8-21%) and a 36-month survival rate of 4% (95% CI, 1-9%).

[0007] However, there is currently no universally recognized effective treatment for recurrent glioblastoma (rGBM) in China.

[0008] There are currently more than 20 different strains of oncolytic viruses, such as herpes simplex virus, adenovirus, measles virus, parvovirus, Newcastle disease virus, reovirus, poliovirus, and Zika virus, which are undergoing clinical trials for the treatment of rGBM.

[0009] However, most oncolytic viruses currently used in the treatment of glioblastoma are administered locally via direct intratumoral injection. This method carries risks such as bleeding, infection, and tissue damage, and is difficult to administer to deep lesions. Furthermore, intravenous administration requires overcoming the blood-brain barrier to reach the tumor bed, and the presence of specific neutralizing antibodies in the blood also limits the spread and effectiveness of oncolytic viruses.

[0010] Therefore, in order to improve the therapeutic effect of oncolytic viruses, it is necessary to further optimize the combination therapy strategy, improve the delivery mode of oncolytic viruses, improve the bioavailability of viruses, and enhance the anti-tumor immune response of oncolytic viruses. Summary of the Invention

[0011] This application provides a composition comprising an oncolytic virus and an Ommaya capsule. In some embodiments, the oncolytic virus comprises poliovirus. In some embodiments, the oncolytic virus comprises a recombinant poliovirus injection. In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 1.25×10 6 CCID 50 1.5×10 6 CCID 50 2.0×10 6 CCID 50 2.5×10 6 CCID 50 3.0×10 6 CCID 50 3.5×10 6 CCID 50 4.0×10 6 CCID 50 4.5×10 6 CCID 50 5.0×10 6 CCID 50 5.5×10 6 CCID 50 6.0×10 6 CCID 50 6.5×10 6 CCID 50 7.0×10 6 CCID 50 7.5×106 CCID 50 8.0×10 6 CCID 50 8.5×10 6 CCID 50 9.0×10 6 CCID 50 1.0×10 7 CCID 50 1.5×10 7 CCID 50 2.0×10 7 CCID 50 2.5×10 7 CCID 50 3.0×10 7 CCID 50 3.5×10 7 CCID 50 4.0×10 7 CCID 50 4.5×10 7 CCID 50 5.0×10 7 CCID 50 5.5×10 7 CCID 50 6.0×10 7 CCID 50 6.5×10 7 CCID 50 7.0×10 7 CCID 50 7.5×10 7 CCID 50 8.0×10 7 CCID 50 8.5×10 7 CCID 50 9.0×10 7 CCID 50 Or 1.0×10 8 CCID 50 .

[0012] In some embodiments, the delivery portion of the Ommaya bag is placed within the tumor. In some embodiments, the Ommaya bag is connected to an external drug delivery pump. The delivery portion of the Ommaya bag is the catheter portion of the Ommaya.

[0013] In some embodiments, the tumor is a human tumor. In some embodiments, the tumor is a glioma. In some embodiments, the tumor is a glioblastoma. In some embodiments, the tumor is a recurrent glioblastoma. In some embodiments, the tumor is a grade IV glioblastoma excluding the IDH-mutant type.

[0014] This application also provides a method for delivering an oncolytic virus via an Ommaya capsule. In some embodiments, the oncolytic virus is slowly delivered via the Ommaya capsule at an infusion rate of 0.5 mL / hour.

[0015] In some embodiments, the oncolytic virus comprises poliovirus. In some embodiments, the oncolytic virus comprises recombinant poliovirus. In some embodiments, the oncolytic virus comprises a recombinant poliovirus injection.

[0016] In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 1.25×10 6 CCID 50 1.5×10 6 CCID 50 2.0×10 6 CCID 50 2.5×10 6 CCID 50 3.0×10 6 CCID 50 3.5×10 6 CCID 50 4.0×10 6 CCID 50 4.5×10 6 CCID 50 5.0×10 6 CCID 50 5.5×10 6 CCID 50 6.0×10 6 CCID 50 6.5×10 6 CCID 50 7.0×10 6 CCID 507.5×10 6 CCID 50 8.0×10 6 CCID 50 8.5×10 6 CCID 50 9.0×10 6 CCID 50 1.0×10 7 CCID 50 1.5×10 7 CCID 50 2.0×10 7 CCID 50 2.5×10 7 CCID 50 3.0×10 7 CCID 50 3.5×10 7 CCID 50 4.0×10 7 CCID 50 4.5×10 7 CCID 50 5.0×10 7 CCID 50 5.5×10 7 CCID 50 6.0×10 7 CCID 50 6.5×10 7 CCID 50 7.0×10 7 CCID 50 7.5×10 7 CCID 50 8.0×10 7 CCID 50 8.5×10 7 CCID 50 9.0×10 7 CCID 50 Or 1.0×10 8 CCID 50 .

[0017] In some embodiments, the Ommaya capsule is placed within the tumor. In some embodiments, the Ommaya capsule is connected to an external drug delivery pump.

[0018] In some embodiments, the tumor is a human tumor. In some embodiments, the tumor is a glioma. In some embodiments, the tumor is a glioblastoma. In some embodiments, the tumor is a recurrent glioblastoma. In some embodiments, the tumor is a grade IV glioblastoma excluding the IDH-mutant type.

[0019] This application also provides the use of the above-described composition in the preparation of a drug delivery device for treating glioblastoma.

[0020] In some embodiments, the drug delivery device further includes an external drug delivery pump. In some embodiments, the drug delivery device enables continuous infusion of oncolytic virus into the glioblastoma via the Ommaya capsule. In some embodiments, the drug delivery device enables slow delivery of oncolytic virus via the Ommaya capsule at an infusion rate of 0.5 mL / hour.

[0021] This application provides a method for treating glioblastoma, the method comprising administering poliovirus to a subject in need, wherein the poliovirus is delivered via an Ommaya sac. In some embodiments, the delivery portion of the Ommaya sac is placed within the tumor. In some embodiments, the Ommaya sac is connected to an external drug delivery pump.

[0022] In some embodiments, the oncolytic virus is slowly delivered via the Ommaya capsule at an infusion rate of 0.5 mL / hour.

[0023] In some embodiments, the poliovirus is prepared as an injectable solution.

[0024] In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 In some embodiments, the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 1.25×10 6 CCID 50 1.5×10 6 CCID 50 2.0×10 6 CCID 50 2.5×10 6 CCID 50 3.0×10 6 CCID 50 3.5×10 6 CCID50 、4.0×10 6 CCID 50 、4.5×10 6 CCID 50 、5.0×10 6 CCID 50 、5.5×10 6 CCID 50 、6.0×10 6 CCID 50 、6.5×10 6 CCID 50 、7.0×10 6 CCID 50 、7.5×10 6 CCID 50 、8.0×10 6 CCID 50 、8.5×10 6 CCID 50 、9.0×10 6 CCID 50 、1.0×10 7 CCID 50 、1.5×10 7 CCID 50 、2.0×10 7 CCID 50 、2.5×10 7 CCID 50 、3.0×10 7 CCID 50 、3.5×10 7 CCID 50 、4.0×10 7 CCID 50 、4.5×10 7 CCID 50 、5.0×10 7 CCID 50 、5.5×10 7 CCID 50 、6.0×10 7 CCID 50 、6.5×10 7 CCID 50 、7.0×10 7 CCID 50 、7.5×10 7 CCID 50 、8.0×10 7 CCID 50 、8.5×107 CCID 50 9.0×10 7 CCID 50 Or 1.0×10 8 CCID 50 .

[0025] In some embodiments, the method includes placing the delivery portion of the Ommaya capsule within a tumor. In some embodiments, the method includes connecting the Ommaya capsule to an external drug delivery pump.

[0026] In some embodiments, the tumor is glioblastoma. In some embodiments, the tumor is recurrent glioblastoma. In some embodiments, the tumor is grade IV glioblastoma excluding IDH mutations. In some embodiments, the tumor is IDH wild-type glioblastoma.

[0027] In some implementations, the subject's glioblastoma has an imagingly measurable lesion, for example, an imaging finding that the tumor size is ≥1 cm and ≤5.5 cm, for example, by enhanced MRI.

[0028] The composition and method provided in this application have the following advantages: 1) The poliovirus provided in this application can proliferate in tumor cells and replicate at a very low level in normal cells; 2) The poliovirus provided in this application can selectively kill GBM cells that highly express CD155, while having a very low killing effect on normal human cells and tumor cells that do not express CD155, demonstrating cell-targeted killing specificity with CD155 as the target; 3) A single intratumoral administration of the poliovirus provided in this application can produce significant and durable antitumor activity; 4) The poliovirus provided in this application has good safety; 5) The poliovirus provided in this application can be delivered via Ommaya capsule, allowing for continuous intratumoral administration under pressure as needed; 6) The poliovirus provided in this application can be delivered to the tumor at an infusion efficiency of 0.5 mL / hour via Ommaya capsule; 7) The poliovirus provided in this application can enhance the intratumoral administration effect via Ommaya capsule.

[0029] Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in the accompanying drawings and specification of this application are merely exemplary and not restrictive. Attached Figure Description

[0030] The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows:

[0031] Figure 1 The figure shows the Kaplan-Meier curve of overall survival compared to historical control (CGGA) data.

[0032] Figure 2 The image displayed is the plasmid map of the JL15003 project. Detailed Implementation

[0033] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification.

[0034] Terminology Definition

[0035] The term "poliovirus" refers to a virus belonging to the genus Enterovirus of the family Picornaviridae. The poliovirus includes wild-type polioviruses of type I, II, or III. It also includes recombinant polioviruses, such as attenuated variants of poliovirus, for example, the variant constructed by Ming Te Yeh et al. (Genetic stabilization of attenuated oral vaccines against poliovirus types 1 and 3, Nature 2023 Jul;619(7968):135-142.). In one embodiment, the poliovirus is an attenuated poliovirus (with lower neurotoxicity), such as the Sabin strain (which may also be type I, II, or III Sabin strains).

[0036] The term "recombinant poliovirus injection" refers to a product derived from Sabin I polio vaccine through genetic recombination. In one embodiment, the recombinant poliovirus injection replaces the IRES sequence of Sabin I with the internal ribosome entry site (IRES) sequence of human rhinovirus type II. The recombinant sequence is constructed by removing the Sabin I poliovirus type I vaccine IRES sequence (110 nt-742 nt) from the viral genome and inserting the human rhinovirus type II IRES sequence into the original position. The resulting recombinant sequence is: 5' human rhinovirus type II IRES sequence — Sabin I poliovirus type I vaccine protein-coding sequence — 3' untranslated region. This recombinant virus exhibits CD155 targeting and highly selective replication within tumor cells, but cannot replicate in normal cells. For example, the recombinant poliovirus injection could be JL15003 injection (code name JL15003).

[0037] Genome sequence (full genome length 7332 nt):

[0038]

[0039] The term "Ommaya capsule" refers to a neurosurgical instrument used for intracerebral drug delivery in the treatment of brain diseases. An Ommaya capsule may comprise a mushroom-shaped, self-sealing reservoir and a drainage tube / catheter that passes through a small opening in the skull to reach the lateral ventricle. The dome of the reservoir is made of specially thickened silicone. Through the catheter within the capsule, the poliovirus described in this application can be directly delivered to the brain lesion area, increasing drug concentration, reducing systemic side effects, and enhancing the therapeutic effect on tumors.

[0040] The term "external drug delivery pump" typically refers to a device used with an Ommaya capsule to deliver drugs into the ventricles of the brain. This pump can be a simple manual syringe or a more complex mechanical or electronic device used to precisely control the volume and rate of drug delivery. Invention Details

[0042] In this application, recombinant oncolytic poliovirus infects and kills GBM cells, inducing GBM cell apoptosis and releasing danger-associated molecular pattern (DAMP) signals and tumor-associated antigens, triggering specific immune killing against GBM cells. Additionally, antigen-presenting cells are infected with recombinant oncolytic poliovirus in JL15003 injection solution, thereby triggering a pro-inflammatory response induced by innate antiviral type I interferon and pathogen-associated molecular pattern (PAMP) signals. The production of tumor-associated antigens, the appearance of DAMP and PAMP signals, the activation of pro-inflammatory tumor-associated macrophages, the release of cytokines, and the activation of specific T cells by antigen-presenting cells after viral killing of tumor cells collectively promote the acquired anti-tumor immune effector cell response.

[0043] In this application, in vitro proof-of-concept / pharmacodynamic studies of recombinant oncolytic poliovirus (e.g., JL15003 injection) showed that JL15003 is a conditionally replicating oncolytic virus that can proliferate in tumor cells but replicates at extremely low levels in normal cells. JL15003 injection selectively kills CD155-overexpressing GBM cells, particularly exhibiting significant selective killing ability in the temozolomide-resistant U138MG cell line, even stronger than the temozolomide-sensitive U87MG cell line. However, it has extremely low killing effect on normal human cells and CD155-non-expressing tumor cells, demonstrating CD155-targeted cell-specific killing. Pharmacodynamic models of subcutaneous and orthotopic tumors using U87MG and U118MG showed that a single intratumoral administration of JL15003 injection produced significant and durable antitumor activity, while no safety concerns related to oncolytic effects were observed in the hPBMC immune reconstitution pharmacodynamic model. Toxicological studies showed that it has good safety; the HNSTD and STD10 in the key toxicology studies in monkeys and hPVR mice were 1.25 × 10⁻⁶. 8 CCID 50 / monkey and 5.0×10 6 CCID 50 / mouse, and at this dose, no active virus was detected in oral secretions, nasal mucosal secretions, feces, and urine sloughs of cynomolgus monkeys and hPVR mice at all time points, indicating that there is no safety hazard to the public and no biosafety risk.

[0044] On one hand, this application provides a composition comprising an oncolytic virus and an Ommaya capsule. In some embodiments, the oncolytic virus may comprise poliovirus. In one embodiment, the poliovirus is a Sabin strain type I vaccine. In some embodiments, the oncolytic virus may comprise a recombinant poliovirus injection. In one embodiment, the recombinant poliovirus injection is JL15003 injection. In some embodiments, the dosage of the recombinant poliovirus injection may be 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 In some embodiments, the dosage of the recombinant poliovirus injection may be approximately 1.0 × 10⁻⁶. 6 CCID 50 Approximately 1.25 × 10 6 CCID 50 Approximately 1.5 × 10 6 CCID 50 Approximately 2.0 × 10 6 CCID50 Approximately 2.5 × 10 6 CCID 50 Approximately 3.0 × 10 6 CCID 50 Approximately 3.5 × 10 6 CCID 50 Approximately 4.0 × 10 6 CCID 50 Approximately 4.5 × 10 6 CCID 50 Approximately 5.0 × 10 6 CCID 50 Approximately 5.5 × 10 6 CCID 50 Approximately 6.0 × 10 6 CCID 50 Approximately 6.5 × 10 6 CCID 50 Approximately 7.0 × 10 6 CCID 50 Approximately 7.5 × 10 6 CCID 50 Approximately 8.0 × 10 6 CCID 50 Approximately 8.5 × 10 6 CCID 50 Approximately 9.0 × 10 6 CCID 50 Approximately 1.0 × 10 7 CCID 50 Approximately 1.5 × 10 7 CCID 50 Approximately 2.0 × 10 7 CCID 50 Approximately 2.5 × 10 7 CCID 50 Approximately 3.0 × 10 7 CCID 50 Approximately 3.5 × 10 7 CCID 50 Approximately 4.0 × 10 7 CCID 50 Approximately 4.5 × 10 7 CCID 50 Approximately 5.0 × 10 7 CCID 50 Approximately 5.5 × 10 7 CCID 50 Approximately 6.0 × 10 7 CCID 50 Approximately 6.5 × 10 7CCID 50 Approximately 7.0 × 10 7 CCID 50 Approximately 7.5 × 10 7 CCID 50 Approximately 8.0 × 10 7 CCID 50 Approximately 8.5 × 10 7 CCID 50 Approximately 9.0 × 10 7 CCID 50 or approximately 1.0 × 10 8 CCID 50 .

[0045] In some embodiments, the Ommaya capsule is placed within the tumor. In some embodiments, the Ommaya capsule is connected to an external drug delivery pump. In some embodiments, the tumor is a human tumor. In some embodiments, the tumor is glioblastoma. In some embodiments, the tumor is glioblastoma. In some embodiments, the tumor is recurrent glioblastoma. In some embodiments, the tumor is grade IV glioblastoma excluding IDH mutations.

[0046] On the other hand, this application also provides a method for delivering an oncolytic virus via an Ommaya capsule. In some embodiments, the oncolytic virus is slowly delivered via the Ommaya capsule at an infusion rate of 0.5 mL / hour.

[0047] In some embodiments, the oncolytic virus may comprise poliovirus. In one embodiment, the poliovirus is a Sabin strain type I vaccine. In some embodiments, the oncolytic virus may comprise recombinant poliovirus injection. In one embodiment, the recombinant poliovirus injection is JL15003 injection. In some embodiments, the recombinant poliovirus injection can be continuously administered intratumorally under pressure and at scheduled intervals via the delivery device of the Ommaya bag. In some embodiments, the dose of the recombinant poliovirus injection may be 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 In some embodiments, the dosage of the recombinant poliovirus injection may be approximately 1.0 × 10⁻⁶. 6 CCID 50 Approximately 1.25 × 10 6 CCID 50 Approximately 1.5 × 10 6 CCID50 Approximately 2.0 × 10 6 CCID 50 Approximately 2.5 × 10 6 CCID 50 Approximately 3.0 × 10 6 CCID 50 Approximately 3.5 × 10 6 CCID 50 Approximately 4.0 × 10 6 CCID 50 Approximately 4.5 × 10 6 CCID 50 Approximately 5.0 × 10 6 CCID 50 Approximately 5.5 × 10 6 CCID 50 Approximately 6.0 × 10 6 CCID 50 Approximately 6.5 × 10 6 CCID 50 Approximately 7.0 × 10 6 CCID 50 Approximately 7.5 × 10 6 CCID 50 Approximately 8.0 × 10 6 CCID 50 Approximately 8.5 × 10 6 CCID 50 Approximately 9.0 × 10 6 CCID 50 Approximately 1.0 × 10 7 CCID 50 Approximately 1.5 × 10 7 CCID 50 Approximately 2.0 × 10 7 CCID 50 Approximately 2.5 × 10 7 CCID 50 Approximately 3.0 × 10 7 CCID 50 Approximately 3.5 × 10 7 CCID 50 Approximately 4.0 × 10 7 CCID 50 Approximately 4.5 × 10 7 CCID 50 Approximately 5.0 × 10 7 CCID 50 Approximately 5.5 × 10 7 CCID 50 Approximately 6.0 × 10 7CCID 50 Approximately 6.5 × 10 7 CCID 50 Approximately 7.0 × 10 7 CCID 50 Approximately 7.5 × 10 7 CCID 50 Approximately 8.0 × 10 7 CCID 50 Approximately 8.5 × 10 7 CCID 50 Approximately 9.0 × 10 7 CCID 50 or approximately 1.0 × 10 8 CCID 50 .

[0048] In some embodiments, the Ommaya capsule is placed within the tumor. In some embodiments, the Ommaya capsule is connected to an external drug delivery pump.

[0049] In some implementations, the oncolytic virus is delivered via the Ommaya capsule every six months, annually, every year and a half, every two years, every two and a half years, every three years, every three and a half years, every four years, every four and a half years, every five years, every six years, every seven years, every eight years, every nine years, or every ten years.

[0050] In some embodiments, the tumor is a human tumor. In some embodiments, the tumor is glioblastoma. In some embodiments, the tumor is glioblastoma. In some embodiments, the tumor is recurrent glioblastoma. In some embodiments, the tumor is grade IV glioblastoma excluding IDH mutations. In some embodiments, the oncolytic virus can be administered via an external infusion pump connected to an Ommaya capsule implanted within the tumor, using accelerated titration combined with a "3+3" experimental design for dose escalation.

[0051] This application also provides the use of the above-described composition in the preparation of a drug delivery device for treating glioblastoma. In some embodiments, the drug delivery device may further include an external drug delivery pump. In some embodiments, the external drug delivery pump may include a syringe, mechanical or electronic equipment. In some embodiments, the drug delivery device enables continuous infusion of oncolytic virus into the glioblastoma via an Ommaya capsule. In some embodiments, the drug delivery device enables slow delivery of oncolytic virus via an Ommaya capsule at an infusion rate of 0.5 mL / hour.

[0052] The embodiments described below are not intended to be limited by any theory, but are merely for illustrating the compositions, delivery methods and uses of this application, and are not intended to limit the scope of the invention.

[0053] Example

[0054] Example 1: Clinical Subject Information

[0055] This study enrolled patients aged ≥18 years with pathological or imaging findings indicating recurrence of supratentorial glioblastoma and a measurable lesion (≥1 cm and ≤5.5 cm, measured on enhanced MRI). Eligible patients had prior histopathological examination conforming to the World Health Organization (2021) diagnostic criteria for glioblastoma, experienced progression or recurrence after standard treatment (postoperative radiotherapy combined with concurrent and adjuvant chemoradiotherapy), had a Karnofsky Performance Status (KPS) score ≥70, and an expected survival of ≥3 months. The primary exclusion criteria included neoplastic lesions in the brainstem, cerebellum, or spinal cord; leptomeningeal diseases; and patients with enhanced tumor margins invading the ventricular wall on cranial MRI or postoperative tumor sac communication with the ventricles. All patients signed informed consent forms and voluntarily participated in this study, which was approved by the ethics committees of the participating centers.

[0056] Example 2 Dosing regimen

[0057] This study used an Ommaya capsule as the drug delivery device, marking the first time that an Ommaya capsule has been used to deliver oncolytic virus based on poliovirus, clinically applied in the treatment of rGBM. The drug was set with an escalation dose of 1.25 × 10⁻⁶. 6 CCID 50 5.0×10 6 CCID 50 2.0×10 7 CCID 50 8.0×10 7 CCID 50 Four dose levels were administered using an external pump connected to an intratumoral Ommaya capsule, with accelerated titration combined with a "3+3" experimental design for dose escalation. The intratumoral drug delivery device for JL15003 injection was designed to continuously deliver medication intratumorally under pressure according to time requirements. The slow infusion of JL15003 injection (0.5 mL / hour) via an external pump connected to the intratumoral Ommaya capsule enhances the intratumoral delivery effect. This delivery method differs from that of similar foreign products like PVSRIPO, resulting in more optimized drug delivery.

[0058] Example 3: Efficacy of JL15003 in the treatment of rGBM

[0059] Of the 17 patients treated, 16 survived for more than 6 months, and 6 survived for more than 12 months (as of September 2024, 6 patients had been treated for less than 12 months but were still alive). The median overall survival (OS) was 19.4 months (95% CI, 11.1–NA), significantly higher than the historical control group CGGA's median OS of 9.8 months (95% CI, 8.2–11.3). See details... Figure 1 The 6-month survival rate of the 17 subjects was 94.1% (95% CI, 65–99.1%), and the 1-year survival rate was 59.2% (95% CI, 27–81%), both significantly better than the historical control CGGA's 6-month survival rate of 73.6% (95% CI, 63.3–81.5%) and 1-year survival rate of 38.3% (95% CI, 28.3–48.1%).

[0060] In Japan, the overall survival (OS) of the oncolytic virus product G47Δ in a Phase I / II clinical trial involving 13 participants was 7.3 months (95% CI, 6.2–15.2%), with a 1-year survival rate of 38.5%. In a Phase II clinical trial involving 19 participants, the 1-year survival rate was 84.2% (95% CI, 60.4–96.6%), with a median OS of 20.2 months (95% CI, 16.8–23.6%). In a similar product, PVSRIPO, a Phase I clinical trial involving 61 participants showed a median OS of 12.5 months (95% CI, 9.9–15.2%), a 1-year survival rate of 54% (95% CI, 40–65%), and 2- and 3-year survival rates of 21% (95% CI, 11–33%). The median overall survival (OS) of the JL15003 injection Phase I clinical trial was 19.4 months (95% CI, 11.1–NA), and the 1-year survival rate was 59.2% (95% CI, 27–81%), which was significantly better than the historical control CGGA database and also better than the Phase I clinical trial results of G47Δ and PVSRIPO (see Table 1).

[0061] Table 1. Summary of overall survival for JL15003 injection, historical controls, G47Δ and PVSRIPO

[0062]

[0063] Unlike the G47Δ and PVSRIPO clinical trials, the JL15003 injection Phase I clinical trial was based on the 2021 World Health Organization (WHO) criteria for glioblastoma, excluding IDH-mutant grade IV high-grade glioblastoma. The study showed that patients with IDH wild-type high-grade glioblastoma had a worse prognosis than those with IDH mutations. Furthermore, compared to the G47Δ Phase I / II, G47Δ Phase II, and PCSRIPO Phase I clinical trials, which had 6 (46.2%), 10 (52.6%), and 17 (27.9%) patients with baseline KPS scores ≤80, respectively, the JL15003 injection Phase I clinical trial had 11 patients (64.7%) with baseline KPS scores ≤80. This demonstrates good efficacy despite the relatively poorer baseline condition of the subjects included in the JL15003 injection Phase I clinical trial.

[0064] Example 4: Safety of JL15003 for rGBM treatment

[0065] A total of 67 TEAEs occurred in 17 subjects, all of which were grade 1 or 2 in severity. No TEAEs of grade 3 or above (CTCAE, version 5.0) occurred. Three subjects (17.6%) experienced 4 TRAEs, all of which were 8.0 × 10⁻⁶. 7 CCID 50 The groups with the most severe adverse events (DLT) were cerebral edema (11.8%) and elevated gamma-glutamyl transferase (5.9%). No DLT, serious adverse events (SAEs), or TEAEs leading to death occurred in any of the dose groups. No infectious viral shedding occurred. A Phase I clinical trial of the similar product PVSRIPO showed that 19% of subjects experienced PVSRIPO-related grade 3 or higher AEs during the dose expansion phase. A Phase II clinical trial of G47Δ showed that 5 subjects (26.3%) experienced G47Δ-related grade ≥3 AEs, and one G47Δ-related SAE, grade 2 fever leading to prolonged hospitalization, occurred. Therefore, compared to other oncolytic virus products, JL15003 injection demonstrates better safety.

[0066] JL15003 injection uses an innovative drug delivery method, which differs from the administration methods of G47Δ and similar foreign products PVSRIPO. This optimized drug delivery method is also conducive to generating good safety and survival data in the Phase I clinical trial of JL15003 injection.

Claims

1. A composition comprising an oncolytic virus and an Ommaya capsule.

2. The composition according to claim 1, wherein the oncolytic virus comprises poliovirus.

3. The composition according to claim 1, wherein the oncolytic virus comprises recombinant poliovirus.

4. The composition according to claim 1, wherein the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 .

5. The composition according to claim 1, wherein the delivery portion of the Ommaya capsule is placed within the tumor.

6. The composition according to claim 1, wherein the Ommaya capsule is connected to an external drug delivery pump.

7. The composition according to claim 5, wherein the tumor is glioblastoma.

8. A method for delivering an oncolytic virus, wherein the oncolytic virus is delivered via an Ommaya capsule.

9. The method of claim 8, wherein the oncolytic virus is slowly delivered through the Ommaya capsule at an infusion efficiency of 0.5 mL / hour.

10. The method of claim 8, wherein the oncolytic virus comprises poliovirus.

11. The method of claim 8, wherein the oncolytic virus comprises recombinant poliovirus.

12. The method according to claim 8, wherein the dose of the oncolytic virus is 1.0 × 10⁻⁶. 6 CCID 50 Up to 1.0×10 8 CCID 50 .

13. The method of claim 8, administered via intratumoral administration of the Ommaya cyst.

14. The method of claim 8, wherein the Ommaya capsule is connected to an external drug delivery pump.

15. The method according to claim 13, wherein the tumor is glioblastoma.

16. Use of the composition of any one of claims 1-7 in the preparation of a drug delivery device for the treatment of glioblastoma.

17. The use according to claim 16, wherein the drug delivery device further comprises an external drug delivery pump.

18. The use according to claim 16, wherein the drug delivery device enables continuous infusion of oncolytic virus into glioblastoma via Ommaya capsule.

19. The use according to claim 16, wherein the delivery device enables the slow delivery of oncolytic virus through the Ommaya capsule at an infusion efficiency of 0.5 mL / hour.

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