Treatment device for brain glioma

Abstract

The invention discloses a treatment device for brain glioma, and belongs to the technical field of biological medicine. The treatment device comprises a recombinant herpes simplex virus injection preparation and an OMMAYA capsule, the recombinant herpes simplex virus injection preparation is administrated through the OMMAYA capsule placed in the body to conduct anti-brain glioma treatment, repeated administration of the recombinant herpes simplex virus can be achieved, the recombinant herpes simplex virus is kept within the effective concentration for a long time, and the treatment effect is good. A more favorable treatment effect is achieved; meanwhile, the medication cost is reduced, and side effects caused by treatment are reduced.

Description

Technical Field

[0001] This application relates to the field of biomedical technology, and particularly to a treatment device for glioma. Background Art

[0002] Glioma is the most common primary malignant tumor in the central nervous system, accounting for about 46% of intracranial tumors. Glioblastoma has the highest incidence among brain tumors, and the peak incidence age is generally 30 - 40 years old or 10 - 20 years old. Glioma is characterized by strong invasiveness, easy recurrence, and high mortality. Currently, radiotherapy combined with chemotherapy after surgery is mostly used clinically to treat glioma. However, due to the different sensitivities of different individuals to antitumor drugs and the drug resistance of glioma to many chemotherapeutic drugs, the clinical efficacy is not satisfactory.

[0003] Oncolytic viruses are a class of viruses that can specifically replicate in tumor cells and exert antitumor effects naturally or after gene editing. Recombinant oncolytic viruses are a type of oncolytic virus with development potential for cancer immunotherapy. Currently, there are 4 approved oncolytic virus therapies globally, and the most commonly used ones are adenovirus (31%), herpes virus (24%), reovirus (20%), and vaccinia virus (12.5%). Recombinant oncolytic herpes simplex virus can selectively infect tumor cells, replicate in tumor cells, finally lyse and kill tumor cells, and release progeny virus particles to further infect surrounding tumor cells. This process also helps to release tumor - associated antigens. There are records of the clinical treatment of recombinant oncolytic herpes simplex virus injection preparations in various tumors such as rectal cancer, melanoma, bladder cancer, and glioma. However, how to more economically and effectively use oncolytic viruses for glioma patients to ensure the treatment effect is one of the problems to be solved.

[0004] Therefore, there is an urgent need for a brand - new method for treating glioma patients. Summary of the Invention

[0005] The problem of the glioma barrier causes many drugs to be ineffective against it. The administration method of oncolytic viruses is local administration, which has a direct effect by directly entering the tumor site. In the prior art, local administration of oncolytic viruses is currently carried out by intraoperative administration during surgery, but this method is not convenient to implement. Therefore, the technical problem to be solved in this application is how to more economically and effectively use recombinant herpes simplex virus injection preparations for glioma patients to ensure the treatment effect.

[0006] To ensure the convenient and effective administration of the recombinant herpes simplex virus injection preparation to glioma patients, this application provides a method of administering the oncolytic virus injection preparation through an Omaya reservoir. The Omaya reservoir is a drug delivery device with a relatively small volume. The drainage tube at the tip of the Omaya reservoir can be punctured into the corresponding site through implantation, with precise positioning. By injecting the anti-tumor drug into the Omaya reservoir, the tumor drug solution can be evenly distributed in the brain through the small drainage tube of the Omaya reservoir, reducing the loss of the anti-tumor drug in the injection process of the prior art, thereby ensuring the efficacy of the anti-tumor drug.

[0007] Therefore, by combining the anti-tumor efficacy of the recombinant herpes simplex virus and the advantages of the Omaya reservoir in the administration method, and through the verification of its effect in anti-glioma, this application provides a drug and a treatment device for glioma to solve or alleviate some of the above technical problems.

[0008] This application achieves the above object through the following technical solutions:

[0009] A treatment device for anti-central nervous system tumors, comprising:

[0010] A recombinant herpes simplex virus injection preparation;

[0011] An Omaya reservoir.

[0012] Further, the recombinant herpes simplex virus in each treatment device contains one or more (at least 2) unit dosage forms; each unit dosage form contains 1×10 6 ~1×10 7 CCID 50 / ml dose of the recombinant herpes simplex virus preparation.

[0013] Further, the dosage of the recombinant herpes simplex virus is 1×10 6 ~1×10 7 CCID 50 / ml, and the administration frequency is once every three weeks. The total number of administrations is determined according to the MRI evaluation of the patient after medication.

[0014] Further, the Omaya reservoir is an implantable device for cerebrospinal fluid drainage and drug management. The Omaya reservoir consists of a small silicone or polyurethane capsule body, with a puncturable lid inside. The Omaya reservoir is surgically implanted into the patient's head or under the skull and connected to a catheter that can extend into the cerebrospinal fluid cavity. The lid of the Omaya reservoir can be punctured regularly for treatment operations such as cerebrospinal fluid sampling, cerebrospinal fluid drainage, or drug injection.

[0015] Furthermore, the central nervous system tumor for treatment is glioma, preferably glioma that recurs or is intolerant to radiotherapy and chemotherapy in patients over 18 years old.

[0016] Furthermore, the treatment device can be used in combination with other supportive drugs for treating tumors.

[0017] The present application provides a treatment device comprising a recombinant herpes simplex virus and an Ommaya reservoir, and the treatment device can be used for treating glioma. Compared with the prior art, the present application has at least the following beneficial effects:

[0018] When the treatment device provided by the present application is used for treating glioma, the Ommaya reservoir is implanted into the patient's intracranial cavity during tumor resection. Through the Ommaya reservoir implanted into the patient's intracranial cavity, repeated administration of the recombinant herpes simplex virus can be achieved, and the dosage can also be adjusted according to the patient's disease progression, so that the recombinant herpes simplex virus can be maintained within the effective concentration for a long time, achieving a more favorable treatment effect; at the same time, the side effects caused by the treatment are reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the clinical trial result of the treatment device provided by the embodiment of the present application.

[0020] Figure 2 It is the treatment flow chart of subject S3 provided by the embodiment of the present application.

[0021] Figure 3 It is the MRI scan result of the lesion of subject S3 before and after treatment provided by the embodiment of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0022] In order to make the objectives, technical solutions and advantages of the present application more clear and understandable, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0023] Glossary of Terms

[0024] The term "injectable preparation" refers to a sterile solution (including emulsion and suspension) prepared from a drug for injection into the body, as well as a sterile powder or concentrated solution for preparing a solution or suspension immediately before use. Injectables act quickly and reliably, are not affected by pH, enzymes, food, etc., have no first-pass effect, can play a systemic or local positioning role, and are suitable for patients who are not suitable for oral administration or cannot take oral medications. In the present application, the terms "injectable solution" and "injectable preparation" are equivalent in definition.

[0025] The terms "SD" and "PR" are the evaluation criteria for the therapeutic efficacy of tumors (only solid tumors). The evaluation criteria are divided into four levels, namely "Complete Remission (CR)": all target lesions disappear, no new lesions appear, and tumor markers are normal, maintaining for at least 4 weeks; "Partial Remission (PR)": the sum of the maximum diameters of the target lesions decreases by ≥30%, maintaining for at least 4 weeks; "Stable Disease (SD)": the sum of the maximum diameters of the target lesions does not shrink to reach PR, or does not increase to reach PD; "Progressive Disease (PD)": the sum of the maximum diameters of the target lesions increases by at least ≥20%, or new lesions appear.

[0026] The terms "ORR" and "DCR" are the evaluation indicators related to the therapeutic efficacy of tumors (only solid tumors). Among them, "Objective Response Rate (ORR)" refers to the proportion of patients whose tumor volume usually shrinks by 30% and can be maintained for more than 4 weeks, that is, the sum of the proportions of Complete Remission (CR) and Partial Remission (PR); the higher the ORR, the more patients achieve tumor shrinkage using this treatment method; "Disease Control Rate (DCR)" refers to the proportion of the number of cases that achieve remission (CR + PR) and Stable Disease (SD) after treatment, that is, the proportion of patients who do not have Progressive Disease (PD).

[0027] Through extensive and in-depth research, the applicant has, for the first time, combined recombinant herpes simplex virus with the efficacy of OMMAYA reservoir, developed a treatment device for anti-central nervous system tumors (such as glioma), and applied it to the clinical trials of glioma treatment. The experimental results have proved the effectiveness of recombinant herpes simplex virus in treating glioma patients for many times. In addition, through the OMMAYA reservoir, a new drug delivery method for recombinant herpes simplex virus is realized, which can not only directly deliver the drug to the internal lesions of glioma patients, but also achieve multiple drug administrations and control the drug dosage, maximizing the efficacy of recombinant herpes simplex virus against glioma, avoiding or reducing the side effects on patients caused by other anti-tumor drugs or drug delivery methods, and realizing personalized and precise treatment for different patients. Based on this research and clinical trials, this application has been completed.

[0028] Ommaya reservoir

[0029] In the treatment device for glioma provided by the embodiment of this application, it includes a drug delivery device for recombinant herpes simplex virus injection solution, which is an OMMAYA reservoir.

[0030] In the embodiments of the present application, the provided OMMAYA reservoir is an implantable device for cerebrospinal fluid drainage and drug management. The OMMAYA reservoir consists of a small sac made of silicone or polyurethane, with a puncturable lid inside. It is surgically implanted into the patient's head or under the skull and connected to a catheter that extends into the cerebrospinal fluid cavity. The lid of the OMMAYA reservoir can be punctured regularly for treatment operations such as cerebrospinal fluid sampling, cerebrospinal fluid drainage, or drug injection.

[0031] Brain glioma treatment device

[0032] In the embodiments of the present application, the provided treatment device for glioblastoma mainly comprises: the aforementioned recombinant herpes simplex virus and the OMMAYA reservoir.

[0033] In the embodiments of the present application, the recombinant herpes simplex virus in each treatment device contains one or more (at least 2) unit dosage forms, preferably 3 - 10; each unit dosage form contains 1×10 6 ~1×10 7 CCID 50 / ml dose of recombinant herpes simplex virus.

[0034] Furthermore, the dosage of the recombinant herpes simplex virus used is 1×10 6 ~1×10 7 CCID 50 / ml, and the administration frequency is once every three weeks. The total number of administrations is determined according to the MRI evaluation of the patient after medication.

[0035] Application of recombinant herpes simplex virus and treatment device

[0036] The present application provides the clinical application of recombinant herpes simplex virus and the treatment device in the treatment of glioblastoma. Using the treatment device containing recombinant herpes simplex virus provided by the present application, the OMMAYA reservoir is implanted into the intracranial cavity of glioblastoma patients, and then an effective amount of recombinant herpes simplex virus is administered repeatedly for many times, so as to maximize the efficacy of recombinant herpes simplex virus and avoid or reduce the side effects caused by administration. The specific implementation scheme is as follows:

[0037] 1. Clinical trial design

[0038] 1.1 Phase I clinical trial

[0039] The main purpose of the Phase I clinical trial is to explore the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the treatment device containing recombinant herpes simplex virus injection in the treatment of glioblastoma, evaluate its safety and tolerance; in addition, preliminarily evaluate the efficacy of recombinant herpes simplex virus injection.

[0040] (1) Determine the key drainage criteria:

[0041] a. Age ≥ 18 years old;

[0042] b. High-grade glioma;

[0043] c. The tumor is partially or completely resected surgically, and an OMMAYA reservoir is placed in the operative area;

[0044] d. Exclude patients with other active extracranial malignancies.

[0045] (2) Subject grouping and dosing frequency

[0046] A total of two groups are divided, namely the low-dose group: 10 6 CCID 50 / ml, the dosing frequency is once every three weeks (Q3W), for a total of 6 doses; high-dose group: 10 7 CCID 50 / ml, the dosing frequency is once every three weeks (Q3W), for a total of 6 doses.

[0047] 1.2 Phase IIa clinical trial

[0048] The main purpose of the Phase IIa clinical trial is to evaluate the preliminary efficacy of recombinant herpes simplex virus (treatment device); in addition, further evaluate the safety of recombinant herpes simplex virus (treatment device).

[0049] (1) Target population: Patients after recurrence of glioblastoma multiforme surgery.

[0050] (2) The recommended Phase II dose (RP2D) is determined by the results of the Phase I clinical trial.

[0051] 2. Subject enrollment

[0052] A total of 9 subjects were enrolled in the examples of this application, and their baseline characteristics are shown in Table 1 below:

[0053] Table 1

[0054]

[0055]

[0056] 3. Clinical trial results:

[0057] 3.1 Safety

[0058] The occurrence of adverse reactions is shown in Table 2:

[0059] Table 2

[0060]

[0061] As can be seen from Table 2, 6 out of 9 subjects had adverse reactions, with a total of 27 cases, and the severity was mostly grade 1 / 2. The common adverse reactions were headache, fever and flu-like symptoms; only 2 cases (2 cases) of serious adverse events possibly related to the study drug occurred, namely cerebral edema (grade 3) and brain hernia (grade 4); no dose-limiting toxicity (DLT) occurred. The above results indicate that the treatment device containing recombinant herpes simplex virus has high safety in the treatment of glioma.

[0062] 3.2 Efficacy

[0063] The results are as Figure 1 shown. A total of 9 subjects were enrolled, and 5 subjects participated in the evaluation (the other 4 did not reach the evaluation time). According to the iRANO efficacy evaluation criteria, 1 patient had a partial response (PR), 1 patient had stable disease (SD), the objective response rate (ORR) was 20%, and the disease control rate (DCR) was 40%.

[0064] As can be seen from the above results, from the overall effect, the administration method of recombinant herpes simplex virus combined with OMMAYA reservoir has a good therapeutic effect on glioma patients.

[0065] The embodiment of the present application further details the treatment stage of the above-mentioned subject S3. Figure 2 Shown is the treatment course of subject S3; among them, the placement site of the OMMAYA reservoir is the right frontotemporal insular surgical area (40.8×29.2 mm), and the recombinant herpes simplex virus injection solution is administered to the subject by injecting into the OMMAYA reservoir; the administration method is the low-dose group administration (10 6 CCID 50 / ml), once every three weeks, for a total of three administrations.

[0066] The embodiment of the present application performed an MRI scan of the lesion site on subject S3 who was treated with recombinant herpes simplex virus injection solution + OMMAYA reservoir administration. As Figure 3 shown, the total maximum cross-sectional area of the postoperative residual lesions at the time of subject enrollment was 1191.36 mm 3 , and after 3 administrations of the recombinant herpes simplex virus injection solution, the total maximum cross-sectional area of the residual lesions was reduced to 387.44 mm 3 , a reduction of 67.5% compared to the baseline.

[0067] In the embodiments of the present application, before and after the administration of the recombinant herpes simplex virus injection, samples such as blood and cerebrospinal fluid of subject S3 were collected at different time points, and the copy number of recombinant herpes simplex virus DNA in the samples was detected. The detection results are shown in Table 3. Recombinant herpes simplex virus DNA was detected in the cerebrospinal fluid samples of subject S3 within 24 hours after administration and 21 days after administration, which were 15.52 copies / μl and 169.92 copies / μl respectively, indicating that the recombinant herpes simplex virus injection infects tumor cells and replicates and proliferates within the tumor cells, and the progeny virus is released into the cerebrospinal fluid.

[0068] Table 3

[0069]

[0070] In the embodiments of the present application, recombinant herpes simplex virus DNA was not detected in the blood, saliva, and urine samples of all subjects. In the embodiments of the present application, no live virus was detected by testing the skin swab and conjunctiva swab samples at the injection site where the injection fell off. Therefore, the treatment with the recombinant herpes simplex virus injection + OMMAYA capsule will not cause shedding.

[0071] In the embodiments of the present application, when glioma subjects received the treatment method of the recombinant herpes simplex virus injection + OMMAYA capsule, the administration doses were as follows: low-dose group: 10 6 CCID 50 / ml, high-dose group: 10 7 CCID 50 / ml, while for other products on the market, such as G47Δ, the dosage stated in the instruction manual is 10 9 PFU; the minimum clinical use dosage of DNX-2401 is 10 10 VP; further indicating that the treatment device provided by the present application reduces the drug cost and side effects during the treatment of glioma patients.

[0072] In summary, the treatment device including the recombinant herpes simplex virus injection and the OMMAYA capsule provided by the present application can be repeatedly administered without re-operation during the treatment of glioma patients, has a lower cost and better curative effect compared with the existing products on the market.

[0073] The above is only the preferred specific embodiment of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present application should be covered within the protection scope of the present application.

Claims

1. A treatment device, characterized in that, It is used for treating central nervous system tumors and includes: Recombinant herpes simplex virus injection preparation; OMMAYA reservoir.

2. The treatment device according to claim 1, wherein The recombinant herpes simplex virus in the treatment device contains one or more (such as at least 2) unit dosage forms; each unit dosage form contains 1×10 6 ~1×10 7 CCID 50 / ml dose of the recombinant herpes simplex virus preparation.

3. The treatment device according to claim 2, characterized in that, The recombinant herpes simplex virus in the treatment device contains 3 to 10 unit dosage forms.

4. The treatment device according to claim 2 or 3, characterized in that, The dosage of the recombinant herpes simplex virus is 1×10 6 ~1×10 7 CCID 50 / ml, the administration frequency is once every three weeks, and the total number of administrations is determined according to the MRI evaluation of the patient after medication.

5. The treatment device according to claim 1, characterized in that, The OMMAYA reservoir is an implantable device for cerebrospinal fluid drainage and drug management. The OMMAYA reservoir consists of a small sac made of silicone or polyurethane, with a puncturable lid inside. The OMMAYA reservoir is surgically implanted into the patient's head or under the skull and connected to a catheter that can extend into the cerebrospinal fluid cavity. The lid of the OMMAYA reservoir can be punctured regularly for treatment operations such as cerebrospinal fluid sampling, cerebrospinal fluid drainage, or drug injection.

6. The therapeutic device according to claim 1, characterized in that, The central nervous system tumor treated by the treatment device is glioma.

7. The treatment device according to claim 6, wherein, The glioma for treatment is glioma that recurs or is intolerant to radiotherapy and chemotherapy in patients over 18 years old.

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