Anti-tumor use of act001 composition

Abstract

A drug combination composition comprising ACT001 has a synergistic anti-tumor effect in a glioblastoma (GBM) animal model, effectively protects or improves, in the process of a phase II clinical trial of treating a GBM patient who was sensitive to temozolomide (TMZ) but subsequently relapses, basic immune functions of said patient, such as relieving lymphocyte reduction caused by chemotherapy, alleviating myelosuppression of TMZ, and suppressing inhibitory Treg lymphocytes in peripheral blood, and reduces DNA damage repair capability in GBM cancer cells, thereby improving the sensitivity of GBM to TMZ.

Description

Anti-tumor use of an ACT001 composition

[0001] This application claims priority to the prior application with patent application number 202311091345.8 filed with the State Intellectual Property Office of China on August 28, 2023, entitled “Anti-tumor use of an ACT001 composition”, the full text of which is incorporated into this application by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and particularly to an anti-tumor use of an ACT001 composition. Background Art

[0003] In 2005, the FDA approved TMZ for the treatment of GBM (glioblastoma) (Stupp et al., 2005). However, the high heterogeneity of cancer and its adaptability during treatment were the main reasons for the failure of almost all subsequent Phase 2 and Phase 3 clinical trials. Years of translational and clinical research have shown that the successful development of GBM drugs should meet the following conditions:

[0004] 1) Early clinical trial data, especially data from a small number of patients who have demonstrated true clinical benefit, are crucial. In GBM drug development, there is a significant gap between preclinical data and real-world clinical outcomes. For example, clinical trials have demonstrated that the combination of ACT001 and pembrolizumab does not produce greater efficacy than ACT001 alone, and that preclinical data for parthenolide combined with PD-1 antibodies are not correlated with real-world clinical outcomes.

[0005] 2) Drugs targeting all GBM subtypes do not conform to the pathogenesis and biological logic of GBM, while patents and R&D directions targeting specific GBM subgroups will have greater opportunities;

[0006] 3) How to screen GBM subgroups of patients suitable for specific drug mechanisms of action is equally important as the pharmacological characteristics of the drug itself;

[0007] 4) The success of therapeutic field therapy (TTF) suggests that, based on the existing effective GBM treatment (TMZ), research on the mechanisms of drug resistance will be more conducive to the development of new systemic treatments;

[0008] 5) Considering the diversity of GBM tumors, combination therapy and multiple targets per drug will have greater opportunities in GBM drug development.

[0009] MGMT gene expression levels are one of the determinants of GBM sensitivity to TMZ. Excessive expression can reduce GBM cell sensitivity to TMZ by repairing TMZ-induced DNA damage. MMR (mismatch repair) is a key player in TMZ treatment of GBM, and downregulation of its expression can affect GBM sensitivity to TMZ (McFaline-Figueroa et al., 2015). Factors influencing GBM sensitivity to TMZ also include other pathways involved in DNA repair. For example, TMZ treatment of GBM cancer cells requires the formation of single-strand breaks (SSBs) or double-strand breaks (DSBs) in DNA to further kill cancer cells.

[0010] After GBM develops resistance to TMZ, restoring its sensitivity to TMZ remains a key clinical issue. Previous clinical studies addressing this issue were hampered by the lack of access to NF-κB inhibitors with a sufficient safety window.

[0011] References

[0012] McFaline-Figueroa, JL, Braun, CJ, Stanciu, M., Nagel, ZD, Mazzucato, P., Sangaraju, D., ...manson, LD (2015). Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide. Cancer Res, 3127-3138.

[0013] Stupp, R., Mason, PW, van den Bent, JM, Weller, M., Fisher, B., & Taphoorn, BM (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 352, 987-996.

[0014] Summary of the Invention

[0015] In order to improve the above technical problems, the present invention provides a drug combination composition comprising ACT001, and use of the drug combination composition in the preparation of drugs for treating and / or preventing tumors.

[0016] The present invention provides a drug combination composition, which comprises:

[0017] (i) DMAMCL or a pharmaceutically acceptable salt thereof;

[0018] and (ii) an alkylating agent or a pharmaceutically acceptable salt thereof;

[0019] The DMAMCL is shown in the following formula:

[0020] In some embodiments, the mass ratio of components (i) to (ii) is 0.1-100:1, preferably 1-50:1, more preferably 5-30:1, for example 5-20:1, 5:1, 10:1, 15:1, 20:1, 25:1, 30:1.

[0021] In some embodiments, the pharmaceutically acceptable salt of DMAMCL is DMAMCL fumarate ACT001, and the ACT001 is represented by the following formula:

[0022] In some embodiments, the alkylating agent is selected from temozolomide TMZ and lomustine (CCNU).

[0023] In some embodiments, DMAMCL or a pharmaceutically acceptable salt thereof is administered at a dosage of 50 mg / kg-500 mg / kg, for example, 100 mg / kg-300 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, or 300 mg / kg.

[0024] In some embodiments, the alkylating agent or a pharmaceutically acceptable salt thereof is administered in an amount of 1 mg / kg to 100 mg / kg, for example, 90 mg / kg, 80 mg / kg, 70 mg / kg, 60 mg / kg, 50 mg / kg, 40 mg / kg, 30 mg / kg, 20 mg / kg, or 10 mg / kg.

[0025] In some embodiments, the dosage of DMAMCL or a pharmaceutically acceptable salt thereof is 100 mg-800 mg, 1-3 times a day; preferably, the dosage is 300 mg-500 mg, 1-3 times a day; more preferably, the dosage is 400 mg, 2 times a day.

[0026] In some embodiments, the dosage of temozolomide TMZ is 50 mg / m 2 / day-400mg / m 2 / day, preferably 150 mg / m 2 / day-250mg / m 2 / day, for example 200mg / m 2 / tender.

[0027] In some embodiments, the administration course of temozolomide TMZ is: administration on days 1 to 5, with one course of treatment every 28 days.

[0028] In some embodiments, in the combination pharmaceutical composition, the DMAMCL or a pharmaceutically acceptable salt thereof and the alkylating agent or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

[0029] In some embodiments, the combination pharmaceutical composition is used to treat and / or prevent tumors.

[0030] In some embodiments, the tumor comprises a nervous system tumor, a glioma.

[0031] In some embodiments, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma, and optic nerve glioma.

[0032] In some embodiments, the glioma is glioblastoma, which is the most common intracranial tumor, the most malignant tumor, prone to recurrence and / or metastasis after surgery, and difficult to cure.

[0033] In some embodiments, glioblastoma includes primary glioblastoma, secondary glioblastoma.

[0034] In some embodiments, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor.

[0035] In some embodiments, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma, lomustine-sensitive glioblastoma.

[0036] In some embodiments, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ.

[0037] In some embodiments, the glioblastoma is methylated MGMT (06-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma.

[0038] In some embodiments, the combination pharmaceutical composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes.

[0039] In some embodiments, the combination pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (eg, TMZ).

[0040] The present invention also provides use of the drug combination composition in preparing drugs for treating and / or preventing tumors.

[0041] In some embodiments, the tumor comprises a nervous system tumor, a glioma.

[0042] In some embodiments, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma, and optic nerve glioma.

[0043] In some embodiments, the glioma is a glioblastoma.

[0044] In some embodiments, glioblastoma includes primary glioblastoma, secondary glioblastoma.

[0045] In some embodiments, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor.

[0046] In some embodiments, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma, lomustine-sensitive glioblastoma.

[0047] In some embodiments, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ.

[0048] In some embodiments, the glioblastoma is methylated MGMT (06-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma.

[0049] In some embodiments, the combination pharmaceutical composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes.

[0050] In some embodiments, the combination pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (eg, TMZ).

[0051] The present invention also provides a method for treating and / or preventing tumors, comprising administering a therapeutically effective amount of the above-mentioned drug combination composition to a patient.

[0052] In some embodiments, the tumor comprises a nervous system tumor, a glioma.

[0053] In some embodiments, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma, and optic nerve glioma.

[0054] In some embodiments, the glioma is a glioblastoma.

[0055] In some embodiments, glioblastoma includes primary glioblastoma, secondary glioblastoma.

[0056] In some embodiments, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor.

[0057] In some embodiments, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma, lomustine-sensitive glioblastoma.

[0058] In some embodiments, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ.

[0059] In some embodiments, the glioblastoma is methylated MGMT (06-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma.

[0060] In some embodiments, the combination pharmaceutical composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes.

[0061] In some embodiments, the combination pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (eg, TMZ).

[0062] In some embodiments, the patient is a glioblastoma GBM patient who is initially diagnosed to be sensitive to temozolomide TMZ, a glioblastoma GBM patient who is initially diagnosed to be sensitive to temozolomide TMZ but relapses after treatment, or a glioblastoma GBM patient who is initially diagnosed to be sensitive to temozolomide TMZ but relapses after treatment and is resistant to TMZ.

[0063] The present invention also provides a medicine kit for treating tumors, which comprises the above-mentioned drug combination composition.

[0064] In some embodiments, the tumor comprises a nervous system tumor, a glioma.

[0065] In some embodiments, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma, and optic nerve glioma.

[0066] In some embodiments, the glioma is a glioblastoma.

[0067] In some embodiments, glioblastoma includes primary glioblastoma, secondary glioblastoma.

[0068] In some embodiments, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor.

[0069] In some embodiments, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma, lomustine-sensitive glioblastoma.

[0070] In some embodiments, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ.

[0071] In some embodiments, the glioblastoma is methylated MGMT (06-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma.

[0072] In some embodiments, the combination pharmaceutical composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes.

[0073] In some embodiments, the combination pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (eg, TMZ). Beneficial effects

[0074] The present invention provides a drug combination composition including ACT001. The drug combination composition has a synergistic anti-tumor effect in a glioblastoma animal model; compared with a single drug, the drug combination composition can significantly reduce tumor volume and mass. In addition, during the phase II clinical trial for the treatment of glioblastoma patients (especially GBM that was previously sensitive to TMZ but subsequently relapsed), the drug combination composition can effectively protect or improve the patient's basic immune function, such as reducing chemotherapy-induced lymphopenia, alleviating the bone marrow suppression effect of TMZ, suppressing peripheral blood suppressive Treg lymphocytes, and reducing the DNA damage repair ability inside GBM cancer cells, thereby increasing GBM's sensitivity to TMZ. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 shows the growth curve of the treatment results of U118 cells with ACT001 combined with TMZ.

[0076] Figure 2 shows the results of ACT001 combined with TMZ treatment on U118 cells - changes in tumor tissue weight.

[0077] FIG3 shows the specific inhibition ratios of tumor volume and tumor weight in each group. DETAILED DESCRIPTION

[0078] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0079] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0080] Example 1

[0081] Model: Human glioma cell line U118MG subcutaneous transplant tumor model in nude mice

[0082] Method for establishing a subcutaneous U118MG cell model: After in vivo passage to the third generation, when the subcutaneous tumor grows to approximately 1-2 cm in diameter, the tumor mass is removed under sterile conditions and cut into approximately 1.5 x 1.5 mm pieces. Five-week-old nude mice are inoculated subcutaneously under the dorsal area of ​​the right forelimb. Once the tumor reaches the appropriate size, the mice are divided into groups and dosed according to tumor volume, with 10 mice per group.

[0083] Dosage:

[0084] Each dosing group started dosing on the day of grouping;

[0085] ACT001 was dissolved in normal saline and administered orally once a day, with one day of drug withdrawal per week.

[0086] Temozolomide capsules: weigh the contents, convert the dose according to the specifications, suspend in normal saline, 1 mg / kg, and administer by gavage once a day for a total of 7 times.

[0087] Data processing:

[0088] Data are expressed as ± s; tumor volume = 1 / 2ab 2 (a = tumor long diameter; b = tumor short diameter); relative tumor volume (RTV) = Vt / Vo (Vo = tumor volume before administration; Vt = tumor volume at each measurement after administration); tumor volume inhibition rate = (control group volume - treatment group volume) / control group volume × 100%; tumor weight growth inhibition rate = (control group tumor weight - treatment group tumor weight) / control group tumor weight × 100%. Statistical analysis between groups was performed using the t-test program in Excel software.

[0089] The Q value of the combined drug treatment was calculated as follows: Q = Ea + b / (Ea + Eb - Ea × Eb), where Ea + b is the inhibition rate of the combined drug treatment, and Ea and Eb are the inhibition rates of drug A and drug B alone, respectively, so as to determine whether the combined treatment has a synergistic effect (Q < 0.85 is antagonistic, 0.85 ≤ Q < 1.15 is additive, and Q ≥ 1.15 is synergistic).

[0090] The efficacy of the combination of ACT001 and TMZ was tested in the aforementioned GBM (U-118) xenograft mouse model. Figures 1, 2, and 3 show the tumor volume and weight measurements and specific inhibition ratios for each group in the model, respectively.

[0091] As shown in Figure 1, at the end of treatment, the tumor volume in the ACT001 plus TMZ combination group was significantly lower than that in the ACT001 and TMZ alone groups. As shown in Figure 2, the tumor weight in the combination group was significantly lower than that in the ACT001 and TMZ alone groups. A Q value ≥ 1.15 also indicates that ACT001 and TMZ have a synergistic anti-tumor effect (Figure 3).

[0092] Example 2

[0093] GBM patients who relapsed after standard treatment were randomly assigned to three cohorts of the Phase 2 ACT001-CN-002 clinical trial:

[0094] Cohort A: ACT001 (400 mg twice daily) alone.

[0095] Cohort B: ACT001 and temozolomide (TMZ) at doses of 400 mg twice daily (ACT001) and 200 mg / m2 / day (TMZ treatment course, administration from the first to the fifth day, one course every 28 days);

[0096] Cohort C: Single-agent CCNU (lomustine, 100-130 mg / m 2 / time, once every six weeks, up to 4 times) or TMZ (dose and administration method are the same as cohort B).

[0097] The trial endpoints were progression-free survival (iRANO criteria) after dosing, the one-year survival rate, and safety assessments: the number of safety events (such as the incidence of decreased peripheral blood lymphocytes). Exploratory endpoints included changes in the ratio of suppressive Treg lymphocytes in peripheral blood. The trial results are summarized below (Table 1):

[0098] Table 1 Results of the Phase II clinical trial of ACT001 combined with TMZ for the treatment of GBM Note: After taking the medicine, the tumor of patient B4 grew larger but the clinical condition remained stable. The tumor then gradually shrank, with a decrease of 30% compared to the peak value.

[0099] Analysis of Table 1 shows that GBM patients B4 and B5 in combination group B were both sensitive to TMZ during first-line treatment. Patient B4, a GBM patient with positive MGMT gene methylation, achieved disease stability according to the iRANO criteria for at least 24 months after combination therapy. The lymphocyte count significantly increased (i.e., the combination therapy alleviated TMZ-induced bone marrow suppression) and peripheral blood suppressive Treg lymphocytes were also suppressed. Patient B5, a GBM patient with unmethylated MGMT, achieved disease stability for at least 23 months after combination therapy, with significant suppression of peripheral blood suppressive Treg lymphocytes. The remaining GBM patients experienced either no progression or stable disease for no more than 9 months.

[0100] The combination therapy with ACT001 enhanced the antitumor effect of TMZ monotherapy in patients with recurrent GBM who met specific clinical criteria. GBM patients B4 and B5 in combination group B both experienced long-term clinical benefits lasting nearly two years, exceeding historically long-term benefits. Both GBM patients who experienced long-term benefits from combination therapy had a history of TMZ sensitivity during first-line treatment. However, other patients with the same history of first-line TMZ sensitivity did not experience significant clinical benefit from ACT001 or TMZ monotherapy, suggesting a unique therapeutic effect of the combination therapy. Given that patients like B4 and B5, who were previously TMZ-sensitive but subsequently relapsed, represent an ideal model for studying drug sensitization, this approach holds direct clinical significance. ACT001 may achieve TMZ sensitization in GBM by reducing MGMT expression in recurrent cancer cells or inhibiting DNA double-strand break repair in these cancer cells. Considering that the methylation rate of the MGMT gene can reach 50% in tumor samples from all cancer patients, the findings of this invention provide the first actionable path for patient clinical background screening and biomarker exploration, which has guiding significance for the future drug development process for GBM and other cancers.

[0101] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A drug combination composition, comprising: (i) DMAMCL or a pharmaceutically acceptable salt thereof; and (ii) an alkylating agent or a pharmaceutically acceptable salt thereof; The DMAMCL is shown in the following formula:

2. The pharmaceutical combination composition according to claim 1, characterized in that: The mass ratio of the components (i) to (ii) is 0.1-100:1, preferably 1-50:1, more preferably 5-30:1; And / or, the pharmaceutically acceptable salt of DMAMCL is DMAMCL fumarate ACT001, and the ACT001 is shown in the following formula: And / or, the alkylating agent is selected from temozolomide TMZ, lomustine (CCNU); And / or, the dosage of DMAMCL or a pharmaceutically acceptable salt thereof is 50 mg / kg-500 mg / kg, for example, 100 mg / kg-300 mg / kg; and / or, the alkylating agent or a pharmaceutically acceptable salt thereof is administered in an amount of 1 mg / kg to 100 mg / kg; And / or, the dosage of DMAMCL or a pharmaceutically acceptable salt thereof is 100 mg-800 mg, 1-3 times a day; preferably, the dosage is 300 mg-500 mg, 1-3 times a day; more preferably, the dosage is 400 mg, 2 times a day.

3. The pharmaceutical combination composition according to claim 1 or 2, characterized in that: The dose of temozolomide TMZ is 50 mg / m 2 / day - 400mg / m 2 / day, preferably 150 mg / m 2 / day - 250mg / m 2 / day, for example 200 mg / m 2 / sky; And / or, the administration course of temozolomide TMZ is: administration on days 1 to 5, one course of treatment every 28 days; And / or, in the combination pharmaceutical composition, the DMAMCL or a pharmaceutically acceptable salt thereof and the alkylating agent or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

4. Use of the drug combination composition according to any one of claims 1 to 3 in the preparation of drugs for treating and / or preventing tumors.

5. The use according to claim 4, characterized in that: The tumors include nervous system tumors and gliomas; Preferably, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma and optic nerve glioma; Preferably, the glioma is glioblastoma; Preferably, glioblastoma includes primary glioblastoma and secondary glioblastoma; Preferably, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor; Preferably, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma or lomustine-sensitive glioblastoma; Preferably, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ; Preferably, the glioblastoma is methylated MGMT (O6-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma; Preferably, the combination drug composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes; Preferably, the combined pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (such as TMZ).

6. A method for treating and / or preventing tumors, comprising administering to a patient a therapeutically effective amount of the pharmaceutical combination composition according to any one of claims 1 to 3.

7. The method according to claim 6, characterized in that The tumors include nervous system tumors and gliomas; Preferably, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma and optic nerve glioma; Preferably, the glioma is glioblastoma; Preferably, glioblastoma includes primary glioblastoma and secondary glioblastoma; Preferably, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor; Preferably, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma or lomustine-sensitive glioblastoma; Preferably, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ; Preferably, the glioblastoma is methylated MGMT (O6-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma; Preferably, the combination drug composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes; Preferably, the combined pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (such as TMZ); Preferably, the patient is a glioblastoma GBM patient who is sensitive to temozolomide TMZ after initial diagnosis, a glioblastoma GBM patient who is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment, or a glioblastoma GBM patient who is sensitive to temozolomide TMZ after initial diagnosis but relapses after treatment and is resistant to TMZ.

8. A drug kit for treating tumors, comprising the drug combination composition according to any one of claims 1 to 3.

9. The medicine box according to claim 8, characterized in that The tumors include nervous system tumors and gliomas. Preferably, the glioma is selected from the group consisting of: astrocytoma, brainstem glioma, ependymoma, mixed glioma, oligodendroglioma and optic nerve glioma; Preferably, the glioma is glioblastoma; Preferably, glioblastoma includes primary glioblastoma and secondary glioblastoma; Preferably, the tumor is a drug-sensitive tumor, such as an alkylating agent-sensitive tumor; Preferably, the tumor is an alkylating agent-sensitive glioblastoma, such as TMZ-sensitive glioblastoma or lomustine-sensitive glioblastoma; Preferably, the tumor is a glioblastoma GBM that is sensitive to temozolomide TMZ after initial diagnosis, Glioblastoma GBM that is sensitive to temozolomide TMZ but relapses after treatment, and glioblastoma GBM that is sensitive to temozolomide TMZ at initial diagnosis but relapses after treatment and is resistant to TMZ; Preferably, the glioblastoma is methylated MGMT (O6-methylguanine-DNA-methyltransferase) glioblastoma or unmethylated MGMT glioblastoma; Preferably, the combination drug composition can protect the basic immune function of tumor patients, such as reducing lymphocytopenia caused by chemotherapy, alleviating the bone marrow suppression effect of TMZ, and suppressing peripheral blood suppressive Treg lymphocytes; Preferably, the combined pharmaceutical composition can increase the sensitivity of glioblastoma GBM to alkylating agents (such as TMZ).

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