A drug for enhancing the efficacy of esophageal squamous cell carcinoma chemotherapy and immunotherapy combination treatment and application thereof

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to a medicine for synergistically improving the curative effect of esophageal squamous cell carcinoma chemotherapy and immunotherapy and application thereof. The application first discovers and proves that S-allyl-L-cysteine (SAC) and / or indole-3-carbinol (I3C) can significantly improve the curative effect of esophageal squamous cell carcinoma chemotherapy and immunotherapy, provides a new synergistic strategy for the clinical treatment of esophageal squamous cell carcinoma, fills the application gap of natural active ingredients in the field of synergistic improvement of esophageal squamous cell carcinoma chemotherapy and immunotherapy, and the S-allyl-L-cysteine and indole-3-carbinol are active metabolites of natural sources, have good biocompatibility and low toxic and side effects, are safer than traditional chemical synergistic medicines, have better patient tolerance, and are beneficial to improving the compliance of clinical medication.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a drug for enhancing the efficacy of combined chemotherapy and immunotherapy for esophageal squamous cell carcinoma and its application. Background Technology

[0002] Esophageal cancer is the seventh most common malignant tumor worldwide, with esophageal squamous cell carcinoma (ESCC) accounting for 85% of all esophageal cancer cases. More than 470,000 new cases are diagnosed annually, making it a leading cause of cancer-related mortality. Surgery is the radical treatment option for locally advanced esophageal squamous cell carcinoma, while systemic therapy can slow cancer progression and prolong overall survival in patients with metastatic esophageal squamous cell carcinoma. However, traditional radiotherapy and chemotherapy strategies have limited clinical benefit. Immune checkpoint inhibitors (ICIs) have shown significant efficacy in locally advanced and metastatic esophageal squamous cell carcinoma, and their combination with platinum-based chemotherapy drugs has become the first-line standard treatment. Key clinical trials providing this first-line standard of care include KEYNOTE-590 (pembrolizumab + cisplatin / 5-fluorouracil), CheckMate 648 (nivolumab + cisplatin / 5-fluorouracil or nivolumab + ipilimumab), and ESCORT-1st (camrelizumab + cisplatin / paclitaxel). These clinical trials established the status of combination chemotherapy and immunotherapy, which significantly prolongs overall survival (OS) and progression-free survival (PFS) compared to chemotherapy alone, with a median OS benefit of 2.5-2.6 months and a median PFS benefit of 0.2-0.5 months.

[0003] Nevertheless, patient responses to combined chemoimmunotherapy are highly heterogeneous, with 30% of patients failing to respond to the treatment, and only 25% of those who respond achieve long-term benefit. Therefore, innovative combination therapy strategies are urgently needed to improve the efficacy of chemoimmunotherapy. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings and deficiencies of the prior art and provide a drug and its application for enhancing the efficacy of combined chemotherapy and immunotherapy for esophageal squamous cell carcinoma.

[0005] To achieve the above objectives, the technical solution adopted by the present invention includes: In a first aspect, the present invention provides the use of S-allyl-L-cysteine ​​and / or indole-3-methanol in the preparation of medicaments that enhance the efficacy of combined chemotherapy and immunotherapy for tumors.

[0006] Preferably, the tumor includes esophageal squamous cell carcinoma.

[0007] This invention is the first to clearly demonstrate the application value of dietary metabolites S-allyl-L-cysteine ​​(SAC) and / or indole-3-methanol (I3C) in enhancing the efficacy of combined chemotherapy and immunotherapy for tumors. It breaks through the limitations of traditional adjuvant cancer therapy relying on chemically synthesized drugs. Based on Phase III clinical trial samples and validation in multiple animal models (AKR subcutaneous tumor, 4NQO-induced esophageal squamous cell carcinoma, and AKR liver metastasis model), it is confirmed that these two dietary metabolites can significantly improve the tumor control effect of combined chemotherapy and immunotherapy through a dual immunomodulatory mechanism that regulates the CCR2 / CCR5 signaling pathway to promote NK cell tumor infiltration and enhance killing function, while reducing CD8+ T cell depletion. This effectively reduces tumor volume and weight. Furthermore, serum biochemical and histopathological evaluations confirmed no significant toxicity. This provides direct clinical translational evidence for dietary intervention to empower precision cancer treatment, filling the technological gap in using natural metabolites to enhance the efficacy of combined chemotherapy and immunotherapy for tumors. It is of great significance for promoting the development of safe and efficient comprehensive cancer treatment strategies.

[0008] Preferably, the chemotherapy-immunotherapy combination regimen includes paclitaxel combined with IgG antibody or αPD-1 antibody.

[0009] Preferably, the effective dose of S-allyl-L-cysteine ​​is 1-5 mg / kg, and the effective dose of indole-3-methanol is 15-25 mg / kg.

[0010] More preferably, the effective dose of S-allyl-L-cysteine ​​is 2 mg / kg, and the effective dose of indole-3-methanol is 20 mg / kg.

[0011] In a second aspect, the present invention provides a medicament for treating tumors, the medicament comprising S-allyl-L-cysteine ​​and / or indole-3-methanol.

[0012] Preferably, the tumor includes esophageal squamous cell carcinoma.

[0013] Preferably, the drug also includes chemotherapy drugs and immunotherapy drugs.

[0014] Experimental studies have revealed that when the S-allyl-L-cysteine ​​(SAC) or indole-3-methanol (I3C) described in this invention are used alone without the combination of chemotherapy and immunotherapy drugs, the tumor size of the subjects is not significantly different from that of the blank control group. This reveals that the core premise for SAC and I3C to exert their anti-tumor synergistic effect is that they are used in combination with chemotherapy and immunotherapy drugs, and that the two do not achieve their anti-tumor effect through a single immune regulatory pathway.

[0015] Preferably, the chemotherapy drug includes paclitaxel, and the immunotherapy drug includes IgG antibody and / or αPD-1 antibody.

[0016] Preferably, the drug further includes a pharmaceutically acceptable carrier or excipient.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention first discovered and confirmed that S-allyl-L-cysteine ​​and / or indole-3-methanol can significantly enhance the efficacy of chemotherapy-immunotherapy combined with esophageal squamous cell carcinoma, providing a new enhancement strategy for the clinical treatment of esophageal squamous cell carcinoma and filling the gap in the application of natural active ingredients in the field of enhancing the efficacy of chemotherapy-immunotherapy combined with esophageal squamous cell carcinoma. (2) The S-allyl-L-cysteine ​​and indole-3-methanol are both natural active metabolites with good biocompatibility and low toxicity. Compared with traditional chemical synergists, they are safer and more tolerable to patients, which helps to improve clinical medication compliance. (3) The two active ingredients in this invention can be used alone or in combination, and the administration method is flexible. They can be conveniently used in combination with existing chemotherapy and immunotherapy regimens for esophageal squamous cell carcinoma without requiring major adjustments to existing treatment regimens. They have broad prospects for clinical translation and application. Attached Figure Description

[0018] Figure 1 The graph shows the synergistic effect of single-drug SAC or I3C in a subcutaneous tumor model. Figure 2 Figure showing the synergistic effect of SAC combined with I3C in a subcutaneous tumor model; Figure 3 The diagram shows the synergistic effect of SAC or I3C in the orthotopic tumor model. Figure 4 The graph shows the synergistic effect of SAC or I3C in the liver metastasis model. Detailed Implementation

[0019] To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention will be further described in detail below with reference to the embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0020] Unless otherwise specified, all reagents used in the examples are conventional reagents available in the art and can be purchased commercially. Experimental procedures not specifically described in the examples are conventional procedures in the art or can be understood or known by those skilled in the art based on their prior knowledge or common general knowledge.

[0021] The S-allyl-L-cysteine ​​mentioned in this embodiment of the invention was purchased from MedChemExpress, catalog number #HY-W013573; the indole-3-methanol (I3C) was purchased from MedChemExpress, catalog number #HY-N0170; the IgG or αPD-1 antibody was purchased from BioXcell, catalog number #BE0083, RRID: AB_1107784 / catalog number #BE0146, RRID: AB_10949053; and the paclitaxel was purchased from Corden Pharma Latina SPA.

[0022] Example 1. Investigation into the efficacy of combined chemotherapy and immunotherapy for esophageal squamous cell carcinoma enhanced by S-allyl-L-cysteine ​​and / or indole-3-methanol. The specific testing method is as follows: 1. Construction and drug administration of subcutaneous tumor models (1) Model construction: 5.0×10 5 A subcutaneous tumor model was established by inoculating AKR cells into the left groin area of ​​mice.

[0023] (2) Tumor monitoring: The long and short diameters of the tumor were measured every 3 days after inoculation using calipers, and the results were calculated using the formula 0.5 × (long diameter × short diameter). 2 Calculate tumor volume.

[0024] (3) Dosage regimen: Treatment began on day 6 and continued until day 18. 1. Immunization group: IgG / αPD-1 antibody (10mg / kg) was administered intraperitoneally once every 3 days for a total of 4 times; 2. Chemotherapy group: Paclitaxel (PTX, 10 mg / kg) was administered intraperitoneally once every 6 days for a total of 2 times; 3. SAC group: S-allyl-L-cysteine ​​(2 mg / kg) orally twice daily for 18 days; 4. I3C group: Indole-3-methanol (20 mg / kg) was administered intraperitoneally once daily for 18 days; 5. Combination group: The above drugs are administered in combination according to the corresponding regimen (such as SAC+PTX+PD1, I3C+PTX+PD1, etc.).

[0025] (4) Endpoint detection: The tumor was removed and weighed at the end of the experiment.

[0026] 2. Orthotopic tumor model and liver metastasis model The dosing frequency and dosage of the in situ tumor and liver metastasis models were the same as those of the subcutaneous tumor model. The experimental endpoints were the volume / weight of the in situ tumor and the status of liver metastases.

[0027] 3. Results Analysis Figure 1 This study demonstrates the synergistic effects of single-agent SAC or I3C in a subcutaneous tumor model. Images show that, compared to the control group (NC+IgG), single-agent immunotherapy (PD1), and chemotherapy combined with immunotherapy (PTX+PD1), the tumor volume in the SAC+PTX+PD1 and I3C+PTX+PD1 combination groups (…) Figure 1 B) Tumor weight ( Figure 1 C) all decreased significantly (P < 0.05); tumor images ( Figure 1 D) also showed that the tumor size in the two combined groups was significantly smaller than that in other groups, suggesting that either SAC or I3C alone can effectively enhance the combined chemotherapy-immunotherapy efficacy of PTX+PD1. Furthermore, the tumor size in the SAC alone combined with immunotherapy control group (SAC+IgG) and the I3C alone combined with immunotherapy control group (I3C+IgG) did not show a significant decrease compared to the blank control group (NC+IgG). This negative result reveals the key prerequisite for the synergistic effect of SAC and I3C—they must be used in combination with chemotherapy drugs (PTX) and immunotherapy (PD1), rather than exerting their anti-tumor effect solely through immune regulatory pathways.

[0028] Figure 2 This study demonstrates the synergistic effect of SAC combined with I3C in a subcutaneous tumor model. The images show the tumor volume in the SAC+I3C+PTX+PD1 combination group (…). Figure 2 B) Tumor weight ( Figure 2 C) was further lower than the SAC monotherapy combination group (SAC+PTX+PD1) and the I3C monotherapy combination group (I3C+PTX+PD1), and significantly lower than the control group and the monotherapy group; tumor image ( Figure 2 D) The superior tumor-suppressing effect is evident, indicating that the combination of SAC and I3C has a stronger synergistic effect on chemotherapy and immunotherapy.

[0029] Figure 3 The synergistic effects of SAC or I3C in the orthotopic tumor model are shown. Orthotopic tumor volume distribution ( Figure 3 A) shows that the proportion of large-volume tumors (V>5000) in the SAC+PTX+PD1 and I3C+PTX+PD1 groups was significantly lower than that in the control group, the chemotherapy-only group, and / or the immunotherapy group; in situ tumor images ( Figure 3 B) It is evident that the combined group had a lighter tumor burden; the average volume and total volume were statistically analyzed ( Figure 3 C) It was also confirmed that SAC or I3C combined with PTX+PD1 could significantly reduce the volume of the tumor in situ (P<0.05), indicating that it could still enhance the efficacy of chemotherapy and immunotherapy in the tumor in situ model.

[0030] Figure 4 The synergistic effects of SAC or I3C in the liver metastasis model are shown. (Image of actual liver metastases) Figure 4A) showed that the number and area of ​​liver metastases in the SAC+PTX+PD1 and I3C+PTX+PD1 groups were significantly less than those in the control group, the chemotherapy-only group, and / or the immunotherapy group; liver weight statistics ( Figure 4 B) Further confirmation showed that the metastatic burden in the combined group was significantly reduced (P<0.05), indicating that SAC or I3C can enhance the inhibitory effect of the chemotherapy-immunotherapy combination regimen on tumor liver metastasis.

[0031] In summary, S-allyl-L-cysteine ​​(SAC) and indole-3-methanol (I3C), whether used alone or in combination, can significantly enhance the efficacy of combined chemotherapy (paclitaxel) and immunotherapy (PD-1 antibody). They have shown excellent tumor-suppressing / anti-metastatic effects in subcutaneous tumors, in situ tumors, and liver metastasis models, and can be used to prepare drugs that enhance the efficacy of combined chemotherapy and immunotherapy for tumors.

[0032] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. The use of S-allyl-L-cysteine ​​and / or indole-3-methanol in the preparation of drugs that enhance the efficacy of combined chemotherapy and immunotherapy for tumors.

2. The application as described in claim 1, characterized in that, The tumors include esophageal squamous cell carcinoma.

3. The application as described in claim 1, characterized in that, The chemotherapy-immunotherapy combination regimen includes paclitaxel combined with IgG antibody or αPD-1 antibody.

4. The application as described in claim 1, characterized in that, The effective dose of the S-allyl-L-cysteine ​​is 1-5 mg / kg, and the effective dose of the indole-3-methanol is 15-25 mg / kg.

5. A drug for treating tumors, characterized in that, The drug includes S-allyl-L-cysteine ​​and / or indole-3-methanol.

6. The drug as described in claim 5, characterized in that, The tumors include esophageal squamous cell carcinoma.

7. The drug as described in claim 5, characterized in that, The drugs also include chemotherapy drugs and immunotherapy drugs.

8. The drug as described in claim 7, characterized in that, The chemotherapy drug includes paclitaxel, and the immunotherapy drug includes IgG antibody and / or αPD-1 antibody.

9. The medicament according to any one of claims 5-8, characterized in that, The drug also includes pharmaceutically acceptable carriers or excipients.

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