Application of local ablation in preparation of product for improving survival benefit in few-residue stage after non-small cell lung cancer immunotherapy

Abstract

The invention provides application of local ablation in preparation of a product for improving survival benefits in a few-residue stage after non-small cell lung cancer immunotherapy, and relates to the technical field of biological medicines. According to the invention, cryoablation, radiofrequency ablation or microwave ablation is carried out on a patient with lesion part alleviation or disease stabilization after immunotherapy and in a few-residue state. Clinical research results show that compared with a conventional immunotherapy method independently using the immune checkpoint inhibitor, after local ablation treatment is added, the progression-free lifetime and the overall lifetime of a patient are remarkably prolonged, the whole body progression time can be delayed, and the disease control rate is increased. The system disclosed by the invention evaluates the survival benefit of the local ablation combined immunotherapy on the non-small cell lung cancer patient in the few-residue stage, makes up the current perspective data gap in the field of local ablation and immunotherapy combined application, and provides a scientific basis and clinical guidance for further optimizing the treatment strategy of the non-small cell lung cancer.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically is the application of local ablation in the preparation of products that improve the survival benefit of oligoresidual stage of non-small cell lung cancer after immunotherapy. Background Art

[0002] Lung cancer remains the most common cancer and the leading cause of cancer-related death. In the past decade, immunotherapy has significantly improved the survival benefit of patients with advanced non-small cell lung cancer (NSCLC), especially for patients without driver gene mutations, improving progression-free survival (PFS) and overall survival (OS). However, due to the lack of response to immunotherapy and acquired drug resistance in some patients, only a few patients can achieve long-term survival through immunotherapy. A variety of treatment strategies have been used to improve the survival benefit of immunotherapy, including combination therapy with other immune checkpoint inhibitors, immune checkpoint agonists, and tumor vaccines.

[0003] Oligo residual disease (ORD) refers to the situation where a small amount of tumor cells remain in the body after treatment, although the primary lesion has been removed. This situation usually occurs during cancer treatment, especially after surgery, radiotherapy or chemotherapy. There is increasing evidence that oligoresidual disease caused by first-line immunotherapy is a common progression pattern in patients with advanced NSCLC, with an incidence rate as high as 36% to 55%. The concept of oligoresidual disease has gradually attracted attention, and many studies have shown that ORD is the source of disease progression. Therefore, it is of great significance to study how to improve oligoresidual disease in patients with non-small cell lung cancer after immunotherapy and further improve the survival benefit of patients with non-small cell lung cancer. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide the application of local ablation in the preparation of a product for improving the survival benefit of the oligoresidual stage of non-small cell lung cancer after immunotherapy. Compared with the use of immunotherapy alone, the addition of local ablation therapy significantly prolongs the patient's progression-free survival and overall survival, and helps to delay the time of systemic progression and improve the control rate of the disease.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides the use of local ablation in the preparation of a product for improving the survival benefit of oligoresidual stage of non-small cell lung cancer after immunotherapy.

[0007] Preferably, the timing of intervention of the local ablation is: local ablation is performed when the non-small cell lung cancer achieves partial lesion remission or disease stability after immunotherapy and is in the oligoresidual stage.

[0008] More preferably, the oligoresidual stage is when the residual tumor lesions after immunotherapy are limited to 3 organs and the number is ≤5.

[0009] Preferably, the local ablation includes cryoablation, radiofrequency ablation or microwave ablation.

[0010] More preferably, the conditions for cryoablation include: the number of cycles is not less than 2 cycles, the freezing time is 10 to 15 minutes, and the rewarming time is 3 to 8 minutes.

[0011] More preferably, the conditions for radiofrequency ablation include: starting with a low power of 20 to 30 W, and gradually increasing the power until the peak impedance is reached.

[0012] More preferably, the microwave ablation conditions include: ablation power of 50 to 65 W, and ablation time of 6 to 10 min.

[0013] More preferably, after completion of local ablation, a chest CT scan is performed to evaluate the ablation range.

[0014] Preferably, the immunotherapy comprises treating non-small cell lung cancer with an immune checkpoint inhibitor.

[0015] More preferably, the immune checkpoint inhibitor comprises a PD-1 inhibitor or a PD-L1 inhibitor.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides the application of local ablation in the preparation of a product that improves the survival benefit of the oligoresidual stage after immunotherapy for non-small cell lung cancer. The present invention performs local ablation on patients who have achieved partial response (PR) or stable disease (SD) after immunotherapy and are in an oligoresidual state. The results of clinical studies have shown that compared with conventional immunotherapy methods using immune checkpoint inhibitors (ICIs) alone, the addition of local ablation therapy significantly prolongs the patient's progression-free survival (PFS) and overall survival (OS), and helps to delay the time of systemic progression and improve the control rate of the disease. The present invention uses local ablation technology (cryoablation, radiofrequency ablation, microwave ablation) to perform targeted ablation of oligoresidual lesions after immunotherapy to reduce tumor burden, and uses the release of antigenic substances and local inflammatory response after ablation to activate the patient's immune system and enhance the efficacy of immunotherapy. The study found that cryoablation performed better in prolonging PFS and stimulating immune response. The present invention systematically evaluates the survival benefit of local ablation combined with immunotherapy for NSCLC patients in the oligoresidual stage, fills the current prospective data gap in the field of combined application of local ablation and immunotherapy, and provides a scientific basis and clinical guidance for further optimizing the treatment strategy of NSCLC. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a schematic diagram of the treatment grouping of patient samples of the present invention;

[0018] Figure 2 The results of survival benefits of patients with oligoresidual lesions in the ablation group and those in the non-ablation group; A is progression-free survival; B is overall survival;

[0019] Figure 3 These are the results of subgroup analysis of the clinical study; Figure A is the forest plot of the subgroup analysis; Figure B is the progression-free survival of cold ablation versus thermal ablation; and Figure C is the overall survival of cold ablation versus thermal ablation.

[0020] Figure 4 The changes in the levels of cytokines and chemokines in the peripheral blood of patients before and after ablation treatment. From top to bottom in the figure are the overall population, thermal ablation population, and cold ablation population.

[0021] Figure 5 The differences in the changes of cytokines and chemokines in peripheral blood before and after ablation treatment were compared between the thermal ablation group and the cold ablation group. DETAILED DESCRIPTION

[0022] The present invention provides the use of local ablation in the preparation of a product that improves the survival benefit of the oligo-residual stage after immunotherapy for non-small cell lung cancer. In the present invention, the intervention timing of the local ablation is preferably to achieve partial remission of lesions or stable disease after immunotherapy for non-small cell lung cancer, and local ablation is performed when it is in the oligo-residual stage. In the present invention, the oligo-residual stage is preferably that the residual tumor lesions after immunotherapy are limited to 3 organs and the number is ≤5. In a specific embodiment of the present invention, imaging evaluation is performed every 2 cycles during immunotherapy, and local ablation is performed when the patient with non-small cell lung cancer achieves partial remission (partial response, PR) or stable disease (stable disease, SD) after immunotherapy, and is in the oligo-residual stage. In the present invention, the judgment criteria for partial remission (partial response, PR) or stable disease (stable disease, SD) refer to the efficacy evaluation criteria in solid tumors version 1.1 "Response Evaluation Criteria in Solid Tumors RECIST Version 1.1".

[0023] In the present invention, according to the actual pathological condition of the patient, the immunotherapy is an immunotherapy combined with chemotherapy or an immunotherapy without chemotherapy. The chemotherapy and / or immunotherapy method can provide a treatment plan according to the actual pathological condition of the patient. In the present invention, as a feasible method, the chemotherapy regimen is determined according to the patient's pathological type. For patients with lung adenocarcinoma, pemetrexed combined with platinum (preferably carboplatin) double-drug chemotherapy is used for 4 to 6 cycles, and the dosage is recommended by the CSCO guidelines. Pemetrexed maintenance medication is subsequently performed once every 3 weeks; for patients with non-lung adenocarcinoma, albumin-bound paclitaxel combined with platinum (preferably carboplatin) double-drug chemotherapy is recommended for 4 to 6 cycles, and the dosage is recommended by the CSCO guidelines, once every 3 weeks. In the present invention, as another feasible method, immunotherapy is preferably anti-PD-1 monoclonal antibody or anti-PD-L1 monoclonal antibody without limitation, and all immunotherapy drugs recommended by the CSCO guidelines can be selected. After 4 to 6 cycles of chemotherapy combined with immunotherapy, immunotherapy maintenance medication is performed once every 3 weeks.

[0024] In the present invention, the local ablation preferably includes cryoablation (CRA), radiofrequency ablation (RFA) or microwave ablation (MWA).

[0025] In the present invention, the conditions of cryoablation preferably include: the number of cycles is not less than 2 cycles, the freezing time is 10 to 15 minutes, and the rewarming time is 3 to 8 minutes. In the present invention, as an implementable method, cryoablation preferably includes the following steps: taking the CT positioning point as the puncture point, routine disinfection and draping, 2% lidocaine local infiltration anesthesia, laying the needle according to the preset needle insertion depth, and re-scanning CT to confirm that the ablation needle is located in the lesion. The surgical plan is formulated according to the morphology of the patient's lesion, and the number and time of ablation cycles are determined according to the size of the lesion, which is usually not less than 2 cycles, the freezing time is 10 to 15 minutes, and the rewarming time is 3 to 8 minutes. Example of cryoablation parameters: cryotherapy for 12 minutes (6 minutes to reach the lowest temperature), recheck chest CT to see that the freezing range has reached the expected treatment purpose and has not damaged the surrounding normal tissues, then rewarming treatment for 5 minutes (3 minutes to reach the highest temperature), completing the first cycle of cryotherapy; rescan chest CT shows that the cryoablation needle is in a good position and has not affected the surrounding tissues and trachea, so the second cycle of cryoablation is performed, with cryotherapy for 10 minutes (5 minutes to reach the lowest temperature), rewarming treatment for 7 minutes (3 minutes to reach the highest temperature), and ending cryoablation. After ablation is completed, rescan chest CT to evaluate whether the ablation range is covered to ensure complete ablation.

[0026] In the present invention, the conditions for radiofrequency ablation preferably include: starting with a low power of 20 to 30 W, and gradually increasing the power until the peak impedance is reached. In the present invention, as an implementable method, radiofrequency ablation includes the following steps: taking the CT positioning point as the puncture point, routine disinfection and laying of towels, local infiltration anesthesia with 2% lidocaine, placing the needle according to the preset needle insertion depth, and re-scanning the CT to confirm that the ablation needle is located in the lesion. The surgical plan is formulated according to the morphology of the patient's lesions, and the ablation power and time are determined according to the size of the lesions. It is usually started with a low power of 20 to 30 W, and the power is gradually increased until the impedance reaches the peak value, and the ablation cycle is performed again after stopping for a while; for larger lesions or irregular lesions, pay attention to adjusting the needle to ensure that the lesions are completely ablated. Radiofrequency ablation parameter example: Distal lesion: ablation start power 20W, maximum power 80W for 6 minutes and 55 seconds until impedance reaches peak value, stop for 30 seconds, perform second cycle ablation at the same site with start power 50W, last for 40 seconds until impedance reaches peak value, third cycle with start power 40W and maximum power 50W for 50 seconds until impedance reaches peak value; proximal lesion: fourth cycle with start power 20W and maximum power 50W for 3 minutes and 15 seconds until impedance reaches peak value, fifth cycle with start power 20W and maximum power 30W for 1 minute and 35 seconds until impedance reaches peak value, sixth cycle with start power 50W for 40 seconds until impedance reaches peak value, and ablation is completed. After ablation is completed, rescan chest CT to evaluate whether the ablation range is fully covered to ensure complete ablation.

[0027] In the present invention, the conditions of microwave ablation preferably include: ablation power of 50-65W, and ablation time of 6-10min. In the present invention, as an implementable method, microwave ablation includes the following steps: taking the CT positioning point as the puncture point, routine disinfection and draping, local infiltration anesthesia with 2% lidocaine, needle placement according to the preset needle insertion depth, and rescanning CT to confirm that the ablation needle is located in the lesion. The surgical plan is formulated according to the morphology of the patient's lesions, and the power and time of ablation are determined according to the size of the lesions. The power is usually set to 50-65W and the time is 6-10 minutes; for larger lesions or irregular lesions, pay attention to adjusting the needle to ensure that the lesions are completely ablated. Example of microwave ablation parameters: 8 minutes of treatment under the condition of microwave power of 65W. After the ablation is completed, rescan the chest CT to evaluate whether the ablation range is covered to ensure complete ablation.

[0028] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0029] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0030] Example 1

[0031] This example aims to evaluate the survival benefit and safety of local ablation of oligoresidual lesions in patients with advanced NSCLC (chictr.org.cn, number: ChiCTR2000032479). The study was approved by the Ethics Committee of Shanghai Pulmonary Hospital, and informed consent was obtained from each patient in accordance with the International Ethical Guidelines for Human Subjects in Biomedical Research, the Good Clinical Practice Guidelines, and the Declaration of Helsinki. The study started on August 1, 2020, and the deadline for analysis was April 30, 2024.

[0032] 1. Patients: Enrolled patients are ≥18 years old, with locally advanced or metastatic NSCLC confirmed by pathology or cytology, no drug-resistant driver gene mutations, and have achieved oligoresidual status under immunotherapy (with or without chemotherapy). Oligoresidual status is defined as partial remission (PR) or stable disease (SD) after 4 to 6 months of PD-1 / PD-L1 inhibitors, and residual tumor lesions are limited to 3 organs and the number is ≤5. ORD lesions must undergo complete ablation. Other inclusion criteria include an ECOG performance status score of 0 or 1, and normal heart, bone marrow, liver, and kidney function. Exclusion criteria include symptomatic brain metastases and patients with contraindications to ablation (see Table 1 for detailed inclusion and exclusion criteria). Among them, the chemotherapy regimen is determined according to the patient's pathological type. For patients with lung adenocarcinoma, 4 to 6 cycles of pemetrexed combined with carboplatin are used, and the dosage is recommended by the CSCO guidelines. Pemetrexed maintenance medication is then used once every 3 weeks. For patients with non-lung adenocarcinoma, albumin-bound paclitaxel combined with carboplatin is recommended for 4 to 6 cycles. The dosage is recommended by the CSCO guidelines and is once every 3 weeks. There is no limit on the use of anti-PD-1 monoclonal antibodies or anti-PD-L1 monoclonal antibodies for immunotherapy. All immunotherapy drugs recommended by the CSCO guidelines can be used. After 4 to 6 cycles of chemotherapy combined with immunotherapy, immunotherapy maintenance medication is used once every 3 weeks.

[0033] Table 1 Patient inclusion and exclusion criteria

[0034]

[0035]

[0036] 2. Grouping: The enrolled patients were randomly divided into two cohorts in a 2:1 ratio, receiving ablation (Group A) or not receiving ablation (Group B). Ablation techniques included cryoablation (CRA), radiofrequency ablation (RFA), and microwave ablation (MWA). After randomization, both groups continued to receive immunotherapy (with or without chemotherapy) until disease progression, unacceptable toxicity, or withdrawal of informed consent as defined by iRECIST. The primary endpoint was progression-free survival (PFS) of immunotherapy, and the secondary endpoints were overall survival (OS), local recurrence-free survival (LRFS), and safety of ablation of lung lesions. Adverse events (AEs) were classified according to the Society of Interventional Radiology AE Classification System.

[0037] Among them, the cryoablation process is as follows: take the CT positioning point as the puncture point, routinely disinfect and lay the drape, perform local infiltration anesthesia with 2% lidocaine, arrange the needle according to the preset needle insertion depth, and re-scan the CT to confirm that the ablation needle is located in the lesion. Cryotherapy for 12 minutes (6 minutes to reach the lowest temperature), re-examine the chest CT to see that the freezing range has achieved the expected treatment purpose, and no damage to the surrounding normal tissues, then perform rewarming treatment for 5 minutes (3 minutes to reach the highest temperature), and complete the first cycle of cryotherapy; re-scan the chest CT to indicate that the cryoablation needle is in a good position and does not affect the surrounding tissues and trachea, and perform the second cycle of cryoablation, cryotherapy for 10 minutes (5 minutes to reach the lowest temperature), rewarming treatment for 7 minutes (3 minutes to reach the highest temperature), and end cryoablation. After the ablation is completed, re-scan the chest CT to evaluate whether the ablation range is covered to ensure complete ablation. The cryoablation cycle and time can be adjusted according to the size of the lesion.

[0038] The radiofrequency ablation process is as follows: take the CT positioning point as the puncture point, routinely disinfect and lay the towel, 2% lidocaine local infiltration anesthesia, arrange the needle according to the preset needle insertion depth, and rescan the CT to confirm that the ablation needle is located in the lesion. Distal lesion: ablation starting power 20W, maximum power 80W for 6 minutes and 55 seconds until the impedance reaches the peak value, stop for 30 seconds, and perform the second cycle of ablation at the same site with a starting power of 50W, which lasts for 40 seconds until the impedance reaches the peak value, and the third cycle starts with a power of 40W and a maximum power of 50W for 50 seconds until the impedance reaches the peak value; proximal lesion: the fourth cycle starts with a power of 20W and a maximum power of 50W for 3 minutes and 15 seconds until the impedance reaches the peak value, the fifth cycle starts with a power of 20W and a maximum power of 30W for 1 minute and 35 seconds until the impedance reaches the peak value, and the sixth cycle starts with a power of 50W for 40 seconds until the impedance reaches the peak value, and the ablation is completed. After the ablation is completed, rescan the chest CT to evaluate whether the ablation range is covered to ensure complete ablation. The surgical plan can be formulated according to the morphology of the patient's lesions, and the radiofrequency ablation power and time can be adjusted according to the size of the lesions.

[0039] The process of microwave ablation is as follows: take the CT positioning point as the puncture point, routinely disinfect and lay the drape, 2% lidocaine local infiltration anesthesia, place the needle according to the preset needle insertion depth, and re-scan the CT to confirm that the ablation needle is in the lesion. The microwave power is 65W for 8 minutes. After the ablation is completed, the chest CT is re-scanned to evaluate whether the ablation range is covered to ensure complete ablation. The surgical plan can be formulated according to the patient's lesion morphology, and the power and time of microwave ablation can be adjusted according to the size of the lesion.

[0040] 3. Ablation affects the immunogenicity of lung lesions

[0041] Peripheral blood samples from patients undergoing lung lesion ablation were collected at baseline and after ablation (within 48 hours), and cytokines (IL levels) were detected and analyzed using BD flow cytometry bead array (CBA) in the clinical laboratory of Shanghai Pulmonary Hospital.

[0042] 4. Statistical analysis

[0043] The sample size was calculated based on a two-sided significance level of 0.05 and a statistical power of 80%, and a two-sample log-rank test was used. Assuming that the progression-free survival (PFS) of patients in the ablation group was extended by 6 months, the estimated PFS of patients in the non-ablation group was 6 months from the start of randomization, and the corresponding hazard ratio (HR) was 0.525. The estimate of PFS was based on data from randomized phase III trials, meta-analyses, and retrospective studies. Considering the 2:1 randomization ratio and 10% dropout rate, a total sample size of 137 patients was required to achieve the expected statistical power, including 91 in the ablation group and 46 in the non-ablation group. A total of 68 patients have been enrolled, including 46 in the ablation group and 22 in the non-ablation group, and the interim analysis criteria have been met.

[0044] The median PFS and overall survival (OS) were estimated using the Kaplan-Meier method, and a two-sided 95% confidence interval (CI) was provided. The HR of the survival difference and its 95% CI were analyzed using COX proportional hazard regression. The chi-square test or Fisher's exact test was used for categorical variables, and the Student's t test was used for numerical variables. All statistical analyses were performed in SPSS statistical software (version 22.0, IBM Corporation). Statistical significance was defined as a two-sided p value < 0.05.

[0045] 5. Results Analysis

[0046] (1) Clinical and pathological characteristics of enrolled patients

[0047] From August 1, 2020 to April 30, 2024, a total of 748 patients who received immunotherapy (PD-1 / PD-L1 inhibitors) were screened, some of whom also received chemotherapy. After screening, 137 patients achieved oligoresidual status after 4 to 6 cycles of immunotherapy. Finally, 68 patients who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis (see Figure 1 ). Among them, 46 patients were randomly assigned to the ablation group (ablation + immunotherapy group), and 22 patients were assigned to the non-ablation group (immunomaintenance therapy group). The clinical pathological characteristics of the two groups were comparable (Table 2). Among them, 1 patient in the ablation group withdrew from the group due to insufficient lung function, 2 patients with thrombocytopenia, and 1 patient voluntarily withdrew from the group. The actual number of patients who finally received treatment in the ablation group was 42; 2 patients in the non-ablation group voluntarily withdrew from the group. The actual number of patients who finally received treatment in the non-ablation group was 20, and 8 patients in the non-ablation group crossed over to the ablation group.

[0048] Table 2 Clinical and pathological characteristics of the two groups

[0049]

[0050] Note: The ECOGPS score in the table is the Eastern Cooperative Oncology Group Performance Status Score, which is a tool used to assess the ability of cancer patients to perform daily living activities. The scoring standard is divided into 6 levels. "Unknown" means that the patient did not undergo this test.

[0051] Of the 42 patients who underwent ablation, 13 underwent cryoablation and 29 underwent thermal ablation. The clinicopathological features of the two groups were generally comparable, but patients who underwent thermal ablation had larger lung lesions compared with those who underwent cryoablation (p = 0.033). The clinicopathological features of patients who underwent radiofrequency ablation and microwave ablation were generally comparable.

[0052] In patients who received ablation, the median time to immunotherapy (TTI) was 32 days (range: 11-85 days). There was no significant difference in TTI between patients who received thermal ablation and cryoablation (mean ± SE: 36.2 ± 14.7 vs. 36.5 ± 16.6, p = 0.950), nor between patients who received radiofrequency ablation and microwave ablation (mean ± SE: 35.6 ± 12.3 vs. 38.1 ± 21.8, p = 0.697).

[0053] (2) Survival benefit of combined ablation and immunotherapy

[0054] The median progression-free survival (PFS) of immunotherapy was 22.4 months (95% CI: 13.5-31.3). The median PFS of patients with and without ablation was 26.7 months (95% CI: 17.6-34.5) and 11.7 months (95% CI: 10.1-13.2), respectively. The PFS of patients who received ablation was significantly prolonged (p < 0.001, HR = 0.213, 95% CI: 0.099-0.461), and the survival of patients who received ablation was significantly prolonged compared with those who did not receive ablation of lung lesions (see Figure 2 A). As of the data cutoff, 8 patients had died. Patients who underwent lung lesion ablation had a significantly longer OS than those who did not (median OS: NA vs. NA months, p = 0.036, HR = 0.242, 95% CI: 0.057-1.019) (see Figure 2 B).

[0055] In the multivariate COX regression analysis, considering factors such as gender, age, ECOG-PS score, histological type, treatment regimen, PD-L1 expression, disease extent, oncogene mutation, and whether ablation was performed, it was further confirmed that lung lesion ablation was associated with significant improvement in PFS (HR = 0.218, 95% CI: 0.099-0.480, p < 0.001) (Table 3). The present invention performed a multivariate COX regression analysis, and the results showed that ablation and OS extension showed marginal significance (HR = 0.304, 95% CI: 0.071-1.308, p = 0.110) (Table 4).

[0056] Table 3 PFS univariate and multivariate analysis

[0057]

[0058] Note: The ECOGPS score in the table is the Eastern Cooperative Oncology Group Performance Status Score, which is a tool used to assess the ability of cancer patients to perform daily living activities. The scoring standard is divided into 6 levels. "Unknown" means that the patient did not undergo this test.

[0059] Table 4 Single and multi-factor analysis of OS

[0060]

[0061] Note: The ECOGPS score in the table is the Eastern Cooperative Oncology Group Performance Status Score, which is a tool used to assess the ability of cancer patients to perform daily living activities. The scoring standard is divided into 6 levels. "Unknown" means that the patient did not undergo this test.

[0062] Subgroup analysis showed that each patient subgroup could benefit from ablation therapy ( Figure 3A). In addition, the present invention further compared the PFS of patients who received thermal ablation and cryoablation, and the results showed that cryoablation was associated with significantly prolonged PFS (median PFS: NA vs. 22.4 months, HR = 0.214, 95% CI: 0.048-0.953, p = 0.011) ( Figure 3 B), and its OS also showed a trend of extension (p=0.241)( Figure 3 C) This may be due to the programmed death of tumor cells caused by low temperature freezing, which releases more antigens and enhances the recognition and clearance of the immune system.

[0063] (3) Safety data of ablation therapy for residual lesions

[0064] In the 42 patients who underwent ablation of lung lesions, ablation-related adverse events (classified according to the SIRAE classification system24) were generally mild (35 / 42, with only 9 patients experiencing moderate adverse events. No serious, life-threatening adverse events or deaths were observed. Pneumothorax was the most common complication associated with percutaneous transthoracic biopsy. Of the 42 patients who underwent ablation, 15 patients developed pneumothorax within 48 hours after ablation, but only 6 patients required transthoracic catheter drainage, 1 patient received a chest drainage tube, and 7 patients were discharged within one week after ablation. The remaining patients experienced very mild adverse reactions, which were clinically routine reactions.

[0065] (4) Antibiotic use after ablation

[0066] Among the 42 patients who underwent ablation of lung lesions, almost all patients received antibiotic treatment after ablation, and only 2 patients did not use antibiotics. Among the types of antibiotics used, 9.5% (4 / 42) used second-generation cephalosporins (cefuroxime), 4.7% (2 / 42) used third-generation cephalosporins (1 case used ceftazidime, 1 case used cefoperazone-sulbactam), 33.3% (14 / 42) used semi-synthetic penicillins (piperacillin-tazobactam), 42.9% (18 / 42) used quinolones (2 cases used levofloxacin, 16 cases used moxifloxacin), and 9.5% (4 / 42) used cephalosporins (lamoxacin). The duration of antibiotic use was within one week, and no antibiotic escalation or improvement in the level of care was observed.

[0067] (5) Changes in immunogenicity after ablation

[0068] In addition, the present invention analyzed the changes in peripheral blood immune components before and after ablation therapy, and collected and analyzed paired peripheral blood samples from patients with lung lesions undergoing cryoablation and thermal ablation at baseline and after ablation. A total of 300 patients were included, including 270 thermal ablations and 30 cryoablations. The results showed that ablation therapy mediated significant changes in peripheral blood interleukins and cytokines ( Figure 4 ), cryoablation had significantly higher IL-12 expression levels compared with thermal ablation ( Figure 5 ).

[0069] The above results show that approximately 21.6% of patients with non-small cell lung cancer who receive immunotherapy are in ORD status. Ablation of residual lung lesions significantly improved the survival benefit of immunotherapy, and no serious adverse events were observed. Subgroup analysis also showed that cryoablation combined with immunotherapy had a better survival benefit than thermal ablation.

[0070] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Application of local ablation in the preparation of products that improve survival benefits in the oligoresidual stage of non-small cell lung cancer after immunotherapy.

2. The use according to claim 1, characterized in that: The timing of local ablation intervention is: local ablation is performed when non-small cell lung cancer achieves partial lesion remission or disease stability after immunotherapy and is in the oligoresidual stage.

3. The use according to claim 1 or 2, characterized in that: The oligoresidual stage refers to the residual tumor lesions after immunotherapy being limited to 3 organs and the number being ≤5.

4. The use according to claim 1, characterized in that: The local ablation includes cryoablation, radiofrequency ablation or microwave ablation.

5. The use according to claim 4, characterized in that: The conditions of cryoablation include: the number of cycles is not less than 2 cycles, the freezing time is 10 to 15 minutes, and the rewarming time is 3 to 8 minutes.

6. The use according to claim 4, characterized in that: The conditions for radiofrequency ablation include: starting with a low power of 20 to 30 W and gradually increasing the power until the peak impedance is reached.

7. The use according to claim 4, characterized in that: The microwave ablation conditions include: ablation power of 50 to 65 W, and ablation time of 6 to 10 minutes.

8. The use according to claim 1 or 4, characterized in that: After local ablation, chest CT was rescanned to evaluate the ablation range.

9. The use according to claim 1, characterized in that: The immunotherapy includes the use of immune checkpoint inhibitors to treat non-small cell lung cancer.

10. The use according to claim 9, characterized in that: The immune checkpoint inhibitors include PD-1 inhibitors or PD-L1 inhibitors.

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