CN113945723A - Kit, system, storage medium and use thereof for predicting risk of development of pneumonia associated with immune checkpoint inhibitor therapy - Google Patents
Kit, system, storage medium and use thereof for predicting risk of development of pneumonia associated with immune checkpoint inhibitor therapy Download PDFInfo
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Abstract
The invention provides a kit, a system, a computer-readable storage medium and application thereof for predicting the risk of pneumonia related to immune checkpoint inhibitor treatment, and relates to the technical field of medical diagnosis. The kit comprises a COPD diagnostic tool, a tumor cell PD-L1 expression state detection reagent and a baseline plasma IL-8 level detection reagent. The system comprises a data acquisition module, a risk assessment module and an output module. The computer readable storage medium includes a program to implement the above system. The kit, the system and the storage medium can predict CIP occurrence risk with higher accuracy.
Description
Technical Field
The invention relates to the technical field of medical diagnosis, in particular to a kit, a system, a storage medium and application thereof for predicting the risk of relevant pneumonia caused by immune checkpoint inhibitor treatment.
Background
In recent years, immunotherapy represented by immune checkpoint inhibitors (ici) has been introduced in clinical practice, including ici directed against programmed cell death protein 1 (PD-1) or its ligand PD-L1, and by blocking the co-suppression signal pathway of immune checkpoints, the anti-tumor immune response of T cells is rescued to promote the elimination of tumor cells, which brings new hopes for cancer therapy.
The de-inhibition of T cell function by ICIs can lead to a series of organ-specific inflammatory side effects known as immune-related adverse events (irAEs), and current evidence suggests that irAEs may involve autoreactive T cells, cytokines, etc. pathways that lead to the development of irAEs through excessive inflammatory cytokine release through T cell activation. Among the reported irAEs, immune checkpoint inhibitor-associated pneumonia (CIP) is the most common lung toxicity in patients receiving ICIs, especially non-small cell lung cancer. Clinical manifestations of CIP are diverse, ranging from asymptomatic, respiratory symptoms to respiratory failure and even death, and are one of the most important causes of ici-related death. Also, CIP sometimes lacks typical imaging and pathological features, which can be life threatening to the patient if not diagnosed in time or disposed of properly. Past clinical trials have reported low incidence of CIP (about 3-5%), whereas CIP incidence in real-world case reports is as high as 5-19%. More importantly, CIP can progress rapidly in a short period of time, even life threatening, while also affecting the effectiveness and consistency of treatment of lung cancer ICIs.
Disclosure of Invention
In order to solve the problems, the invention provides a kit, a system, a storage medium and an application thereof for predicting the risk of incidence of pneumonia related to immune checkpoint inhibitor treatment, which can effectively evaluate the risk of incidence of CIP, recognize and diagnose CIP early so as to reduce the incidence of CIP, intervene in time and treat reasonably.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a kit for predicting the risk of pneumonia related to immune checkpoint inhibitor treatment, which comprises a COPD diagnostic tool, a tumor cell PD-L1 expression state detection reagent and a baseline plasma IL-8 level detection reagent.
Preferably, the kit further comprises instructions for carrying an evaluation formula determined according to the following method:
multifactorial analysis and quantification of each factor weight score in samples with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor treatment, whether COPD is present, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels, an nomographic equation based on multifactorial logistic regression analysis was established.
Preferably, the description is written with the following evaluation formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
The invention also provides a system for predicting the risk of the relevant pneumonia treated by the immune checkpoint inhibitor, which comprises a data acquisition module, a risk evaluation module and an output module;
the data acquisition module acquires data including whether COPD is suffered or not, tumor cell PD-L1 expression level and baseline plasma IL-8 level;
the risk evaluation module comprises a risk evaluation formula determined according to the following mode;
multifactorial analysis and quantification of each factor weight score in samples with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor treatment, whether COPD is present, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels, an nomographic equation based on multifactorial logistic regression analysis was established.
Preferably, the risk assessment module comprises the following risk assessment formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
The invention also provides a computer readable storage medium containing computer instructions, which when executed by a processor, implement the system of the above technical solution.
The invention also provides the application of the kit in the technical scheme, the system in the technical scheme or the computer readable storage medium in the technical scheme in the preparation of an agent for preventing or diagnosing the pneumonia related to the treatment of the tumor patient by the immune checkpoint inhibitor.
Preferably, the tumor patient comprises a non-small cell lung cancer patient.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the kit, the system or the computer-readable storage medium for predicting the risk of the related pneumonia treated by the immune checkpoint inhibitor, disclosed by the invention, COPD, the expression level of tumor cells PD-L1 and the baseline plasma IL-8 level are found to be independent risk factors of CIP, the risk of CIP can be effectively predicted by comprehensively evaluating the COPD, the tumor cells PD-L1 and the baseline plasma IL-8 level, the prediction accuracy is 0.883, the CIP risk evaluation of patients treated by ICIs is facilitated, clinical decision support is provided for the subsequent ICIs management, and the personalized treatment scheme can be conveniently formulated.
2. The factor for predicting the risk of the immune checkpoint inhibitor for treating the related pneumonia is convenient to detect, is favorable for clinical popularization, and reduces the burden of patients.
Drawings
FIG. 1 is a CIP risk prediction nomogram constructed in example 1;
FIG. 2 is a ROC curve of the prediction model constructed in example 1;
fig. 3 is a calibration curve of the actual CIP occurrence probability and the prediction probability in example 1.
Detailed Description
The invention provides a kit for predicting the risk of pneumonia related to immune checkpoint inhibitor treatment, which comprises a COPD diagnostic tool, a tumor cell PD-L1 expression state detection reagent and a baseline plasma IL-8 level detection reagent. In the present invention, the COPD diagnostic tool can be any tool capable of determining whether a subject has COPD, including but not limited to COPD diagnostic instrumentation, diagnostic reagents, diagnostic guidelines, and patient medical record questionnaires.
Preferably, the kit further comprises an instruction, and the instruction records an evaluation formula determined according to the following method:
multifactorial analysis and quantification of each factor weight score in samples with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor treatment, whether COPD is present, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels, an nomographic equation based on multifactorial logistic regression analysis was established.
In one embodiment of the present invention, the evaluation formula determined by the above method described in the specification is:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
The invention also provides a system for predicting the risk of the relevant pneumonia treated by the immune checkpoint inhibitor, which comprises a data acquisition module, a risk evaluation module and an output module; the data acquisition module acquires data including whether COPD is suffered or not, tumor cell PD-L1 expression level and baseline plasma IL-8 level; the risk evaluation module comprises a risk evaluation formula determined according to the following mode; multifactorial analysis of whether COPD is present in a sample with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor therapy, tumor cell PD-L1 expression status and baseline plasma IL-8 levels and quantification of the respective factor weight scores, an nomographic equation based on multifactorial logistic regression analysis was established.
The data acquisition module is used for collecting data required by evaluation, and the data can be data obtained by detection of a related kit and can also comprise all or part of data called from other detection items. The data acquisition module transmits the obtained data to a risk evaluation module for evaluation, and the risk evaluation module comprises a program capable of calculating an evaluation formula. And the risk evaluation module outputs the result calculated based on the evaluation formula to the output module, and the output module judges the calculation result to obtain and output a prediction result. The system can quickly and accurately predict the risk of the relevant pneumonia treated by the immune checkpoint inhibitor, and further provides reference basis for clinical diagnosis, medication guidance, prognosis evaluation and the like.
In the present invention, the data acquisition module preferably includes a data receiving device and/or a storage device, the data receiving device may be a computer capable of inputting external data, or may be an electronic component including a data instruction for calling a hospital system or a related system; the storage device is mainly used for storing the acquired data. In the present invention, the output module preferably includes a liquid crystal display.
In some embodiments of the invention, the risk assessment module comprises the following risk assessment formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
The invention also provides a computer readable storage medium containing computer instructions, which when executed by a processor, implement the system of the above technical solution.
The invention also provides the application of the kit in the technical scheme, the system in the technical scheme or the computer readable storage medium in the technical scheme in the preparation of an agent for preventing or diagnosing the pneumonia related to the treatment of the tumor patient by the immune checkpoint inhibitor. Preferably, the tumor patient includes a non-small cell lung cancer patient, that is, the kit, system or computer readable storage medium of the present invention can be used for preparing a reagent for preventing or diagnosing pneumonia related to the treatment of the non-small cell lung cancer patient with the immune checkpoint inhibitor.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1 construction of a kit, System and computer-readable storage Medium for predicting the risk of development of pneumonia associated with immune checkpoint inhibitor treatment
1. The present invention included 164 total NSCLC patients receiving anti-PD-1/anti-PD-L1 treatment between 3 months in 2017 and 12 months in 2020, of which 20 (12.2%) developed CIP after ici treatment. Although less than half of the patients in the cohort (43.9%) had a history of COPD, the proportion of COPD patients in the CIP group was greater (70.0%). Of the 136 patients in the cohort who evaluated tumor cell PD-L1 expression, 51 (37.5%) observed tumor cell PD-L1 expression of > 50%, while 85 (62.5%) had tumor cell PD-L1 expression of less than 50%. Furthermore, the baseline plasma IL-8 levels in the CIP group were significantly lower than in the non-CIP group, while no statistical differences were observed for the other cytokines in the presence or absence of CIP.
2. Statistical analysis: and (3) carrying out single-factor analysis and multi-factor analysis on the CIP group and the non-CIP group by adopting logistic regression analysis to evaluate the influence of risk factors on the occurrence of CIP. The results of the single factor analysis show that: the presence or absence of COPD, tumor cell PD-L1 expression status and baseline plasma IL-8 levels were correlated with risk of CIP development, all with significant differences (P < 0.05). The results of the multi-factor analysis show that: COPD (OR, 7.485; 95% CI, 1.083-51.72; P ═ 0.041) with tumor cell PD-L1 expression > 50% (OR, 6.857; 95% CI, 1.086-43.299; P ═ 0.041) with baseline plasma IL-8 levels <9.0 (OR, 0.08; 95% CI, 0.012-0.534; P ═ 0.009) being an independent risk factor for CIP development.
3. Establishing an evaluation model: constructing a nomogram based on a multifactor logistic regression analysis (fig. 1) after scoring and quantifying the weight of each variable using COPD, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels as independent variables, the nomogram comprising a scale of scores in the first row, wherein the scores range from 0 to 100; (ii) whether or not COPD is present in the patient in the second row prior to treatment with the ICIs, wherein the presence or absence of COPD gives a corresponding score for the first row; the third row represents the patient's tumor cell PD-L1 expression, wherein a corresponding score is obtained for greater than 50% tumor cell PD-L1 expression relative to the first row; the fourth line represents the patient's baseline plasma IL-8 level, wherein a score corresponding to whether the baseline plasma IL-8 level exceeds 9.0pg/mL corresponds to the first line; the fifth row is the total score of the patient, and the scores of the 3 indexes from the second row to the fourth row corresponding to the first row are added to obtain the total score of the patient; and (3) correspondingly projecting the total score of the patient in the fifth row to the sixth row to obtain the estimated risk probability of the patient in the CIP.
The evaluation formula of the nomogram is as follows:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
4. And (3) model verification: and drawing an ROC curve, calculating the area under the ROC curve (AUC), and carrying out internal verification through random resampling for 1000 times to draw a calibration curve of the prediction model so as to evaluate the accuracy and the identification capability of the nomogram prediction model.
5. And (3) test results: the histogram model AUC constructed by the invention reaches 0.883 (95% CI, 0.806-0.959) and has high prediction accuracy (figure 2).
Through the analysis of the calibration curve, the prediction curve and the calibration prediction curve, the observed probability and the predicted probability of CIP occurrence risk have good consistency (figure 3).
Example 2
A kit for predicting the risk of an immune checkpoint inhibitor treatment-related pneumonia occurrence comprising a COPD diagnostic tool, a tumor cell PD-L1 expression status detection reagent and a baseline plasma IL-8 level detection reagent, further comprising instructions describing the following evaluation formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
Example 3
A system for predicting the risk of an immune checkpoint inhibitor treating related pneumonia comprises a data acquisition module, a risk assessment module and an output module;
the data acquisition module acquires data including whether COPD is suffered or not, tumor cell PD-L1 expression level and baseline plasma IL-8 level;
the risk evaluation module operates the acquired data according to the following risk evaluation formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, 100 scores for subject baseline plasma IL-8 levels <9.0pg/mL, 0 scores otherwise;
the output module comprises a liquid crystal display screen.
In operation of the system, data on whether COPD is present, tumor cell PD-L1 expression levels, and baseline plasma IL-8 levels are input to the data acquisition module. The data acquisition module transmits the data to the risk assessment module, the risk assessment module carries out budget estimation on the data according to an assessment formula and outputs a calculation result to the output module, and the output module displays a judgment result through the liquid crystal display.
Example 4
A computer readable storage medium containing computer instructions for carrying out the equations of embodiment 3, which when executed by a processor, carry out the system of embodiment 3.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be construed as the protection scope of the present invention.
Claims (8)
1. A kit for predicting the risk of an immune checkpoint inhibitor treatment-related pneumonia occurrence comprising a COPD diagnostic tool, a tumor cell PD-L1 expression status detection reagent and a baseline plasma IL-8 level detection reagent.
2. The kit of claim 1, further comprising instructions that carry an evaluation formula determined according to the following method:
multifactorial analysis and quantification of each factor weight score in samples with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor treatment, whether COPD is present, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels, an nomographic equation based on multifactorial logistic regression analysis was established.
3. The kit of claim 1, wherein the instructions are written with the following evaluation formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
4. A system for predicting the risk of an immune checkpoint inhibitor treatment-related pneumonia occurrence, comprising a data acquisition module, a risk assessment module, and an output module;
the data acquisition module acquires data including whether COPD is suffered or not, tumor cell PD-L1 expression level and baseline plasma IL-8 level;
the risk evaluation module comprises a risk evaluation formula determined according to the following mode;
multifactorial analysis and quantification of each factor weight score in samples with or without the occurrence of pneumonia associated with known immune checkpoint inhibitor treatment, whether COPD is present, tumor cell PD-L1 expression status, and baseline plasma IL-8 levels, an nomographic equation based on multifactorial logistic regression analysis was established.
5. The system of claim 4, wherein the risk assessment module comprises a risk assessment formula:
P＝[-3.008+(a×2.013)+(b×1.925)+(c×-2.520)]×100％
wherein P is the probability of risk of development of pneumonia associated with treatment with an immune checkpoint inhibitor;
a is the subject's COPD score, with 80 points for subjects having COPD, and 0 points otherwise;
b is the score of PD-L1 of the tumor cells of the subject, 76 scores are recorded when the expression of the tumor cells PD-L1 of the subject is more than or equal to 50 percent, and 0 score is recorded when the expression of the tumor cells PD-L1 of the subject is not less than or equal to 0 percent;
c is subject baseline plasma IL-8 score, with subject baseline plasma IL-8 levels <9.0pg/mL scored as 100 points, otherwise scored as 0 points.
6. A computer readable storage medium containing computer instructions which, when executed by a processor, perform the system of claim 4 or 5.
7. Use of a kit according to any one of claims 1 to 3, a system according to any one of claims 4 to 5 or a computer readable storage medium according to claim 6 for the manufacture of a medicament for the prophylaxis or diagnosis of pneumonia associated with treatment with an immune checkpoint inhibitor in a patient suffering from a tumour.
8. The use of claim 7, wherein the tumor patient comprises a non-small cell lung cancer patient.
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