METHOD FOR PROVIDING INFORMATION ON THERAPEUTIC REACTION OF CANCER IMMUNOTHERAPY AND KIT USING SAME

Abstract

Provided in the present disclosure are a method for providing information on a therapeutic reaction of cancer immunotherapy and a kit using same for providing information, the method comprising the steps of: measuring respective expression levels of PD-L1 and PVR in a biological sample isolated from a subject; and evaluating the therapeutic reaction of cancer immunotherapy for the subject on the basis of the measured expression levels of PD-L1 and PVR.

Claims

1. A method for providing information on a therapeutic response to a cancer immunotherapy, the method comprising: measuring expression levels of PD-L1 and PVR, respectively, for a biological sample isolated from a subject; and evaluating the therapeutic response to the cancer immunotherapy for the subject, based on the measured expression levels of PD-L1 and PVR.

2. The method of claim 1, wherein the subject is a subject suspected of non-small lung cancer, wherein the biological sample includes at least one selected from a group consisting of tumor tissue, blood, serum, and plasma, and is isolated from the subject before or after the cancer immunotherapy is performed.

3. The method of claim 1, wherein the evaluating of the therapeutic response to the cancer immunotherapy includes: when the measured expression level of each of the PD-L1 and PVR is greater than or equal to a predetermined level, determining each of expressions of PD-L1 and PVR as positive and when the measured expression level of each of the PD-L1 and PVR is lower than the predetermined level, determining each of expressions of PD-L1 and PVR as negative; and evaluating the therapeutic response to the cancer immunotherapy, based on whether the expressions of PD-L1 and PVR are negative or positive, wherein the cancer immunotherapy includes one therapy selected from a group consisting of anti-PD-1 therapy, anti-TIGIT therapy, and anti-PD-1/anti-TIGIT combination therapy.

4. The method of claim 3, wherein the evaluating of the therapeutic response to the cancer immunotherapy includes: evaluating that a subject having the PD-L1 expression positive and the PVR expression negative has the therapeutic response to the anti-PD-1 therapy higher than the therapeutic response to the anti-PD-1 therapy of one of a subject having the PD-L1 expression positive and the PVR expression positive, a subject having the PD-L1 expression negative and the PVR expression negative, and a subject having the PD-L1 expression negative and the PVR expression positive.

5. The method of claim 3, wherein the evaluating of the therapeutic response to the cancer immunotherapy includes: evaluating that a subject having the PD-L1 expression negative and the PVR expression positive has the therapeutic response to the anti-TIGIT therapy or the anti-PD-1/anti-TIGIT combination therapy higher than the therapeutic response to the anti-PD-1 therapy.

6. The method of claim 3, wherein the predetermined levels for the PD-L1 and the PVR are TPS (Tumor Proportion Score) 10% and TPS 60%, respectively.

7. The method of claim 1, wherein the cancer immunotherapy includes at least one therapy selected from a group consisting of anti-CTLA-4 therapy, anti-PD-1 therapy, anti-CD28 therapy, anti-KIR therapy, anti-TCR therapy, anti-LAG-3 therapy, anti-TIM-3 therapy, anti-TIGIT therapy, anti-A2aR therapy, anti-ICOS therapy, anti-OX40 therapy, anti-4-1BB therapy and anti-GITR therapy.

8. A method for providing information on a therapeutic response to a cancer immunotherapy, the method comprising: a first step of respectively measuring expression levels of PVR for biological samples isolated from a subject before and after the cancer immunotherapy is performed; and a second step of evaluating the therapeutic response to the cancer immunotherapy for the subject, based on the expression levels of PVR.

9. The method of claim 8, wherein the cancer immunotherapy is anti-PD-1 therapy, wherein the evaluating of the therapeutic response to the cancer immunotherapy for the subject includes: evaluating, that a subject whose expression level of PVR after the anti-PD-1 is performed is higher than a level thereof before the anti-PD-1 is performed, has the therapeutic response to the anti-PD-1 therapy lower than the therapeutic response to the anti-PD-1 therapy of a subject whose expression level of PVR after the anti-PD-1 is performed is lower than or equal to a level thereof before the anti-PD-1 is performed.

10. A kit for providing information on a therapeutic response to a cancer immunotherapy, the kit containing formulations configured to measure expression levels of PD-L1 and PVR, respectively, for a biological sample isolated from a subject.

11. The kit of claim 10, wherein the kit is configured to present a positive or negative therapeutic response to the cancer immunotherapy based on a predetermined expression level of each of the PD-L1 and PVR, wherein the cancer immunotherapy includes one selected from a group consisting of anti-PD-1 therapy, anti-TIGIT therapy, and anti-PD-1; anti-TIGIT combination therapy.

12. The kit of claim 11, wherein the kit is further configured to present the positive therapeutic response to the anti-PD-1 therapy when the subject has the expression level of PD-L1 higher than or equal to the predetermined expression level and the expression level of PVR lower than the predetermined expression level.

13. The kit of claim 11, wherein the kit is further configured to present the negative therapeutic response to the anti-PD-1 therapy, or the positive therapeutic response to the anti-TIGIT therapy or the anti-PD-1/anti-TIGIT combination therapy when the subject has the expression level of PD-L1 lower than the predetermined expression level and the expression level of PVR greater than or equal to the predetermined expression level.

14. The kit of claim 11, wherein the predetermined expression level is in a range of an expression rate of 1% to 10% for each of the PD-L1 and PVR.

15. The kit of claim 10, wherein the subject is a subject suspected of non-small lung cancer, wherein the biological sample includes at least one selected from a group consisting of tumor tissue, blood, serum, and plasma and is isolated from the subject before or after the cancer immunotherapy is performed.

16. The kit of claim 10, wherein the cancer immunotherapy includes at least one therapy selected from a group consisting of anti-CTLA-4 therapy, anti-PD-1 therapy, anti-CD28 therapy, anti-KIR therapy, anti-TCR therapy, anti-LAG-3 therapy, anti-TIM-3 therapy, anti-TIGIT therapy, anti-A2aR therapy, anti-ICOS therapy, anti-OX40 therapy, anti-4-1BB therapy and anti-GITR therapy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1 shows an exemplary procedure of a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure.

[0043] FIGS. 2A and 2B show the expression correlation and expression pattern of PD-L1 and PVR in cancer tissues of non-small lung cancer patients.

[0044] FIGS. 3A to 3C show the evaluation results for therapeutic response prediction to anti-PD-1 therapy of non-small lung cancer patients, according to the expression patterns of PD-L1 and PVR used as biomarkers in various embodiments of the present disclosure.

[0045] FIGS. 4A to 4D show the results of verifying the therapeutic response to the anti-PD-1 therapy in a mouse model, according to the expression patterns of PD-L1 and PVR used as biomarkers in various embodiments of the present disclosure, using gene regulations.

[0046] FIGS. 5A and 5B show the results that can suggest an appropriate cancer immunotherapy method based on whether therapeutic response to the PD-1 blockage is low or high or immune checkpoint ligand expression, according to a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure.

BEST MODES FOR CARRYING OUT THE INVENTION

[0047] Advantages and features of the present disclosure, and a method of achieving them will become apparent with reference to the embodiments described later in detail together with the accompanying drawings. However, the present disclosure is not limited to the embodiments disclosed below, but will be implemented in various different forms. Only these embodiments make the disclosure of the present disclosure complete and are provided to completely inform the scope of the disclosure to those with ordinary knowledge in the technical field to which the present disclosure belongs. The present disclosure is only defined by the scope of the claims.

[0048] Hereinafter, a procedure of a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure will be described in detail with reference to FIG. 1.

[0049] FIG. 1 shows an exemplary procedure of a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure.

[0050] Referring to FIG. 1, a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure includes first, measuring expression levels of PD-L1 and PVR, respectively for a biological sample isolated from a subject (S110), and evaluating a therapeutic response to cancer immunotherapy for the subject, based on the measured expression levels of PD-L1 and PVR (S120).

[0051] According to an embodiment of the present disclosure, in the step of measuring the expression level (S110), the expression levels of PD-L1 and PVR are measured for biological samples such as tumor tissue, blood, serum, or plasma isolated from a subject suspected of the non-small lung cancer.

[0052] According to an embodiment of the present disclosure, the step of evaluating the therapeutic response to cancer immunotherapy (S120) can include: when the measured expression level of each of the PD-L1 and PVR is greater than or equal to a predetermined level, determining each of expressions of PD-L1 and PVR as positive; when the measured expression level of each of the PD-L1 and PVR is lower to the predetermined level, determining each of expressions of PD-L1 and PVR as negative; and evaluating the therapeutic response to the cancer immunotherapy, based on whether the expressions of PD-L1 and PVR are negative or positive.

[0053] In this connection, the cancer immunotherapy includes one therapy selected from a group consisting of anti-PD-1 therapy, anti-TIGIT therapy, and anti-PD-1/anti-TIGIT combination therapy. However, the disclosure is not limited thereto. For example, the cancer immunotherapy can include at least one therapy selected from the group consisting of anti-CTLA-4 therapy, anti-CD28 therapy, anti-KIR therapy, anti-TCR therapy, anti-LAG-3 therapy, anti-TIM-3 therapy, anti-A2aR therapy, anti-ICOS therapy, anti-OX40 therapy, anti-4-1BB therapy, and anti-GITR therapy.

[0054] According to another embodiment of the present disclosure, the step of evaluating the therapeutic response to cancer immunotherapy (S120) can include evaluating that a subject having the PD-L1 expression positive and the PVR expression negative has the therapeutic response to anti-PD-1 therapy higher than the therapeutic response to anti-PD-1 therapy of one of a subject having the PD-L1 expression positive and the PVR expression positive, a subject having the PD-L1 expression negative and the PVR expression negative, and a subject having the PD-L1 expression negative and the PVR expression positive.

[0055] According to the above procedure, the method tier providing information on a therapeutic response according to an embodiment of the present disclosure can measure the levels of various markers, and thus can provide information to allow a therapeutic response to the cancer immunotherapy for a subject, particularly, a therapeutic response to anti-PD-1 to be early predicted.

EXAMPLE 1

Biomarker Setup for Early Prediction of Therapeutic Response to PD-1 Blockade

[0056] Hereinafter, with reference to FIGS. 2A and 2B, biomarkers used for prediction method of therapeutic responses to the cancer immunotherapy, in particular, anti-PD-1 therapy, according to various embodiments of the present disclosure, and therapeutic response prediction method using the same will be described.

[0057] FIGS. 2A and 2B show the expression correlation and expression pattern of PD-L1 and PVR in cancer tissues of non-small lung cancer patients.

[0058] Referring to FIG. 2A, the results of correlation analysis on the expression of immune checkpoint ligands for non-small lung cancer patient data using TCGA (the cancer genome atlas) as a common patient database are shown. More specifically, the expression of the immune checkpoint ligand PD-L1 (CD 274), which is a target for the treatment of non-small lung cancer, appeared to have a high correlation with CD 86, CD 80, and BTN3A1. On the other hand, PVR appeared to have a low correlation with PD-L1 and a ligand that correlates with PD-L1. Accordingly, since the expression of PVR is independent of PD-L1 expression, PVR can be used as a biomarker that can be used together with or independently of PD-L1 in the prediction of a PD-1 blockage therapeutic response.

[0059] Referring to (a), (b), and (c) in FIG. 2B, the results of the analysis of the expression patterns of PD-L1 and PVR in tumor tissue obtained from non-small lung cancer patients subjected to anti-PD-1 therapy are shown. Referring to (b) in FIG. 2B, the distribution pattern of the tumor proportion score (TPS) of PD-L1 and PVR as analyzed in the tumor tissue of each patient is shown. The median cut-off values for PD-L1 and PVR were TPS 10% and TPS 60%, respectively. Based on these values, in this experiment, it is determined that when the expression level for each of PD-L1 and PVR is higher than or equal to the median cut-off value (PD-L1: TPS 10%, PVR: TPS 60%), the expression of each of PD-L1 and PVR is positive, whereas when the expression level for each of PD-L1 and PVR is lower than the median cut-off value, the expression of each of PD-L1 and PVR is negative. Accordingly, patients with non-small lung cancer can be classified into patents having PD-L1 positive and PVR positive (PD-L1+/PVR+), PD-L1 positive and PVR negative (PD-L1+/PVR−), PD-L1 negative and PVR positive (PD-L1−/PVR+) and PD-L1 negative and PVR negative (PD-L1−/PVR−). Referring to (c) in FIG. 2B, about 24% of patients with non-small lung cancer belong to PD-L1−/PVR−, and about 22% thereof belong to PD-L1+/PVR−.

[0060] Based on a result of Example 1 above, PVR, or PD-L1 and PVR can be used as biomarkers for prediction of a therapeutic response in a method for providing information about a therapeutic response according to various embodiments of the present disclosure.

EXAMPLE 2

Early Prediction of Therapeutic Response to PD-1 Blockade Based on PD-L1 and PVR Expression Patterns for Non-Small Lung Cancer Patients

[0061] Hereinafter, an evaluation result of the therapeutic response prediction to the anti-PD-1 therapy according to the expression patterns of PD-L1 and PVR in the tumor tissue of anon-small lung cancer patient will be described with reference to FIGS. 3A to 3C.

[0062] FIGS. 3A to 3C show the evaluation results for therapeutic response prediction to the anti-PD-1 therapy of non-small lung cancer patients according to the expression patterns of PD-L1 and PVR used as biomarkers in various embodiments of the present disclosure.

[0063] In the following experiment, 119 patients having recurrent/metastatic non-small lung cancer over the age of 20 as confirmed, for which previous platinum-based chemotherapy failed, and who underwent the PD-1 blockage at least once were set as the experimental group. In this connection, treatment efficacy was evaluated based on clinical responses defined as CR (complete response), PR (partial response) and SD (stable disease) using contrast-enhanced CT approximately 8 weeks after the first injection of nivolumab. A responder (R) was defined as a patient with a PR or SD of greater than or equal to 6 months and a non-responder (NR) was defined as a patient having a PD or SD of smaller than 6 months.

[0064] Referring to (a) and (b) in FIG. 3A, the evaluation results of the response to anti-PD-1 therapy according to RECAST (response evaluation criteria in solid tumors) are shown. More specifically, referring to (a) in FIG. 3A, 38% of the total patient group exhibited a response to anti-PD-1 therapy at the baseline level (pretreatment). In one example, referring to (b) in FIG. 3A, when the expression levels of PD-L1 and PVR were considered together, the response prediction ability to anti-PD-1 therapy was improved than when the expression of PD-L1 was used alone. In particular, among the patient group with PD-L1 expression positive, patients with PVR expression negative (PD-L1+/PCR−) had higher response to PD-1 blockade therapy, compared to patients with PVR expression positive (PD-L1+/PCR+). Referring to (c), (d) and (e) in FIG. 3A, the accuracy of prediction can be improved when both PD-L1 and PVR were used as biomarkers for response prediction to PD-1 blockade therapy, compared to when PD-L1 or PVR was used alone.

[0065] Referring to FIG. 3B, progression-free survivals of non-small lung cancer patients with 4 expression patterns of PD-L1+/PVR−, PD-L1+/PVR+, PD-L1−/PVR− and PD-L1−/PVR+ are shown. More specifically, when considering both PD-L1 and FM as markers of the response to the PD-1 blockade therapy, the PD-L1+/PVR− patient group as predicted to have the highest therapeutic response exhibited the highest progression-free survival compared to the rest of the groups. Furthermore, the PD-L1−/PVR− and PD-L1−/PVR+ patient groups predicted to have a low therapeutic response to PD-1 blockage exhibited lower progression-free survival compared to the rest of the groups.

[0066] Referring to (a) and (b) in FIG. 3C, progression-free survival and overall survival for patients with non-small lung cancer haying 4 expression patterns: PD-L1+/PVR−, PD-L1+/PVR+, PD-L1−/PVR− and PD-L1−/PVR+ are shown. As shown in FIG. 3C, the PD-L1+/PVR− patient group, which is predicted to have the highest therapeutic response, exhibited the highest progression-free survival and overall survival according to the treatment course, compared to the other groups. Then, in the order of PD-L1+/PVR+ patient group, PD-L1−/PVR− patient group, and PD-L1−/PVR+ patient group, progression-free survival and overall survival according to the treatment course were higher. That is, the PD-L1−/PVR+ patient group predicted to have a low therapeutic response to PD-1 blockage exhibited the lowest progression-free survival and overall survival.

[0067] Based on a result of Example 2 above, PD-L1 and PVR can be used as markers for response prediction to cancer immunotherapy, and the response to PD-1 therapy can be evaluated according to the expression pattern for two biomarkers. For example, a patient group with positive PD-L1 expression and negative PVR expression can be evaluated as having a higher response to the PD-1 blockade therapy. Furthermore, the patient group with PD-L1 expression negative and PVR expression positive can be evaluated as having a lower response to the PD-1 blockade therapy. For this patient group, immune checkpoint blockade strategy different from PD-1 blockade strategy, for example, TIGIT blockade strategy in which TIGIT is a receptor for PVR can be proposed, or a combination therapy of PD-1 blockade strategy and TIGIT blockade strategy can be proposed.

EXAMPLE 3

Early Prediction of Therapeutic Response to PD-1 Blockades Based on the Expression Patterns of PD-L1 and PVR in Mouse Model

[0068] Hereinafter, the evaluation results of the therapeutic response prediction to the anti-PD-1 therapy according to the expression patterns of PD-L1 and PVR in the tumor tissue of a mouse model will be described with reference to FIGS. 4A to 4D.

[0069] FIGS. 4A to 4D show the results of verifying the therapeutic response to anti-PD-1 therapy in a mouse model according to the expression patterns of PD-L1, and PVR used as biomarkers in various embodiments of the present disclosure using gene regulations.

[0070] Referring to FIG. 4A, in order to obtain tumor cell lines having 4 expression patterns of PD-L1+/PVR−, PD-L1+/PVR+, PD-L1−/PVR− and PD-L1−/PVR+, CRISPR-Cas9 technique was performed to selectively knock-out (KO) PD-L1 and/or PVR for the tumor cell line MC38 of a mouse model having positive PD-L1 and PVR expressions. As a result, the PD-L1+/PVR+ cell line WT (wild type) MC 38, the PD-L1−/PVR+ cell line PD-L1 KO MC 38, the PD-L1+/PVR− cell line PVR KO MC 38 and PD-L1−/PVR− cell line dKO MC 38 were obtained.

[0071] Referring to FIG. 4B, after implanting the four tumor cell lines constructed by the above-described method in FIG. 4A into a mouse model, the results of analyzing tumor progression are shown. More specifically, the PD-L1 or PVR expression negative mouse model (PD-L1 KO MC 38 implanted model and PVR KO MC 38 implanted model) has slower tumor progression than the mouse model (WT MC 38 implanted model) having positive PD-L1 and PVR expressions has. In particular, the mouse model (dKO MC 38 implanted model) in which both PD-L1 and PVR expressions are negative exhibited to be significantly slower in tumor progression than other mouse models.

[0072] Referring to (a) and (b) in FIG. 4C, the analysis results of tumor progression based on whether the expression of PD-L1 or PVR is positive in a tumor cell line and a mouse as the host into which the tumor cell line was implanted are shown. More specifically, when knocking out PD-L1 or PVR in the mouse model, the tumor progressed rapidly to a degree similar to that of the WT mouse model having PD-L1 and PVR expression positive. These results can mean that whether the expression of PD-L1 or PVR is positive in the mouse model as the host in which the tumor cell line was implanted is less influential than whether the expression of PD-L1 or PVR is positive in the tumor cell line. That is, the tumor progression can dependent on the tumor cell line implanted in the mouse.

[0073] Referring to (a) to (d) in FIG. 4D, the results of survival and tumor progression analysis for a mouse model transplanted with a tumor cell line of PD-L1 KO MC38 and a mouse model transplanted with a tumor cell line of PVR KO MC38 are shown. More specifically, the mouse model transplanted with the tumor cell line of PVR. KO MC38 of PD-L1+/PVR− has significantly increased survival and significantly slowed progression of tumor under anti-PD-1 blockade (αPD-1) treatment than the mouse model transplanted with the tumor cell line of PD-L1 KO MC38 of PD-L1−/PVR+ has.

[0074] Based on a result of Example 3 above, the therapeutic response to the anti-PD-1 therapy can vary based on the expression patterns of PD-L1 and PVR in the tumor tissue obtained from the mouse model, and more specifically, the expression patterns of PD-L1 and PVR of the transplanted tumor cell line and the host. Accordingly, a method for providing information on a prediction response for a therapeutic response according to various embodiments of the present disclosure and a kit using the same can predict the therapeutic response to cancer immunotherapy based on the expression patterns of PD-L1 and PVR, and then propose customized cancer immunotherapy in consideration of the patient's tumor microenvironment.

EXAMPLE 4

Setting Up Cancer Immunotherapy having High Therapeutic Response Based on the Expression Patterns of PD-L1 and PVR

[0075] Hereinafter, a method of setting an alternative treatment therapy to PD-1 based on the expression patterns of PD-L1 and PVR will be described in detail with reference to FIGS. 5A and 5B.

[0076] FIGS. 5A and 5B show the results that can suggest an appropriate cancer immunotherapy method based on whether a therapeutic response to the PD-1 blockage is low or high or immune checkpoint ligand expression, according to a method for providing information on a therapeutic response to cancer immunotherapy according to an embodiment of the present disclosure.

[0077] Referring to (a) and (b) in FIG. 5A, the analysis results of the therapeutic response to the cancer immunotherapy in the mouse model having PD-L1−/PVR+ implanted with the tumor cell line of PD-L1 KO MC38 as described above in Example 3 are shown. In this connection, the cancer immunotherapy as performed is anti-PD-1 therapy, anti-TIGIT therapy, and combination therapy of anti-PD-1/anti-TIGIT. The mouse model having PD-L1−/PVR+ can be predicted to have the lower therapeutic response to PD-1 blockage, according to the method for providing information on the therapeutic response according to various embodiments of the present disclosure.

[0078] Referring to (a) and (b) in FIG. 5A, the PD-L1−/PVR+ mouse model exhibited high survival and low tumor progression when anti-TIGIT therapy, or anti-PD-1/anti-TIGIT combination therapy was performed than when anti-PD-1 therapy was conducted. That is, in the mouse model of PD-L1−/PVR+, the response to the anti-TIGIT therapy and the combination therapy of anti-PD-1/anti-TIGIT can be higher than that of the anti-PD-1 therapy. As described above, cancer immunotherapy having a high therapeutic response can vary depending on the expression patterns of PD-L1 and PVR.

[0079] Referring to FIG. 5B, in non-small lung cancer patient 1 (patient no. 1), B7-1 and B7-2 were expressed together with PD-L1 as an immune checkpoint ligand. In other words, even when a PD-1 blockade that inhibits the reaction of PD-L1 and PD-1 was administered thereto, the patient 1 can have low response to anti-PD-1 therapy, due to the reaction of B7-1 and B7-2 in tumor tissue and CTLA-4 in T cells. Accordingly, the patient 1 can be expected to have higher anti-cancer treatment effects when anti-PD-1 therapy and anti-CTL-4 treatment were combined with each other than when anti-PD-1 therapy was performed alone.

[0080] Furthermore, in the non-small lung cancer patient 2 (patient no. 2), B7-1 and B7-2, and PVR were expressed along with PD-L1. In other words, even when a PD-1 blockade that inhibits the reaction of PD-L1 and PD-1 was administered theret the patient 2 can have lower response to anti-PD-1 therapy due to reaction of B7-1 and B7-2 of the tumor tissue and CTLA-4 of T-cells, or due to the reaction of PVR of the tumor tissue and TIGIT of T-cells. Thus, the patient 2 can be expected to have a higher anticancer treatment effect when anti-PD-1 therapy was combined with anti-CTL-4 therapy or/and anti-TIGIT therapy than when anti-PD-1 therapy was conducted alone.

[0081] Based on a result of Example 4 above, it is confirmed that anti-TIGIT therapy or combination therapy of anti-PD-1/anti-TIGIT can effectively act as an alternative treatment to the PD-L1−/PVR+ patient group evaluated to have a low response to anti-PD-1 therapy according to the method for providing information on the therapeutic response to cancer immunotherapy in the present disclosure. Accordingly, the present disclosure predicts the early therapeutic response of the subject to the cancer immunotherapy, especially, PD-1 blockage at high sensitivity, and thus can provide information to quickly determine whether to further proceed with anti-PD-1 therapy or whether the anti-PD-1 therapy is to be combined with other immunotherapies.

[0082] The results of Examples 1 to 4 indicate that responses to the first treatment of patients with non-small lung cancer can be predicted early based on the expression patterns of PD-L1 and PVR. That is, PD-L1 and PVR, or PVR can act as practical indicators for prediction of the therapeutic response to immunotherapies of non-small lung cancer.

[0083] However, the present disclosure is not limited to the above, and can be used to provide information for the prediction of a therapeutic response to a variety of immunotherapy methods. For example, the present disclosure can be configured to provide information for prediction of the therapeutic response to at least one therapy selected from the group consisting of anti-CTLA-4 therapy, anti-PD-1 therapy, anti-CD28 therapy, anti-KIR therapy, anti-TCR therapy, anti-LAG-3 therapy, anti-TIM-3 therapy, anti-TIGIT therapy, anti-A2aR therapy, anti-ICOS therapy, anti-OX40 therapy, anti-4-1BB therapy, and anti-GITR therapy.

[0084] Furthermore, the present disclosure can further provide an information providing kit configured to predict a therapeutic response to cancer immunotherapy as the kit contains a formulation configured to measure the expression levels of PD-L1 and PVR, respectively, for a biological sample isolated from a subject.

[0085] The features of the various embodiments of the present disclosure can be partially or entirely coupled or combined with each other. As those skilled in the art can fully understand, various technical associations and operations therebetween can be realized. The embodiments may be implemented independently of each other and may be implemented together in a combined relationship.

[0086] Although the embodiments of the present disclosure have been described in more detail with reference to the accompanying drawings, the present disclosure is not necessarily limited to these embodiments. Various modifications can be made within the scope of the technical idea of the present disclosure. Therefore, the embodiments disclosed in the present disclosure are not intended to limit the technical idea of the present disclosure thereto. The scope of the technical idea of the present disclosure is not limited to the embodiments. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of protection of the present disclosure should be construed by the claims below. All technical ideas within the scope of the equivalents thereto should be construed as being included in the scope of the present disclosure.

[0087] National R&D project 1 that supported the present disclosure, Project Identification Number: 2017R1A5A1014560, Ministry Name: Ministry of Science and Technology Information and Communication, Research Management Organization: Korea Research Foundation, Research Project Name: Leading Research Center Business Science (SRC), Research Project Title: Center for Immune Research on Non-lymphoid Organ, Contribution Percentage: 1/5, Host Institution: Yonsei University Industry-Academic Cooperation Foundation, Research Period: 20170601 to 20240228

[0088] National R&D project 2 that supported the present disclosure, Project Identification Number: 2018M3A91-13024850, Ministry Name: Ministry of Science and Technology Information and Communication, Research Management Organization: Korea Research Foundation, Research Project Name: Biomedical Technology Development Project-Grand Challenge, Research Project Title: Developing a precision immunotherapy method based on engineered bacteria, Contribution Percentage: 1/5, Host Institution: Yonsei University Industry-Academic Cooperation Foundation, Research Period: 20180401 to 20261231,

[0089] National R&D project 3 that supported the present disclosure, Project identification Number: 2015R1A2A1A10056084, Ministry Name: Food and Drug Safety Evaluation Institute, Research Management Organization: Food and Drug Safety Evaluation Institute, Research Project Name: Safety Evaluation Technology Development Research Project (Personalized Drug Evaluation Base Research), Research Project Title: Research on development of immune anticancer drug response prediction/evaluation method, Contribution Percentage: 1/5, Host Institution: Yonsei University Industry-Academic Cooperation Foundation, Research Period: 20180516 to 20201130,

[0090] National R&D project 4 that supported the present disclosure, Project Identification Number: NRF-2017M3A9E9072669, Ministry Name: Ministry of Science and Technology Information and Communication, Research Management Organization: Korea Research Foundation, Research Project Name: Biomedical Technology Development Project, Research Project Title: High-precision preclinical model using patient-derived circulating tumor cells, identification of the mechanism of acquired resistance to anticancer drugs through construction and presentation of treatment strategies, Contribution Percentage: 1/5, Host Institution: Yonsei University Industry-Academic Cooperation Foundation, Research Period: 20170901 to 20220531

[0091] National R&D project 5 that supported the present disclosure, Project identification Number: NRF-2017R1D1A1B03029874, Ministry Name: Ministry of Science and Technology information and Communication, Research Management Organization: Korea Research Foundation, Research Project Name: individual basic research in science and engineering (basic, regional), Research Project Title: Immuno-anticancer drugs using immune markers in peripheral blood of lung cancer patients, establishment of effective immuno-cancer treatment strategies through identification of treatment predictors. Contribution Percentage: 1/5, Host institution: Yonsei University Industry-Academic Cooperation Foundation, Research Period: 20170601 to 20200531