COMBINATION OF MARKERS TO PREDICT THE RESPONSE TO VX-001

Abstract

The invention relates to the use of an antitumor vaccine composed of two nine-amino-acid peptides - the original, cryptic TERT572 (RLFFYRKSV, SEQ ID NO:1) expressed by tumor cells and its optimized variant TERT572Y (YLFFYRKSV, SEQ ID NO: 2), for the treatment of a tumor expressing telomerase reverse transcriptase (TERT) in an HLA-A*0201 patient with normal levels of gamma-glutamyl transferase (gGT) and / or lactate dehydrogenase (LDH).

Description

COMBINATION OF MARKERS TO PREDICT THE RESPONSE TO VX-001 FIELD OF INVENTION The present invention relates to the field of anticancer immunotherapy, more particularly to the field of antitumor vaccination. BACKGROUND OF THE TECHNOLOGY The general condition of cancer patients is assessed by routine blood tests, such as LDH (lactate dehydrogenase), gGT (gamma glutamyl transferase), ALP (alkaline phosphatase), markers of liver function and inflammation, and / or a blood count to determine the absolute number and proportion of neutrophils and lymphocytes and the platelet count. These constants are known as prognostic markers in cancer patients and patients with a deteriorated general condition who have a worse prognosis. It has also been shown that these markers can influence the response to certain treatments, particularly immune checkpoint inhibitors, molecules developed in recent years that have revolutionized the treatment of certain cancers (Ferrucci et al., Annals Oncol. 2016). Cancer immunotherapy is designed to stimulate cytotoxic T lymphocytes (CTLs) to recognize peptides derived from tumor antigens presented on the tumor cell surface by human leukocyte antigen (HLA) class 1 (HLA-I) molecules. Peptides targeting CTLs can be dominant or cryptic depending on their affinity for HLA molecules. Tumor-associated antigens (TAAs) are frequently expressed in both tumor cells and normal tissues, unlike neoantigens, which are specific to the tumor and, generally, to the patient. TAAs have the advantage of being expressed by a wide range of tumors, unlike neoantigens, but they have the disadvantage of being subject to tolerance mechanisms that prevent autoimmunity—that is, the recognition of self-antigens by an individual's immune system. Telomerase reverse transcriptase (TERT), an enzyme involved in tumor cell immortalization, is an AAT-type antigen expressed by many tumors (85% of tumors). To circumvent the problem of immune tolerance to AATs while targeting an antigen widely expressed by tumors, the inventors proposed a vaccine (Vx-001) targeting a cryptic peptide of TERT—that is, a TERT peptide that has low affinity for the HLA-A*0201 molecule (the most frequently expressed MHC-I molecule in humans) and forms unstable peptide / HLA-I complexes (Tourdot S. et al., 2000; Menez-Jamet J. et al., 2016). Given the strong correlation between HLA-I affinity and immunogenicity, this cryptic peptide is not naturally immunogenic. For use as a cancer vaccine, this cryptic peptide was optimized to enhance its immunogenicity. Therefore, Vx-001 is a therapeutic antitumor vaccine composed of two nine-amino-acid peptides: the native cryptic peptide TERT572 (RLFFYRKSV, SEQ ID NO:1), expressed by cells MA / IOO / or tumor cells and its optimized variant TERT572Y (YLFFYRKSV, SEQ ID NO:2). These two peptides are administered separately, each with the adjuvant Montanide ISA51®VG (a mixture of a highly purified mineral oil (Drakeol 6VR) and a surfactant (mannide monooleate)). The optimized immunogenic peptide TERT572Y is used in the first two vaccinations to trigger a strong immune response. The native TERT572 peptide is administered in subsequent vaccination steps to select, from among all TERT572Y-stimulated T cells, those with the highest specificity for native TERT572, which is present on the surface of HLA-A*0201-associated tumor cells. Vx-001 was recently tested in patients with metastatic or recurrent stage I-III NSCLC (non-small cell lung cancer) in a randomized phase IIb clinical trial (study Vx-001-201). The vaccination protocol in this study included 6 doses at 3-week intervals (2 doses with TERT572Y, then 4 doses with TERT572), followed by boosters every 12 weeks (with TERT572) until disease progression (Georgoulias et al., Clin Lung Cancer. 2013). The patients included expressed HLA-A*0201 and had a TERT-expressing tumor. The primary objective of the study was to monitor overall survival. The results of this study were not statistically significant overall. However, Vx-001 showed significant efficacy in some patients. Therefore, the inventors investigated whether certain blood parameters might be related to clinical response or lack of response to the vaccine. This study led to patient stratification, identifying categories of patients for whom vaccination with Vx-001 was statistically beneficial. BRIEF DESCRIPTION OF THE INVENTION The inventors have demonstrated that the Vx-001 antitumor vaccine provides a statistically significant benefit to patients with normal gGT and / or LDH levels, with those exhibiting the best response to treatment. Further stratification showed that male patients with non-squamous cell carcinomas responded particularly well to the treatment. The present invention relates, therefore, to the use of Vx-001 in a method of treating a tumor expressing telomerase reverse transcriptase (TERT), in an HLA-A*0201 patient with normal levels of gamma Glutamyl Transferase (gGT) and / or lactate dehydrogenase (LDH), preferably in a male patient with a non-squamous cell tumor. The present invention also relates to a method for determining in vitro whether an HLA-A*0201 patient with a TERT-expressing tumor is likely to respond favorably to cancer vaccination with Vx-001, comprising measuring the patient's gGT and LDH levels, who is likely to respond favorably to vaccination with Vx-001 if at least one of these levels is normal. DESCRIPTION OF THE FIGURES Figure 1: OS and TTF in patients with normal serum LDH levels. Thick gray curve: patients who received Vx-001; thin black curve: patients who received placebo. Figure 2: OS and TTF in patients with normal serum gGT levels. Thick gray curve: patients who received Vx-001; thin black curve: patients who received placebo. Figure 3: Clinical response to Vx-001 in patients with normal serum ALP levels. Thick gray curve: patients who received Vx-001; thin black curve: patients who received placebo. Figure 4: Clinical response to Vx-001 and absolute neutrophil count. Thick gray curve: patients who received Vx-001; thin black curve: patients who received a placebo. Figure 5: Clinical response to Vx-001 and neutrophil-to-lymphocyte ratio. Thick gray curve: patients who received Vx-001; thin black curve: patients who received a placebo. Figure 6: Clinical response to Vx-001 and platelet count. Thick gray curve: patients who received Vx-001; thin black curve: patients who received a placebo. Figure 7: OS and TTF in patients with normal serum LDH and gGT levels. Thick gray curve: patients who received Vx-001; thin black curve: patients who received a placebo. Figure 8: Survival analysis of subgroups of patients with normal serum LDH and gGT levels. NSQ: non-squamous cell carcinoma. SQ: squamous cell carcinoma. OR: objective response to chemotherapy. SD: stable disease. ECOG: Eastern Cooperative Oncology Group functional class. Figure 9: Analysis of TTF (Time to Treatment Failure) in subgroups of patients with normal serum LDH and gGT levels. NSQ: non-squamous cell carcinoma. SQ: squamous cell carcinoma. OR: objective response to chemotherapy. SD: stable disease. ECOG: Eastern Cooperative Oncology Group functional class. Figure 10: Patient survival according to the combination of markers studied. Thick gray curve: patients who received Vx-001; thin black curve: patients who received a placebo. Figure 11: Patient survival according to tumor immunogenicity defined by TIL (Tumor Infiltrating Lymphocytes) infiltration and PD-L1 expression. Gray curve: patients who received Vx-001; black curve: patients who received a placebo. Figure 12: TTF of patients according to tumor immunogenicity defined by TIL (Tumor Infiltrating Lymphocytes) infiltration and PD-L1 expression. Gray curve: patients who received Vx-001; black curve: patients who received a placebo. Figure 13: Survival of patients with non-immunogenic or immunogenic tumors according to the markers studied. LDH / gGT UNL = LDH / gGT below the upper limits of normal. Figure 14: TTF of patients with non-immunogenic or immunogenic tumors according to the markers studied. LDH / gGT UNL = LDH / gGT below the upper limits of normal. DETAILED DESCRIPTION The present invention is based on the identification of patient categories for whom the results of the Vx-001-201 study showed that vaccination with Vx-001 was significantly beneficial. The present invention relates, for each of these patient categories (set out below), to the use of Vx-001 to treat a tumor expressing TERT. The present invention also relates, for each of these patient categories, to the use of the TERT572Y peptide of SEQ ID NO:2, to induce a CTL response against the cryptic epitope TERT572 of the SEQ ID NO:1 sequence. The invention also relates, for each of these patient categories, to the use of the TERT572 peptide of sequence SEQ ID NO:1 to maintain a CTL response induced by the TERT572Y peptide of SEQ ID NO:2 previously administered to the patient. As illustrated in the experimental section below, a first category of patients are HLA-A*0201 patients with tumors that express TERT and have normal levels of lactate dehydrogenase (LDH). Another category of patients likely to respond favorably to vaccination with Vx-001 are HLA-A*0201 patients with tumors expressing TERT and normal levels of gamma Glutamyl Transferase (gGT). HLA-A*0201 patients with tumors expressing TERT who also have normal levels of gGT and LDH are a category of patients especially likely to respond favorably to vaccination with Vx-001. Normal gGT and LDH levels are defined as levels below the upper limits of normal (UNL) established by each laboratory according to the techniques and reagents used. Identifying whether a level is normal or not presents no difficulty for a trained technician. The present invention relates, therefore, to the use of Vx-001 to treat a TERT-expressing tumor in an HLA-A*0201 patient with normal levels of gGT and / or LDH. "Treatment" here means at least slowing the progression of the tumor and / or prolonging the patient's survival. According to a particular embodiment of the invention, Vx-001 is administered to a patient with a normal gGT level and / or a normal LDH level after having received at least one chemotherapy treatment. Vx-001 is administered after first-line chemotherapy. According to another particular embodiment of the invention, Vx-001 is administered to a patient with non-small cell lung cancer (NSCLC), for example, metastatic or recurrent NSCLC, said patient having a normal level of gGT and / or a normal level of LDH. The inventors have also shown that patients with normal gGT levels and / or LDH, male patients respond statistically better to vaccination with Vx-001 than female patients. According to another particular embodiment of the invention, Vx-001 is therefore administered to a male patient with normal levels of gGT and / or LDH. Furthermore, the results of the Vx-001-201 study show that Vx-001 is statistically more effective in treating non-squamous cell tumors than squamous cell tumors. According to another particular embodiment of the invention, Vx-001 is therefore administered to a patient with a normal level of gGT and / or a normal level of LDH who suffers from a non-squamous cell tumor. According to another particular embodiment of the invention, Vx-001 is administered to a patient under 65 years of age with normal gGT and / or normal LDH. According to another particular embodiment of the invention, Vx-001 is administered to a patient with a normal level of gGT and / or a normal level of LDH and whose cancer no longer progresses after chemotherapy, for example, after first-line chemotherapy. According to another particular embodiment of the invention, Vx-001 is administered to a patient with a normal gGT level and / or a normal LDH level and who has an ECOG score of 0. The results of the Vx-001-201 study also show that normal serum LDH and gGT levels correlate with improved survival and longer time to full treatment (TTF) in patients with non-immunogenic tumors. A non-immunogenic tumor is defined as a tumor that does not express the PD-L1 molecule (i.e., if less than 1% of tumor cells express PD-L1: tumor proportional score <1%) and / or is not infiltrated by lymphocytes (i.e., when tumor-infiltrating lymphocytes, or TILs, are entirely absent or very scarce). According to another particular embodiment of the invention, Vx-001 is administered to a patient with normal levels of gGT and / or LDH, and whose tumor does not express the PD-L1 molecule and / or is not infiltrated by lymphocytes. The present invention also relates to a method for determining in vitro whether an HLA-AA*0201 patient with a tumor expressing TERT is likely to respond favorably to a therapeutic anticancer vaccination with Vx-001, comprising a step of measuring, from a biological sample of said patient, the gGT level and the LDH level of said patient; according to this method, the patient is considered likely to respond favorably to the anticancer vaccination if at least one of these levels is normal, ya fortiori if the patient's gGT and LDH levels are both normal. According to the method of the invention, the probability of the patient responding favorably to anticancer vaccination with Vx-001 is considered even higher if the tumor is non-immunogenic, i.e., it does not express the PD-L1 molecule and / or is not infiltrated by lymphocytes. According to the method of the invention, the probability of the patient responding favorably to therapeutic anticancer vaccination with Vx-001 is considered to be even greater if the MA / t / ZUZZ / U IOO l or patient also has one or more of the following characteristics: (i) is a male patient (iii) has a non-squamous cell tumor (iv) is under 65 years of age (v) has a tumor that has stopped progressing after first-line chemotherapy (v) has an ECOG score=0. Of course, the different modalities of the invention are not mutually exclusive, and classes of patients possessing several of the above criteria are more likely to be good responders to vaccination with Vx-001. The present invention is illustrated in more detail in the experimental section below, which does not limit its scope. EXAMPLES Blood tests were performed during patient recruitment for the clinical study, after chemotherapy treatment. Since each laboratory uses its own tests and upper limits of normal (ULN), data were collected from patient medical records and classified according to the results obtained compared to the laboratory's applicable upper limits of normal (Table 1). The elements studied were LDH, gGT, ALP, absolute neutrophil count, absolute platelet count, and neutrophil-to-lymphocyte ratio. The efficacy of the investigational product (Vx-001) in this clinical study was evaluated by comparing two endpoints between patients who received the investigational product and those who received a placebo: Patient survival or overall survival (OS) is the period during which the disease no longer progresses and the patient receives no treatment other than the investigational product (or placebo), referred to as Time to Treatment Failure (TTF). Paciente LDH (UNL) gGT (UNL) ANC> 6000 N / L>3 Plaq. (UNL) ALP> UNL Paciente LDH (UNL) gGT (UNL) ANC> 6000 N / L>3 ALP> UNL Plaq. (UNL) 01 -02-004 L L N S N N 04-07-021 ND ND N N N N 01 -03-007 L L N N N N 04-07-029 H L N N N N 01-03-012 L H N N N N 04-09-005 L L S S N N 01-03-018 L L N N N N 04-10-007 ND ND S S N S 01-03-023 L H N N S N 04-10-008 H ND N S N N 01-04-011 L H N S S S 04-10-014 L L N S N N 01-05-001 L L N N N N 04-10-024 L L S S N S 01-05-011 L ND N N N N 04-10-025 ND L N S N N 01 -06-006 L L N N N N 04-10-031 H L N N N S 01-07-001 H H N s S S 04-10-034 ND L N S N N 01 -08-002 L L N S N N 04-12-001 L L N N N N 01 -08-003 L H S S N N 04-12-002 ND L N S N N 01 -08-005 L L N N N N 04-12-009 L L N N N N 01 -09-002 L L N N N N 04-13-003 L L N N N N 01-09-006 H L N N N N 04-13-004 L L N N N N 01-10-002 L L N N N N 04-13-011 ND L N S N S 01-10-004 H L N S N N 04-13-015 L L N S N S 02-03-001 ND LNNSN 05-01-013 LLNSNN 02-05-002 ND LNNNN 05-03-003 LLNNSN 02-06-002 LLNNNN 05-04-001 HLNSNN 02-06-005 HHNNNN 05-04-010 LLNNNN 02-07-004 ND LNNNN 05-04-012 LHNSSS 02-07-006 LLNSNN 05-04-014 LLNNNN 02-07-007 ND LNNS ND 05-06-005 LLSSNN 03-01-005 HLNNNN 05-07-006 ND ND NNNN 03-01-008 HHNNNN 05-07-009 LLNSNN 03-02-001 LHSSNN 05-07-012 LLNSNN 03-02-033 LHNSNS 05-07-015 LLNSNN 03-02-042 LLNNSN 05-07-016 HLNNNN 03-02-044 LLNSNN 05-08-002 HLNNSN 03-02-056 LLNNSN 05-08-027 LLNNNN 03-02-060 ND LNSNN 05-09-004 LLNN ND S 03-02-070 LLNNNN 05-09-006 HHSN ND N 03-02-100 LLSSNN 05-09-008 LLNSNN 03-03-001 LLNNSN 05-10-008 HLNSNN 03-03-012 LHNNNN 05-11-001 ND LNNNN 03-03-015 LLNNS ND 05-11-007 LLNNSN 03-03-019 LHSSNN 05-13-005 LLNSNN 03-03-020 LLNNN ND 05-13-006 LLSSNN 03-03-023 LHNSSNND 06-01-002 L ND SSS ND 03-03-025 LLNNN ND 07-02-004 LHNNNN 03-03-028 HHNNN ND 07-02-013 L ND SNSN 03-03-031 LLNNNN 07-03-002 ND ND NSNN 03-03-035 LLSNNN 07-03-004 LLSSNN 03-03-049 LLNNN ND 07-03-009 HLNSSS 03-03-058 LLSNNN 07-03-011 HLSNSN 03-03-062 LLNNSN 07-03-013 LLNNSS 03-03-065 LHSSN 07-03-015 LHSSSSS 03-03-086 LLNSSS 07-03-016 L ND NNNN 03-04-001 HLNSNS 07-03-019 HLNNNS 03-04-014 LLNNSS 07-03-021 L ND NSNN 03-04-025 HLSSNN 07-03-022 H ND NNNN 03-04-040 LLNNNN 07-03-030 LLNNNN 03-04-042 LLSNNN 07-03-032 LLSSNN 03-05-006 HLNNNS 07-04-006 L ND NSNN 03-05-007 ND HNNNN 07-04-010 LLNNNN 03-06-005 LLNNNN 07-04-011 L ND NNNN 03-06-009 LLNNNN LLNNNS 03-07-007 HLSSSN 07-06-006 LHNSNN 03-07-008 LLSSNN 07-06-016 LLNNNN 03-07-013 LLNSNS 07-06-018 HHNNNN 03-07-021 ND ND NNNN 07-06-020 LHNNNS 03-07-028 HLNNNN 07-06-024 LHNNSS 03-07-030 LLNSNN 07-07-011 LLNNSN 03-07-040 HLSSNN 07-08-001 LLNNNN 03-07-060 LLNSNN 07-09-001 LLNNSN 03-07-066 LLNNNN 07-10-002 LHNNSN 03-07-071 LLNNNN 07-10-005 LLNNNN 03-08-013 HHNSNN 07-10-012 LLNNNN 03-08-014 LLNNNN 07-10-017 LLNSNN 03-10-001 LLNNNN 08-01-022 LLNNNN 04-01-010 LLNNNN 08-01-031 LHNNNN 04-01-023 LLNNNN 08-01-043 LLNSNN 04-01-057 LHNNNS 08-01-046 LLNNNN 04-02-002 ND ND NSNN 08-01-050 HLNSNN 04-02-004 LLNNNN 08-01-051 HLNNNN 04-03-008 LLSSNN 08-01-056 HHNSNN 04-03-010 HLNNNN 08-01-059 LLNNNN 04-03-011 LLNNNN 08-01-060 HHNSSN 04-04-002 LLNSNS 08-01-061 HLNNNN 04-05-002 LLNSNN 08-01-064 LLNSNN 04-05-006 HLSSNN 08-01-069 HLNNNN 04-05-026 LLNNNN 08-01-070 HLNNNN 04-05-036 LHSNNN 08-01-071 HLNNNN 04-05-046 ND LNSNN 08-01-072 LLNSNN 04-06-001 LHNNNN 08-01-073 LHNNNS 04-06-002 HLNNNN 08-02-006 LLNNNN 04-07-007 HLNNNN 08-02-011 LLNSNN 04-07-012 HLNNNN 08-02-016 HLNNNN 04-07-013 LLNNNN 08-02-017 HLNNSN 04-07-017 LLNSSN 08-03-008 LHNNNN Table 1: Measurement of serum lactate dehydrogenase (LDH), gamma-glutamyl transferase (gGT), alkaline phosphatase (ALP), absolute neutrophil count (ANO), neutrophil / lymphocyte ratio (N / L), and platelet count (Plaq.). Patients included in the Vx001-201 study were classified into several subgroups: L for patients with a normal level for the marker of interest, according to the standards of the laboratory that performed the study, and H for patients with a level above the normal limit established by each laboratory; N = No; S = Yes; ND = not measured. 1. Clinical response to Vx-001 and LDH levels Of the 190 patients included in the Vx-001-201 study, 127 had normal serum LDH levels. In this population, vaccination with Vx-001 significantly increased OS and TTF compared with patients in the placebo group (Figure 1). 2. Clinical response to Vx-001 and gGT levels Of the 190 patients included in the Vx-001-201 study, 139 had normal serum gGT levels. In this population, vaccination with Vx-001 increased overall survival (OS) compared to placebo, but not significantly (p=0.10). In contrast, time to full duration of transmission (TTF) increased significantly (Figure 2). 3. Clinical response to Vx-001 and alkaline phosphatase (ALP) Of the 190 patients included in the Vx-001-201 study, 160 had normal serum ALP levels. In this population, vaccination with Vx-001 did not result in an increase in overall survival (OS) compared to patients in the placebo group (p=0.74, Figure 3). There was no impact of patients' ALP levels on their responsiveness to Vx-01. The TTF results were identical. 4. Clinical response to Vx-001 and blood counts Blood counts are routinely used to assess a patient's inflammatory status. Therefore, the absolute neutrophil count, as well as the neutrophil-to-lymphocyte ratio and the platelet count, are characteristic of the patient's overall health. a. Clinical response to Vx-001 and absolute neutrophil count The absolute neutrophil count is a commonly used marker of inflammation. In particular, elevated neutrophil counts have been shown to be associated with a poor response to treatment with immune checkpoint inhibitors (ICIs) (Ferrucci et al., Annals Oncol 2016). In the case of treatment with Vx-001, no impact on neutrophil count was observed. There were no differences in survival between patients in the placebo and treatment groups, nor between patients with elevated neutrophil counts and those with normal neutrophil counts (Figure 4). b. Clinical response to Vx-001 and neutrophil-to-lymphocyte ratio The same type of result was observed with the neutrophil-to-lymphocyte ratio. No differences in survival were observed between patients in the placebo and treatment groups, either in patients with a neutrophil-to-lymphocyte ratio below 3, a ratio commonly used as a cutoff point in the literature (Mezquita et al., 2018; Ferrucci et al., 2016), or in those with a ratio above 3 (Figure 5). c. Clinical response to Vx-001 and platelets Finally, platelet count had no impact. There were no differences in survival between patients in the placebo and treatment groups, nor between patients with elevated platelet counts and those with normal platelet counts (ULN: upper limit of normal) (Figure 6). 5. Combined factors a. gGTyLDH Next, the clinical efficacy of Vx-001 was evaluated by combining factors, including those that had shown an impact on patient survival and TTF. In the 97 patients with normal LDH and gGT, treatment with Vx-001 significantly increased survival and TTF: p=0.003 and p=0.0019, respectively (Figure 7). Further analysis of survival in subgroups of this patient population with normal serum LDH and gGT levels shows that Vx-001 has a highly significant effect in patients with non-squamous cell carcinoma (NSC, p=0.0038), males (p=0.0024), smokers (p=0.0099), patients younger than 65 years (p=0.0019), patients who entered the study with an objective response to chemotherapy (OR, p=0.036) or in stabilization (SD, p=0.034), with an ECOG score of 0 (0.041) or ECOG 1 (p=0.039). Surprisingly, Vx-001 did not significantly increase survival in patients with squamous cell carcinoma (SC, p=0.39), females (p=0.27), and patients older than 65 years. (p=0.08) (Figure 8). Furthermore, the TTF analysis of subgroups of this patient population with normal serum levels of LDH and gGT confirmed that Vx-001 had a highly significant effect in patients with non-squamous cell carcinoma (NSQ, p=0.0009), men (p=0.0064), smokers (p=0.001), patients under 65 years of age (p=0.0017), patients who entered the study with an objective response to chemotherapy (OR, p=0.021), with an ECOG score of 0 (0.021), but also in patients over 65 years of age (p=0.0017). Conversely, Vx-001 did not significantly increase the TTF in patients with squamous cell carcinoma histology (SQ, p=0.49), in women (p=0.25), in patients who entered MA / IOO / or the study with the disease stabilized after chemotherapy (SO, p=0.074) or with ECOG 1 (p=0.14) (figure 9). The combination of LDH and gGT levels was the only combination of factors with a synergistic effect; the other combinations gave results that, at most, were identical to the analysis with LDH alone (Figure 10). 6. Effect of LDH and gGT markers on tumor immunogenicity The immunogenicity of a tumor depends on several factors, the most important being the presence of TILs (Tumor-Infiltrating Lymphocytes) within the tumor and the expression of the PD-L1 molecule by tumor cells. The effect of Vx-001 on these two parameters was analyzed in 136 patients for whom biopsy sections were available. The 22C3 pharmDx kit was used for PD-L1 detection. PD-L1 expression was analyzed according to the Agilent kit recommendations for quantifying PD-L1-expressing tumor cells (TPS: tumor proportional score). Tumors were classified into three groups: i) PD-L1 negative (<1% of labeled cells; TPS <1%), ii) PD-L1 positive (1–49% of labeled cells; TPS 1–49%), and iii) PD-L1 overexpression (>50% of positive cells; TPS >50%). Tumor infiltration (intratumoral site, IS, and stromal site, SS) by TILs was classified as i) absent (score 0), ii) very rare (score 1), iii) weak (score 2), iv) moderate (score 3), and v) strong (score 4). Tumors were classified as PD-L1 negative if less than 1% of tumor cells expressed PD-L1 (TPS; tumor proportional score, <1%) and TIL negative if TILs in the tumor nucleus and stroma were completely absent (score 0) or very rare (score 1). MA / t / ZUZZ / U IOO l or individual results are presented in Table 2. Patient Group TIL (IS) TIL (SS) TPS Patient Group TIL (IS) TIL (SS) TPS 01-02-004 V 0 0 <1% 04-07-029 P 1 4 <1% 01-03-007 V 0 0 >50% 04-09-005 P 1 4 <1% 01-03-012 P 1 4 <1% 04-10-007 P 1 2 <1% 01-03-018 V 0 0 <1% 04-10-008 V 1 3 <1% 01-03-023 P 0 3 1-49% 04-10-014 V 1 2 <1% 01-04-011 V 0 1 <1% 04-10-024 V 1 4 <1% 01-05-001 P 1 2 <1% 04-10-031 P 0 0 <1% 01-05-011 V 1 3 <1% 04-10-034 P 0 1 <1% 01-06-006 P 1 2 <1% 04-12-001 P 1 2 <1% 01-08-002 V 1 2 1-49% 04-12-002 V 0 0 <1% 01-08-003 V 2 3 1-49% 04-12-009 P 0 1 <1% 01-08-005 V 0 2 <1% 04-13-003 P 0 0 <1% 01-09-002 V 1 2 1-49% 04-13-004 V 0 0 <1% 01-09-006 P 0 0 >50% 04-13-011 P 1 3 <1% 01-10-002 V 1 1 <1% 04-13-015 P 1 3 1 -49% 01-10-004 P 0 0 <1% 05-01-013 V 1 1 <1% 02-03-001 P 2 2 1-49% 05-03-003 V 0 0 <1% 02-06-005 P 1 2 <1% 05-04-012 V 0 0 <1% 02-07-004 V 0 0 <1% 05-06-005 V 2 4 <1% 02-07-007 V 0 1 <1% 05-07-006 P 2 4 1 -49% 03-01-005 V 0 1 <1% 05-09-004 V 1 1 <1% 03-01-008 P 2 2 <1% 05-09-006 P 0 0 <1% 03-02-001 P 2 3 <1% 05-09-008 V 1 3 <1% 03-02-042 V 1 1 <1% 05-11-001 V 1 3 <1% 03-03-015 P 0 0 <1% 05-11-007 P 1 4 <1% 03-03-019 P 1 3 <1% 07-02-004 P 0 0 <1% 03-03-020 V 1 1 <1% 07-03-002 V 1 2 <1% 03-03-023 V 0 0 <1% 07-03-004 P 0 1 <1% 03-03-025 P 1 3 <1% 07-03-011 P 2 3 >50% 03-03-028 V 1 4 <1% 07-03-015 V 1 2 1 -49% 03-03-031 P 0 2 1-49% 07-03-016 P 1 2 <1% 03-03-049 P 0 0 <1% 07-03-019 V 1 2 <1% 03-03-058 P 1 2 <1% 07-03-021 P 1 3 >50% 03-03-062 P 0 0 <1% 07-03-022 V 1 2 1 -49% 03-03-065 V 0 2 <1% 07-03-030 V 0 1 <1% 03-03-086 V 0 0 <1% 07-03-032 V 0 0 <1% 03-04-001 V 1 2 <1% 07-04-006 V 1 3 <1% 03-04-014 P 1 0 <1% 07-04-010 P 1 2 <1% 03-04-025 P 1 0 <1% 07-04-011 P 0 1 >50% 03-04-042 P 0 1 <1% 07-04-020 V 1 3 1 -49% 03-05-006 P 0 3 1-49% 07-04-023 P 0 0 1 -49% 03-05-007 V 0 2 <1% 07-05-001 V 1 3 <1% 03-06-005 P 1 3 1-49% 07-06-006 V 1 3 <1% 03-06-012 V 0 1<1% 07-06-016 V 0 0 <1% 03-06-016 P 0 0 <1% 07-06-018 V 1 3 1 -49% 03-07-001 V 1 3 1-49% 07-06-020 V 1 1 <1% 03-07-007 V 0 0 <1% 07-07-011 V 0 0 <1% 03-07-008 P 0 1 <1% 07-08-001 P 0 0 <1% 03-07-013 P 0 1 <1% 07-10-002 P 1 2 1 -49% 03-07-060 P 0 0 <1% 07-10-005 V 0 0 <1% 03-07-066 V 0 0 <1% 07-10-012 V 0 0 <1% 03-07-071 P 1 2 <1% 07-10-017 P 1 2 1 -49% 03-08-013 P 0 0 <1% 08-01-043 P 0 0 <1% 03-08-014 P 0 1 <1% 08-01-046 P 0 0 <1% 03-10-001 V 2 4 <1% 08-01-050 V 0 1 1 -49% 04-01-023 P 1 4 1-49% 08-01-051 P 0 0 <1% 04-01-057 V 0 0 <1% 08-01-056 V 1 3 <1% 04-02-002 V 1 3 <1% 08-01-059 V 1 3 <1% 04-03-008 P 1 3 <1% 08-01-060 V 1 2 <1% 04-03-010 V 1 2 <1% 08-01-061 V 1 2 >50% 04-04-002 P 0 2 <1% 08-01-064 P 0 1 <1% 04-05-002 P 1 2 1-49% 08-01-069 P 1 3 <1% 04-05-026 V 1 3 <1% 08-01-070 V 0 1 <1% 04-05-036 V 0 0 <1% 08-01-071 P 1 2 >50% 04-06-001 V 1 3 <1% 08-01-072 P 1 3 <1% 04-06-002 P 0 0 <1% 08-01-073 P 0 1 >50% 04-07-013 P 1 3 <1% 08-02-016 P 1 2 <1% 04-07-021 P 1 2 <1% 08-03-008 P 0 1>50% MA / t / ¿ U1OO l or > Table 2: TIL and TPS scores of patients for whom these data are available. The results presented in Figure 11 show that Vx-001 prolongs survival in patients with TIL-negative (8.7 vs. 20.7 months; p=0.0089) and PD-L1-negative (9.9 vs. 15.5 months; p=0.13) tumors but does not prolong survival in patients with TIL-positive (16.3 vs. 14.3 months; p=0.197) and PD-L1-positive (24.9 vs. 7.9 months; p=0.29). The clinical efficacy of Vx-001 was even greater in patients with tumors that were both TIL- and PD-L1-positive (6.6 vs. 20.7 months; p=0.0049). Similar results were obtained with the TTF analysis. Vx-001 prolonged TTF in patients with TIL-positive (2.7 vs. 3.6 months; p=0.041), PD-L1-positive (2.3 vs. 3.5 months; p=0.079), and TIL- / PD-L1-positive (2.2 vs. 3.6 months; p=0.011) tumors (Figure 12). Analysis of the effect of the two factors LDH and gGT in relation to tumor immunogenicity, defined as the presence of TIL and PD-L1 expression, showed that normal serum levels of LDH and gGT correlate with greater survival (Figure 13) and a longer TTF (Figure 14) in patients with non-malignant tumors, but not in patients with immunogenic tumors (TIL+, PD-L1+, TIL+ and / or PDI-L1+). References Ferrucci PF, Asvierte PA, et al., Baseline neutrophils and derived neutrophil-to- lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilímumab. Ann Oncol. 2016 Apr;27(4):732-8. Georgoulias V, et al., A multicenter randomized phase / Ib efficacy study of Vx- 001, a peptide-based cáncer vaccine as maintenance treatment in advanced non-small-ce / 1 lung cáncer: treatment rationale and protocol dynamics. Clin Lung Cáncer. 2013 Jul;14(4):461- 5. Menez-Jamet J, et al., Optimized tumor cryptic peptides: the basis for universal neo-antigen-like tumor vaccines. Ann Transí Med. 2016 Jul;4(14):266. Mezquita, L. et al., Association of the Lung Immune Prognostic Index With Immune checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cáncer. JAMA Oncol. 2018 Mar 1 ;4(3):351 -357.Tourdot S, et al., A general strategy to enhance immunogenicity of low-affinity HLA-A2. 1associated peptides: implication in the identification of cryptic tumor epitopes. Eur J Immunol. 2000 Dec;30(12):3411-21.

Claims

1. An anticancer vaccine comprising the peptide from SEQ ID NO:1 and the peptide from SEQ ID NO:2 (Vx-001), for use in a method of treating a tumor expressing telomerase reverse transcriptase (TERT) in an HLA-A*0201 patient, characterized in that it is administered to a patient with normal levels of gamma glutamyl transferase (gGT) and / or lactate dehydrogenase (LDH).

2. The Vx-001 anticancer vaccine according to claim 1, for use according to claim 1, characterized in that it is administered to a patient with a normal gGT level and a normal LDH level.

3. The Vx-001 anticancer vaccine according to claim 1, for use according to claim 1 or claim 2, characterized in that it is administered to a patient with non-small cell lung cancer.

4. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 3, characterized in that it is administered to a patient after first-line chemotherapy.

5. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 4, characterized in that it is administered to a male patient.

6. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 5, characterized in that it is administered to a patient with a non-squamous cell tumor.

7. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 6, characterized in that it is administered to a patient under 65 years of age.

8. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 7, characterized in that it is administered to a patient whose cancer no longer progresses after first-line chemotherapy.

9. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 8, characterized in that it is administered to a patient with an ECOG score of 0.

10. The Vx-001 anticancer vaccine according to claim 1, for use according to any of claims 1 to 9, characterized in that it is administered to a patient whose tumor does not express the PD-L1 molecule and / or is not infiltrated by lymphocytes.

11. A method for determining in vitro whether an HLA-A*0201 patient with a tumor expressing LA TERT is likely to respond favorably to cancer vaccination with Vx-001, comprising the step of measuring, in a biological sample from said patient, the gGT level and the LDH level of said patient, characterized in that if at least one of these levels is normal, the patient is likely to respond favorably to cancer vaccination.

12. The method according to claim 11, characterized in that if the patient's gGT and LDH levels are both normal, the patient is likely to respond favorably to anticancer vaccination with Vx-001.

13. The method according to claim 11 or claim 12, characterized in that the probability of the patient responding favorably to anticancer vaccination with Vx-001 is even greater if the tumor does not express the PD-L1 molecule and / or is not infiltrated by lymphocytes.

14. The method according to any of claims 11 to 13, characterized in that the probability of the patient responding favorably to anticancer vaccination with Vx-001 is even greater if the patient exhibits one or more of the following characteristics: (i) is a male patient (ii) has a non-squamous cell tumor (ii) is under 65 years of age (iv) has a tumor that has stopped progressing after first-line chemotherapy (v) has an ECOG score of 0.