USE OF THERAPEUTIC COMPOSITIONS FOR THE TREATMENT OF PATIENTS WITH TUMORS OF EPITHELIAL ORIGIN

Abstract

The present invention relates to the branches of Biotechnology and Medicine. It describes the use of therapeutic compositions comprising a compound that blocks epidermal growth factor and an antibody that blocks the PD-1/PD-1 ligand signaling pathway in the treatment of tumors of epithelial origin, particularly those that express the native form for human KRAS protein. In patients with cancer of epithelial origin expressing native KRAS treated with said therapeutic compositions, an increase in their survival was observed.

Claims

1. A method of treating a tumor of epithelial origin in a patient, comprising administering to the patient i) a vaccine composition that induces the production of specific antibodies (Ab) against epidermal growth factor (EGF) and ii) a compound that blocks PD1/PD1 ligand (PD-1L) signaling pathway.

2. The method of claim 1, wherein the tumor of epithelial origin comprise the wild-type form of human KRAS protein.

3. The method of claim 2, wherein the wild-type KRAS is characterized by having the sequence selected from the group consisting of SEQ ID NO.: 1 and SEQ ID NO.: 2.

4. The method of claim 1, wherein the vaccine composition that induces the Ab production against the EGF comprises a conjugate between human recombinant EGF and a carrier protein.

5. The method of claim 4, wherein the carrier protein is selected from the group consisting of: cholera toxin B subunit, tetanus toxoid, KLH and P64k of Neisseria meningitidis.

6. The method of claim 5, wherein the vaccine composition additionally comprises an adjuvant selected from the group consisting of: incomplete Freund's adjuvants, squalene-based adjuvants, synthetic origin adjuvants, mineral origin adjuvants, vegetable origin adjuvants, animal origin adjuvants, particulated proteic adjuvants and liposomes.

7. The method of claim 1, wherein the compound that blocks PD1/PD-1L signaling pathway is selected from the group consisting of: an anti-PD1 Ab and an anti-PD-L1 Ab.

8. The method of claim 7, wherein the anti-PD1 Ab is selected from the group consisting of: nivolumab, pembrolizumab, cemiplimab, MEDI0608 and pidilizumab.

9. The method of claim 7, wherein the anti-PD1L Ab is selected from the group consisting of: atezolizumab, durvalumab, avelumab and MDX-1105.

10. The method of claim 1, wherein the patient is selected by determining the presence or absence of wild-type KRAS in a sample of tumoral cells of the patients, being selected for treatment the patient in whose tumor sample wild-type KRAS is detected.

11. The method of claim 1, wherein the tumor of epithelial origin is selected from the group consisting of: non-small cell lung cancer, squamous cell head and neck cancer, urothelial carcinoma, colorectal cancer, gastric cancer, esophagus cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, endometrial carcinoma, breast cancer and skin cancer.

12. A method of stratification of a patient into a responder or non-responder to treatment with a therapeutic regimen comprising i) a compound that blocks epidermal growth factor (EGF) and ii) an Ab that blocks PD1/PD-L1 signaling pathway, comprising selecting the patient by determining the presence or absence of wild-type KRAS in a sample of tumoral cells of the patient.

13. The method of claim 12, wherein the patient is considered responsive to treatment if wild-type KRAS is detected in the tumor sample.

14. The method of claim 13, wherein in the tumor sample of the patient the PD-L1 level is below 1%.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0033] FIG. 1. Anti-EGF Ab titer in serum of patients treated with CIMAvax-EGF and Nivolumab mAb.

[0034] FIG. 2. EGF levels in the serum of patients treated with CIMAvax-EGF and the mAb Nivolumab.

[0035] FIG. 3. Cumulative survival of patients treated with CIMAvax-EGF and Nivolumab over time, in patients with native KRAS and mutated KRAS tumors.

[0036] FIG. 4. Cumulative survival of patients treated with CIMAvax-EGF and Nivolumab over time, for patients with PD-L1 tumors <1%, which are native KRAS or mutated KRAS.

EXAMPLES

Example 1. The Combined Administration of CIMAvax-EGF and the Anti-PD1 mAb Nivolumab is Safe and Induces a Potent Anti-Human EGF Abs Response

[0037] In a phase I/II clinical trial, at the Roswell Park Comprehensive Cancer Center, Buffalo, New York (NCT02955290), a therapeutic composition comprising the vaccine composition CIMAvax-EGF, with the anti-PD1 mAb Nivolumab, was used to the treatment of advanced NSCLC patients.

[0038] This study had a Phase I dose escalation and a Phase II efficacy evaluation. In total, 29 patients with metastatic NSCLC were included. Nivolumab was used at a dose of 240 mg every 2 weeks, intravenously. The CIMAvax-EGF vaccine composition was used at a dose of 2.4 mg intramuscularly every 2 weeks during the induction phase (4 doses), followed by monthly injections in the maintenance phase. The first 6 patients received half the dose of CIMAvax-EGF (1.2 mg).

[0039] The safety profile was favorable and there were no serious adverse reactions related to the applied therapy. CIMAvax-EGF induced a good response in all patients, defined by an anti-EGF Ab titer equal to or greater than 1:4000 (serum dilution (FIG. 1). A rapid reduction of the EGF concentration in the serum of the patients, measured by ELISA (Human EGF Quantikine ELISA Kit, R&D Systems), was also observed in patients treated with CIMAvax-EGF and mAb nivolumab (FIG. 2).

[0040] The median overall survival for the 29 patients treated was 10.36 months. The overall survival rate at one year was 44%.

Example 2. The Combined Administration of CIMAvax-EGF and the Anti-PD1 mAb Nivolumab Significantly Benefits Native KRAS Patients

[0041] In the trial described in Example 1, an analysis was carried out by stratifying the patients, according to the presence or not of mutations in the KRAS gene in the tumor. The presence or absence of mutations and the number of copies of the KRAS gene was verified using a new generation sequencing assay that uses multiparametric PCR-based DNA sequencing. Surprisingly, the survival of patients with native KRAS was significantly higher than that of patients with mutated KRAS (FIG. 3).

[0042] Median survival was 22.06 months in native KRAS patients and 10.26 months in mutated KRAS patients. The one-year survival rate was 69% in the native KRAS patients and 37% in the mutated KRAS patients.

[0043] Additionally, after combination therapy, patients with native KRAS had a significant improvement in the disease control rate (patients with at least stabilization of the disease according to irRECIST criteria (Seymour L et al. RECIST working group (2017) Lancet Oncol. 18 (3): e143-e152). In patients with native KRAS, the disease control rate after the combination of CIMAvax-EGF and Nivolumab was 56.3% compared to 12.5% in patients with tumors containing KRAS mutations.

[0044] The survival observed with the combined therapy in patients with native KRAS is clinically relevant since, according to the literature, stratification according to KRAS mutations does not influence the survival of patients treated only with Nivolumab mAb. In these patients with advanced NSCLC, monotherapy with Nivolumab resulted in a median survival of 11.2 months and 10 months, in patients with mutated or native KRAS, respectively (Passiglia F et al. (2019) Br J Cancer 120 (1): 57-62).

Example 3. The combined Administration of CIMAvax-EGF and the anti-PD1 Ab Nivolumab Significantly Benefits Patients with Native KRAS Tumors and PDL1<1%

[0045] Given the known history in the literature of a lower response to monotherapy with anti-PD1 mAb in patients with low expression of PDL1 in the tumor, the analysis of example 2 was repeated for patients whose tumors did not express PDL1 (PDL1<1%). PDL1 expression was determined using pharmDx assay 28-8 for PDL1 determination. Surprisingly, it was observed that the stratification of the patients according to the mutations in KRAS again differentiated the survival of the patients. Median survival was 22.06 months in native KRAS patients and 10.26 months in mutated KRAS patients. The one-year survival rate was very high, 80% in patients with native KRAS (FIG. 4).