A Phase I Study of a Therapeutic Vaccine Candidate in Patients With Localized Breast Cancer at High-Risk of Relapse

Inclusion Criteria:

1. All patients must have a diagnosis of epithelial breast carcinoma which is, according to TNM classification:

   * Any T
   * With Positive (N+) or Negative (N-) Lymph-Node depending on the patient profile (see below criteria n°3)
   * And Non metastatic (M0)
2. HER2/neu-negative (Immunohistochemical expression "0-1+", and/or FISH/CISH "non amplified" according to ASCO 2012 criteria)
3. First line treatment population with a High-Risk of Relapse as defined by:

   * with at least one positive lymph nodes (LN) at primary surgery
   * or after completion of 6-8 cycles of anthracyclins/taxanes-based neoadjuvant chemotherapy

   OR

   Negative hormone receptors: ER- and PR- , (\<10%), i.e "Triple Negative breast cancer"
4. Patients must have completed all their local and regional treatments including adequate surgery and radiation therapy, and at least 6 cycles of chemotherapy (neoadjuvant and/or adjuvant) according to institutional and national standards.
5. The time interval between the end of all the first line standard treatment (completion of surgery, chemotherapy and radiation therapy) should be at least 1 month and within a maximum of 18 months before inclusion in the study.
6. Patients eligible to adjuvant hormone therapy should have started their treatment for at least 2 months at the time of inclusion in the study.
7. Patients treated by biphosphonates should have started their treatment for at least 28 days at the time of inclusion in the study
8. Patients must be free of any breast cancer recurrence as shown by standard diagnostic tests at the entry into the study.
9. Patients should have an expected life expectancy of at least 12 months as evaluated by the investigator at the entry into the study.
10. Written informed consent must be obtained prior to any protocol-specific procedures.
11. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
12. Patients must not be pregnant. Non-menopausal women must have a negative pregnancy test prior to enrolment, and must use adequate contraception (1 barrier method) throughout the study.
13. Patients must be aware of the potential harm of the study treatment on any future pregnancy and must agree not to become pregnant within 24 months following the last study vaccine injection.
14. Patients must not be lactating.
15. Patients must be between 18 and 70 years of age.
16. Patients must have adequate bone marrow reserve (testing within 2 weeks before inclusion) as evaluated by the investigator.

    WBC ≥3000/mm3, neutrophils ≥1500/mm3, platelets ≥100,000/mm3, and hemoglobin ≥10 g/dL.
17. Patients must have an absolute lymphocytes count \>800 cells/mm3
18. Patients with creatinine clearance considerate as normal as evaluated by the investigator calculated creatinine clearance \> 50 ml/min (using the Cockcroft-Gault Formula)
19. Patients must have adequate hepatic function as evaluated by the investigator serum total bilirubin \<1.5\* times the upper limit of normal (ULN), AST and ALT \< 3\* times the ULN, and alkaline phosphatases\<2.5\* times, the ULN. Patients with an alkaline phosphatase above normal must have negative bone scans and abdominal CT scans prior to entry onto the study.

    \* biological limit values specified into the NCI-CTCAE V4.03 of June 2010
20. Before inclusion patients must have negative test for HIV1 and HIV2; no history of active hepatitis B or C and no chronic hepatitis B or C requiring treatment with antiviral therapy
21. The patients must be covered by national social security insurance.
22. In the view of the investigator, the patients can and will comply with the requirements of this protocol.

Exclusion Criteria:

1. Any breast cancer recurrence or metastasis.
2. Patients with HER2/neu positive breast carcinoma (IHC score 2+ or 3+ and/or FISH/CISH-amplified).
3. Patients with any uncontrolled bleeding disorder including coagulation disorder or thrombocytopenia or prothrombotic disorder.
4. Patients with a personal history of autoimmune disease (including but not limited to multiple sclerosis, lupus, rheumatoid polyarthritis, inflammatory bowel diseases, Graves' disease and Hashimoto's disease).
5. Patients with a history of previous anaphylaxis or severe allergic reaction to vaccines or other known or unknown allergens.
6. Patients with previous splenectomy or radiation to the spleen.
7. Patients who have received a major organ graft (including bone-marrow transplantation).
8. Patients who require chronic oral treatment (defined as more than 14 days) with immunosuppressive agents including glucocorticosteroïds or other immune-modifying drugs. Use of topical and eye drops containing glucocorticosteroïds is acceptable, as well as inhaled corticosteroids.
9. Patients with previous or concomitant malignancies at other sites except effectively treated malignancy that has been in remission for \>5 years and highly likely to have been cured. However patients with non-melanoma skin cancers or carcinoma in situ of the cervix can be included.
10. Concurrent severe medical problems unrelated to the malignancy, which would significantly limit full compliance with the study or expose the patient to unacceptable risk.
11. Patient with previous congestive heart failure or difficult-to-control hypertension and any uncontrolled vascular or cardiac disease.
12. Patient who has medically documented history of or active major depressive episode, bipolar disorders (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others).
13. Patient selects a response of "1,2 or 3" to question 9 on the PHQ-9 question regarding potential for suicidal thought or ideation (independent of the total score of PHQ-9)
14. Patient who has \> CTCAE grade 3 anxiety.
15. Patients who have received (within 30 days before the inclusion) any investigational (biological or non-biological) or non-registered drug or non-registered vaccine other than the study vaccine, or who plan to receive such a drug during the study period.
16. Patients who have received any immunoglobulins and/or blood products within the 3 weeks prior to vaccine injection.
17. Patients who have received any commercial vaccine within one month before the first dose of study vaccine or are planned to receive any vaccine till 3 weeks after the 6th vaccine injection.
18. Patients who have out of range laboratory results as specified in the inclusion criteria.
19. Patients with a family history of congenital or hereditary immunodeficiency.