Newly diagnosed HLA-A2-positive MGMT-methylated glioblastoma patients will be vaccinated with a Multi peptide vaccination with Pam3Cys-GDPKHPKSF (XS15) as an immunomodulator in addition to standard postoperative radiation therapy and temozolomide chemotherapy to assess immunogenicity, efficacy, safety of the combination of multipeptide vaccination and the immune modulator XS15 emulsified in Montanide ISA 51 VG

Inclusion Criteria:

• Subjects meeting all of the following criteria will be considered for admission to the trial:

For screening phase: (Consent C1)

1. .Must be ≥ 18 years at the time of signing the informed consent 2. Suspected Glioblastoma (presenting with a MRI suggestive of glioblastoma and eligible for gross or subtotal resection and standard radiotherapy with temozolomide) For Vaccination phase (Consent C2)

1. Histologically confirmed, newly diagnosed IDH1-wildtype glioblastoma (astrocytoma WHO grade IV)

2. MGMT gene promoter methylation

3. HLA phenotype HLA-A*02:01 (as determined by a PCR-based 4-digit typing method)

4. Gross or subtotal resection (20%, as determined by MRI)

5. Postoperative MRI

6. KPS ≥70%

7. Life expectancy > 6 months

8. Patient is a candidate for and willing to receive standard radiation therapy with TMZ followed by maintenance TMZ cycles

9. Patient is not on steroids or on stable or decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent doses of other steroids) during the last 3 days prior to first dose of IMP (Vaccination 1)

10. Absolute lymphocyte count (ALC) >0.5 x109/L (re-screening of lymphocyte counts is allowed at day of vaccination)

11. Ability of subject to understand and the willingness to sign written informed consent for study participation prior to any study related assessments/procedures. Able to adhere to the study visit schedule and other protocol requirements.

12. Female Patient of childbearing potential1 and male patients with female partner of childbearing potential1 is willing to use highly effective contraceptive methods during treatment and for 30 days after the end of treatment. According to the CTFG Recommendations highly effective contraceptive methods are:

    • combined hormonal contraceptive associated with inhibition of ovulation (oral,-intravaginal,-transdermal)
    • progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable)
    • intrauterine device (IUD)
    • intrauterine hormone-releasing system (IUS)
    • bilateral tubal occlusion,
    • vasectomized partner2,
    • sexual abstinence3.

13. Negative Covid 19 Quick Test

14. Female subjects must abstain from breastfeeding during study participation and 30 days after study drug discontinuation.

15. Male subjects must refrain from donating semen or sperm while on study

16. All subjects must agree to refrain from donating blood while on study drug and for 30 days after discontinuation from this study treatment.

17. All subjects must agree not to share medication.

Exclusion Criteria:

• Subjects presenting with any of the following criteria will not be included in the trial:

  1. Karnofsky performance score (KPS) < 70%

  2. Patient who cannot undergo MRI assessments

  3. Only Biopsy available

  4. Women during pregnancy and lactation.

  5. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.

  6. Participation in other clinical trials or observation period of competing trials.

  7. Platelet count decrease < 75 x109/L

  8. Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab's reference range)

  9. ALT4 > 3 x ULN

  10. AST5 > 3 x ULN

  11. GGT > 2.5 x ULN

  12. Serum creatinine increased > 1.5 x ULN

  13. HIV infection or active Hepatitis B or C infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies).

  14. Prior therapy for glioma (except surgery and steroids) including but not limited to carmustine wafers and immunotherapy. Note: History of low grade glioma that did not require prior treatment with chemotherapy or radiotherapy is not an exclusion criterion.

  15. Clinically relevant autoimmune diseases (with the exception of thyroid diseases).

  16. Immunosuppression, not related to prior treatment for malignancy, or prior drug reaction

  17. Other vaccinations with active or attenuated viruses should be restricted during the peptide vaccination period.

  18. Enzyme-inducing antiepileptic drugs

  19. Patients with prior stem cell transplantation or solid organ transplantation.

  20. Any condition that in the judgment of the investigator interferes with the probability that an individual patient may receive and benefit from APVAC vaccinations (e.g. high risk of early disease progression / recurrence; immunocompromised status; anticipated compliance problems)

  21. Serious illness or condition, which according to the investigator, poses an undue risk for the patient when participating in the trial, including, but not limited to, any of the following:

      • Clinically symptomatic cardiovascular disease:(New York Heart Association class III-IV congestive heart failure)
      • Symptomatic peripheral vascular disease (Definition z.B. > Stage III)
      • Severe pulmonary dysfunction (Definition: z.B. requirement for oxygen supplement
      • Severe diabetes
      • History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 5 years unless the patient has been disease-free for 5 years