H3.3K27M specific peptide vaccine combined with poly-ICLC for the treatment of newly diagnosed HLA-A2+ H3.3K27M positive diffuse intrinsic pontine glioma (DIPG) as well as other newly diagnosed HLA-A2+ H3.3K27M-positive gliomas
Eligible patients will undergo focal radiation therapy after initial diagnosis as part of their standard of care per institutional guidelines. Patients must begin radiation therapy within 28 days of diagnosis by imaging or pathology, whichever is later. Vaccination should start 2-8 weeks after completion of radiation therapy. Children will receive subcutaneous injections of synthetic peptides of the H3.3.K27M epitope and tetanus toxoid-derived helper epitope (K27M/TT) emulsified in Montanide ISA-51 along with concurrent intramuscular injections of immunoadjuvant poly-ICLC every 3 weeks for 8 times. If the patient demonstrates response to the vaccine therapy, patients may receive additional vaccinations every 6 weeks after the 8th dose for a total of 96 weeks (approximately 2 years).
Rationale for Study
Immunotherapy, particularly active vaccinations, has the potential to develop as an effective and safe modality for patients with pediatric malignant gliomas. Vaccines using specific peptides, in comparison to whole glioma-derived antigens, may induce glioma-specific immune responses without theoretical concerns of auto-immune encephalitis. Use of modified peptides (peptides in which amino acid residues are replaced from the wild-type sequence) may allow us to induce more efficient T-cell responses than natural antigens in whole glioma cells. Recent published laboratory data have also shown that administration of poly-ICLC along with the synthetic peptides remarkably enhances the induction of anti-peptide cytotoxic T lymphocyte (CTL) responses and trafficking of antigen-specific T-cells to the brain tumor sites.
1. To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in HLA-A2+ children with H3.3K27M-positive DIPGs.
2. To determine the overall survival at 12 months in HLA-A2+ children with DIPG that are being treated with repeated administration of the H3.3K27M peptide.
Induction of the H3.3K27M epitope-specific CTL response in post vaccine peripheral mononuclear cells (PBMC) in HLA-A2+ children with DIPG.
Stratum A: Children (3-21 years old) with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) and who have undergone standard radiation therapy.
Stratum B: Children (3-21 years old) with newly diagnosed glioma other than DIPG, including spinal cord gliomas, who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) and who have undergone standard radiation therapy.
The following inclusion criteria appply to both Stratum A and B:
- Patients must test positive for HLA-A2 (CLIA-approved laboratory; any HLA A2 subtype is eligible)
- mPatients must be either off systemic steroids or be on stable dose of dexamethasone (max 0.1 mg/kg/day; maximum 4mg/day) at time of enrollment.
- Patients must not have received any prior chemotherapy, immunotherapy or bone marrow transplant for the treatment of their tumor. Prior use of temozolomide during radiation at the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed.
- Patients must have undergone radiation therapy and surgery as part of their standard of care.
- Stratum A: Radiation therapy must have started within 28 days of diagnosis by imaging or surgery, whichever is later.
- Stratum B: For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery.
- H3.3K27 mutation must have been confirmed in the tumor tissue in a CLIA approved laboratory
- Karnofsky Performance Status ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- Adequate bone marrow defined as:
- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3
- Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
- Hemoglobin ≥ 8 g/dl (can be transfusion dependent)
8. Adequate Renal function defined as:
- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR a serum creatinine within normal limits based on age and gender as follows:
- Age 3 to <6 years: 0.8 (male); 0.8 (female)
- Age 6 to < 10 years: 1 (male); 1 (female)
- Age 10 to <13 years: 1.2 (male); 1.2 (female)
- Age 13 to <16 years: 1.5 (male); 1.4 (female)
- Age ≥ 16 years: 1.7 (male); 1.4 (female)
9. Adequate liver function defined as:
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
- SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
- Serum albumin ≥ 2 g/dL
10. The effects of the H3.3K27M vaccine on a developing human fetus are unknown. For this reason, females of child-bearing potential and men must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation.
11. Ability to understand a written informed consent document, and the willingness to sign it. Assent will be obtained when appropriate based on the patient's age.
- Patients who are currently receiving another investigational drug are not eligible.
- Prior treatment with another investigational drug.
- Patients who are currently receiving other anti-cancer agents are not eligible.
- Prior treatment with other anti-cancer agents.
- Patients with a known disorder that affects their immune system, such as HIV, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible.
How to Enroll
If you believe your child or patient is eligible for this trial, contact the closest participating site for more information or contact us at firstname.lastname@example.org.