Immune Modulatory DC Vaccine Against Brain Tumor

Phase 1

• Conditions: Diffuse Intrinsic Pontine Glioma or Glioblastoma
• Interventions: Biological: Immunomodulatory DC vaccine to target DIPG and GBM

• Registration Number: NCT03914768
• Lead Sponsor: Shenzhen Geno-Immune Medical Institute

Brief Summary

This study is designed to treat patients who have been diagnosed with brain cancer, including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). The treatment uses immunomodulatory vaccine generated by autologous dendritic cells (DCs) pulsed with genetically modified tumor cells or tumor-related antigens including neoantigens to inject into patients. Vaccine-induced T cell responses have been associated with improved survival. The study will evaluate the safety and potential benefit of the novel immunomodulatory DC vaccines.

Detailed Description

Diffuse intrinsic pontine glioma (DIPG) or glioblastoma (GBM) is an aggressive malignancy. DIPG mainly occurs in the ventral pontine of childhood. The overall median survival time is 9 to 11 months. The 2-year survival rate is less than 10%. Thus DIPG has become one of the most fatal diseases in children. These tumors invade and infiltrate the surrounding brain, making complete surgical excision impossible. Several studies focused on the identification of GBM or DIPG-specific antigens and evaluated their potential for vaccine application. Immunomodulatory DC vaccines based on ex vivo genetic modifications in combination with known tumor-specific antigens may substantially enhance the activation potential of tumor-specific T cells with improved benefit to patients.

Although certain antigens are highly specific in DIPG or GBM, existing immune tolerance suppresses anti-tumor immunity in cancer patients. To induce anti-cancer immune response in patients, ex vivo modification of immune modulatory antigens or immune cells will be necessary. Advanced whole exome sequencing has been developed to identify specific mutations in tumors and predict best-fit MHC-specific neoepitopes for T cell activation. In this study we will investigate novel DC vaccines based on autologous DCs pulsed with genetically modified tumor cells or related antigens such as neoantigens to induce a strong anti-tumor immunity. Early studies of DC-based vaccines targeting gliomas have shown acceptable safety and low toxicity profile. This is a multi-center randomized Phase I study to evaluate safety of novel DC vaccines.

Study Timeline

• Study Start: 2019-03-31
• Study First Submitted: 2019-04-11
• Study First Submitted QC: 2019-04-11
• Study First Posted: 2019-04-16
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-10
• Last Update Posted: 2020-06-12
• Primary Completion: 2021-01-31
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

1. Abilities to understand and the willingness to provide written informed consent. Assent will be obtained when appropriate based on the subjects age;
2. Patients are ≥ 6 months and ≤ 80 years old;
3. DIPG or GBM patients with existing or measurable tumors in the brain. Patients have received standard care of medication, such as gross total resection with concurrent radio chemotherapy (~54 - 60 Gy, TMZ);
4. Patients with adequate neurological function and epileptic symptoms that are well controlled;
5. Observing the condition after surgery or without surgery;
6. Karnofsky performance score (KPS) ≥ 60;Life expectancy >3 months;
7. Important organ function is satisfied: Cardiac ultrasound indicates a cardiac ejection fraction ≥50%; and there is no obvious abnormality in the electrocardiogram; blood oxygen saturation ≥90%; creatinine <2.5 times normal range; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 times normal range; Total bilirubin ≤ 2.0 mg / dl; Hgb (hemoglobin) ≥ 80g / L;
8. Peripheral blood absolute lymphocyte count must be above 0.8×10^9/L;
9. Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if seizure disorder is well controlled;
10. Patients must be willing to follow the orders of doctors.

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Exclusion Criteria

1. A prior history of gliadel implantation 4 weeks before this study start or antibody based therapies;
2. The patient was still using dexamethasone at a dose greater than 4 mg/day during mononuclear cell collection;
3. Patients have a history of autoimmune diseases or other diseases requiring long-term use of hormones or immunosuppressive drugs;
4. Patients with a history of allergies or allergies to immune cells and adjuvants of cellular products;
5. Active infection with fever;
6. Patients with neutropenia (> 10 days) that are difficult to correct after treatment;
7. Infection with bacteria, fungi or viruses, uncontrolled;
8. Patients with HIV and those living with active HBV and HCV;
9. Pregnant, pregnant and lactating women;
10. Important organ failure (heart, liver, kidney, lung);
11. Patients who had previously been treated with cell therapy but were ineffective after physical examination were discussed and confirmed by team experts and were not suitable for re-treatment;
12. Anything that researchers believe may increase the risk of subjects or interfere with test results.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Immunomodulatory DC vaccine to target DIPG and GBM	Immunomodulatory DC vaccine to target DIPG and GBM	Patients will receive immune modulatory treatment consisting of cyclophosphamide (200 mg/m2) and bevacizumab (15 mg/kg), before and after DC vaccine injection, respectively.

Primary Outcome Measures

Name	Time	Method
Safety of infusion of autologous immunomodulatory DC Vaccine is assessed by the NCI CTCAE V4.0 criteria.	2 years	Safety of the vaccine will be assessed by monitoring for adverse events (AEs) based on scheduled laboratory assessments.
Overall survival (OS) at 12 months (OS12).	12 months	OS12 will be the clinical efficacy primary endpoint. For subjects who are still alive at 12 months, OS12 will be censored at the last contact date. OS will be estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Name	Time	Method
Treatment response rate of DIPG or GBM	6 months]	Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) based on brain MRI imaging analysis.
ELISPOT or antigen specific functional assays for evaluation of antigen specific immune response in patients	1 year	Tumor antigen specific immune response in the peripheral blood evaluated by ELISPOT or antigen specific functional assays.
Overall survival Rate	1 year follow up	Percentage of participants with objective response as determined by the investigator based on Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)
Progression-free survival rate	1 years	Progression-free Survival (PFS) as determined by the investigator based on RECIST v1.1
Magnetic resonance imaging for evaluation of disease progression and prognosis	1 years	The prognosis of GBM or DIPG will be determined by MRI

Trial Locations

Locations (3)

Shenzhen Geno-immune Medical Institute; 🇨🇳 Shenzhen, Guangdong, China

Department of Neurosurgery, Shenzhen Hospital, Southern Medical University; 🇨🇳 Shenzhen, Guangdong, China

Shenzhen Children's Hospital; 🇨🇳 Shenzhen, Guangdong, China