Immune Modulatory DC Vaccine Against Brain Tumor

Immune Modulatory DC Vaccine Against Diffuse Intrinsic Pontine Glioma (DIPG) and Glioblastoma (GBM)

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.

Study Overview

• Status: Unknown
• Conditions: Diffuse Intrinsic Pontine Glioma or Glioblastoma
• Intervention / Treatment: Biological: Immunomodulatory DC vaccine to target DIPG and GBM

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 Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518038
      • Shenzhen Children's Hospital
    • Shenzhen, Guangdong, China, 518000
      • Shenzhen Geno-immune Medical Institute
    • Shenzhen, Guangdong, China, 518100
      • Department of Neurosurgery, Shenzhen Hospital, Southern Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Biological: Immunomodulatory DC vaccine to target DIPG and GBM; This study will inject DC vaccine cells near lymphoid tissue close to the tumor. The patient will receive intravenous cyclophosphamide (200 mg/m2) or oral (cytoxan) before the vaccine, followed by DC vaccine and intravenous bevacizumab (15 mg/kg) the next day. The cells will be repeatedly infused every month for six consecutive months depending on the response and the condition of the patient. The amount of DC vaccine cells per injection is based on prior report at 5-10x106. An initial dose escalation scheme will be imposed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of infusion of autologous immunomodulatory DC Vaccine is assessed by the NCI CTCAE V4.0 criteria.	Safety of the vaccine will be assessed by monitoring for adverse events (AEs) based on scheduled laboratory assessments.	2 years
Overall survival (OS) at 12 months (OS12).	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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response rate of DIPG or GBM	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.	6 months]
Overall survival Rate	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)	1 year follow up
Progression-free survival rate	Progression-free Survival (PFS) as determined by the investigator based on RECIST v1.1	1 years
ELISPOT or antigen specific functional assays for evaluation of antigen specific immune response in patients	Tumor antigen specific immune response in the peripheral blood evaluated by ELISPOT or antigen specific functional assays.	1 year
Magnetic resonance imaging for evaluation of disease progression and prognosis	The prognosis of GBM or DIPG will be determined by MRI	1 years

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute
• Collaborators: Shenzhen Children's Hospital; Shenzhen Hospital of Southern Medical University

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2019
• Primary Completion (Anticipated): January 31, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Actual): June 12, 2020
• Last Update Submitted That Met QC Criteria: June 10, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: GBM; DIPG; neoantigen; DC vaccine therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Glioblastoma; Glioma; Diffuse Intrinsic Pontine Glioma
• Other Study ID Numbers: GIMI-IRB-19001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No