DNA Vaccination Against Neuroblastoma

Pilot Clinical Study of DNA Vaccination Against Neuroblastoma

This is pilot open-label study to evaluate the safety and immunogenicity of a DNA vaccine strategy in relapsed neuroblastoma patients following chemotherapy and HSC transplantation. The combined form of the vaccine includes an intramuscular injection of the DNA-polyethylenimine conjugate and oral administration using the attenuated Salmonella enterica as DNA vaccine carriers.

Objectives of the study:

1. To assess safety and document local and systemic toxicity to combined DNA vaccine
2. To determine immunogenicity of the vaccine
3. To evaluate clinical response to vaccination. Control of minimal residual disease in bone marrow and duration of remission.

Study Overview

• Status: Recruiting
• Conditions: Relapsed Neuroblastoma
• Intervention / Treatment: Biological: DNA vaccine; Biological: Salmonella oral vaccine; Drug: Lenalidomide

Detailed Description

DNA vaccine construction includes chimeric fusion of neuroblastoma-associated antigen and potato virus X coat protein (PVXCP) as an immune enhancer. In each course vaccine for one antigen is applies. The selection of antigens is carried out after analyzing of their expression in the tumor biopsy material by PCR and IHC. The list of antigens used in the study: tyrosine hydroxylase (TH), Phox2B, Survivin, MAGEA1, MAGEA3, PRAME. The antigens with the highest level of expression in the tumor sample of each patient are selected for vaccination.

Vaccination schedule for each patient includes three courses of vaccination. One course includes three administrations of vaccines against a single antigen. Vaccination is repeated at intervals of 1 week (plus minus 3 working days). Break between courses - 3-4 weeks. Each vaccination includes an injection and taking a capsule with a dose of bacteria.

For intramuscular injection, we use conjugate (polyplex) DNA with linear polyethylenimine 20 kDa (PEI). One dose includes 400 µg of DNA and 500 µg of PEI. When administered orally, the patient receives a suspension 10^10 CFU of an attenuated Salmonella enterica serovar typhimurium strain (SS2017) containing the plasmid of the corresponding DNA vaccine.

Before and during vaccination, an accompanying chemotherapy is carried out, including cyclophosphamide, propranolol, celecoxib and lenalidomide. Cyclophosphamide is prescribed three days before the start of each vaccination course in a single dose of 300 mg / m2. Lenalidomide is prescribed in a dose of 25 mg / day in a course of three weeks starting 7 days before the first vaccination course and ending on the day of the last vaccination course

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Alexander N Meleshko, PhD; Phone Number: +375296940023; Email: alexander.meleshko@gmail.com

Study Locations

• Belarus
  • Minsk Region
    • Minsk, Minsk Region, Belarus, 223053
      • Recruiting
      • Belarussian Research Center for Pediatric Oncology, Hematology and Immunology
      • Contact: Phone Number: +375 17 265 42 22; Email: mail@oncology.by

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The diagnosis of neuroblastoma recurrence with morphological / cytological confirmation;
2. The presence of tumor tissue for biopsy;
3. The absence of progression or a large tumor mass (bulky disease);
4. The physical status on the scale of ECOG 0 - 2.
5. Life expectancy of at least 12 months
6. Indicators of cellular immunity of the blood: lymphocytes - at least 1 * 10^9;
7. Availability of written informed consent of the patient and his parents (legal representatives) to participate in this protocol.
8. Compliance of parents (legal representatives) and the patient himself with participation in the study protocol.

Exclusion Criteria:

A. Based on the anamnesis:

1. The presence of any primary immunodeficiency;
2. The presence of a primary multiple malignant tumor;
3. The presence of autoimmune diseases in history (except thyroiditis);
4. Polyalgia;
5. Severe diseases, including those with severe symptoms, untreated inflammatory and infectious processes, due to which the patient cannot receive treatment in accordance with the study protocol.
6. Socioeconomic or geographical circumstances that cannot guarantee proper compliance with the requirements of the protocol for treatment and further observation.

B. based on survey data:

1. The absence of expression in the tumor tissue of two or more antigens used in the protocol;
2. The level of peripheral blood leukocytes <1.5 × 10^9 /L, platelet <50.0 × 10^9 /L, Hemoglobin less than 80 g / L;
3. Positive tests for human immunodeficiency virus (HIV), hepatitis B or C.
4. Severe impaired liver function - the levels of AST / SGOT or ALT / SGPT exceed the upper limit of normal 5 times or more.

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: All subjects; All subjects will receive the vaccine and be followed per the schedule of procedures.

Biological: DNA vaccine; conjugate of plasmid DNA with linear polyethylenimine 20 kDa (PEI) One dose includes 400 µg of DNA and 500 µg of PEI.; Other Names: DNA-PEI polyplex; Biological: Salmonella oral vaccine; suspension 10^10 CFU of an attenuated Salmonella enterica serovar typhimurium strain (SS2017) containing the plasmid of the corresponding DNA vaccine.; Drug: Lenalidomide; Lenalidomide is prescribed in a dose of 25 mg / day in a course of three weeks starting 7 days before the first vaccination course and ending on the day of the last vaccination course.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events experienced by subjects	To assess the safety of the DNA-PEI and Salmonella vaccines	for 3 months from the first vaccination
Immune response to the vaccine	Immunogenicity will be evaluated by assessing T-cell IFN-γ production in ELISPOT and PVXCP antibody production by ELISA	In check point after 2nd course (9 week after first vaccine)
Immune response to the vaccine	Immunogenicity will be evaluated by assessing T-cell IFN-γ production in ELISPOT and PVXCP antibody production by ELISA	In check point after 3rd course (14 week after the first vaccine)
Minimal residual disease - MRD	MRD in bone marrow measured by RQ-PCR and flow cytometry	up to 4 weeks after the last vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival - PFS	Time from treatment to date of first documented progression or date of death	Up to 12 months

Collaborators and Investigators

• Sponsor: Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
• Investigators: Study Director: Inna V Proleskovskaya, PhD, MD, Belarussian Research Center for Pediatric Oncology, Hematology and Immunology

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2019
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: July 31, 2019
• First Submitted That Met QC Criteria: August 7, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: neuroblastoma; DNA vaccine; Salmonella vaccine; polyethylenimine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Vaccines; Lenalidomide
• Other Study ID Numbers: BelarusianPediatric

Drug and device information, study documents

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