Clinical trial NCT04180774: Safety and Efficacy of Tag-7 Gene-modified Vaccine in Locally Advanced or Metastatic Malignant Melanoma or Kidney Cancer
Official title: An Open-label Study of the Safety and Efficacy of Tag-7 Gene-modified Tumor Cell-based Vaccine in Patients With Locally Advanced or Metastatic Malignant Melanoma or Renal Cell Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Kidney Cancer
Keywords: gene modified vaccine
tag-7
immunotherapy
tumor cells-based vaccine
Lead sponsor: N.N. Petrov National Medical Research Center of Oncology
Sponsor class: OTHER
Collaborators: name: Institute of Gene Biology Russian Academy of Sciences
First posted: 2019-11-29
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Studied therapy - tag-7 gene-modified vaccine (GMV) is administered intradermally at three spots (3 cm from each other) in the paravertebral area 4-6 weeks after surgery in an adjuvant or metastatic setting in patients with melanoma or kidney cancer (4 cohorts in parallel). Treatment with GMV will be administered as described until the patient experiences either unacceptable toxicity or unequivocal disease progression (PD). Biomarkers were assessed at the end of the study.
Primary purpose: TREATMENT

Brief summary: This study was designed to assess the safety and efficacy of inactivated tumor cells genetically modified with the TAG-7 gene as immunotherapy for cancer. Patients with melanoma or kidney cancer were included since they have immune-dependent tumors. Treatment was done in the adjuvant setting after complete cytoreduction of locally advanced or metastatic disease or in the therapeutic setting in patients where complete cytoreduction was impossible.

Detailed description: During the last decade, novel approaches for cancer treatment have been developed. Antitumor vaccines are one of the most promising approaches in tumor immunotherapy. Tumor cells possess low immunogenicity properties due to a number of the not completely understood mechanisms of resistance. One of the ways to overcome it is immune genes transfection. Genes encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and IL-12 have been used most commonly, both in preclinical studies and clinical trials. These cytokines are well known to participate in the systemic immune response. Several studies have shown that the professional antigen-presenting cells (APCs) of the host, rather than the vaccinating tumor cells themselves, are responsible for priming CD4+ and CD8+ T cells, both of which are required to generate systemic antitumor immunity. Recent findings indicate that the adaptive arm of immunity is governed by the innate immune mechanisms that control the co-stimulatory signaling of APCs. Recently, investigators identified a novel gene, tag7, also know as PGRP-S. The insect ortholog of the tag7/PGRP-S was shown to be involved in the innate immune response in Drosophila. In preclinical studies, tag7-modified mouse tumor cells induced a long-lasting T-cell dependent immune response in mice. The effectiveness of antitumor vaccination was demonstrated on different models of mouse tumors, particularly for melanoma cells (M3, B16, F10). Clinically important results of vaccine therapy were achieved in patients with melanoma and renal carcinoma in a number of studies. The results with this treatment are comparable to chemotherapy and immunotherapy. Investigators assume that one has to activate the innate component of immunity first, followed by the activation of the adaptive one, to make anticancer vaccines more effective. Thus, a phase I/II clinical trial has been performed to evaluate the feasibility and toxicity of treatment with autologous tumor cells modified with the tag7 gene, which has been shown to be involved in innate immunity mechanisms,

Eligibility criteria: Inclusion Criteria:

1. Signed inform consent form.
2. Patients age ≥ 18 years of age at the time of informed consent.
3. Ability to provide and understand written informed consent prior to any study procedures.
4. Histologically confirmed locally advanced or metastatic MM or RCC.
5. Tumor cell culture should be obtained and successfully transfected before inclusion.
6. No evaluable therapy with a proved survival advantage in the current patient setting.
7. The life expectancy of \> 3 months as estimated by the investigator
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 -2 at Screening.

Exclusion Criteria:

1. Patient with any out-of-range laboratory values defined as:

   * Serum creatinine \> 1.5 × upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) \< 50 mL/minute
   * Total bilirubin \> 2.5 × ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 × ULN or direct bilirubin \> 1.5 × ULN
   * Alanine aminotransferase \> 2.5 × ULN
   * Aspartate aminotransferase \> 2.5 × ULN
   * Absolute neutrophil count \< 1.5 × 109/L
   * Platelet count \< 100 × 109/L
   * Hemoglobin \< 80 g/L (blood transfusions permitted)
2. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
3. Any clinically significant unstable disease
4. Presence of symptomatic or untreated central nervous system (CNS) metastases
5. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug
6. Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated
7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection
8. Malignant disease, other than that being treated in this study
9. Patients receiving systemic steroid therapy or any other systemic immunosuppressive medication at any dose level, as these may interfere with the mechanism of action of study treatment. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable
10. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)

Primary outcomes:
measure: Adverse events rate
timeFrame: From the fist injection to 3 month after the last injection
Secondary outcomes:
measure: Response rate
timeFrame: every 8 weeks until disease progression or therapy completion, then every 3 month for 2 years, every 6 month for the next 2 years and annually thereafter
measure: Concentration of MICA in patient's cultures supernatants
timeFrame: Samples obtained before therapy start
measure: Concentration of TGF-β1 in patient's cultures supernatants
timeFrame: Samples obtained before therapy start
measure: Concentration of IL-10 in patient's cultures supernatants
timeFrame: Samples obtained before therapy start
measure: Concentration of VEGF in patient's cultures supernatants
timeFrame: Samples obtained before therapy start
measure: Number of T-cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of T-helper lympocytes in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of Cytotoxic lymphocytes in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of NK-lymphocytes in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of CD38+ cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of HLA-DR+ cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of CD71+ cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of B-lymphocytes cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Number of CD25+ cells in peripheral blood of patients
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: IgA level
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: IgG level
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: IgM level
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Spontaneous lymphocytes migration
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Kon-A stimulated migration
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: PGA stimulated migration
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Ingestion rate of monocytes
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Ingestion rate of neutrophils
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
measure: Circulating immune complex level
timeFrame: 1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Other outcomes:
Locations:
city: St. Petersburg
country: Russian Federation
facility: N.N. Petrov Research Institute of Oncology Chemotherapy and Innovative Technologies Department
Study officials:
affiliation: Institute of Gene Biology of the Russian Academy of Sciences
name: Georgy P Georgiev
role: STUDY_DIRECTOR
References: