Safety and Efficacy of Tag-7 Gene-modified Vaccine in Locally Advanced or Metastatic Malignant Melanoma or Kidney Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Melanoma; Kidney Cancer
• Intervention / Treatment: Biological: Tag-7 gene modified inactivated tumor cells

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,

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • St. Petersburg, Russian Federation, 197758
    • N.N. Petrov Research Institute of Oncology Chemotherapy and Innovative Technologies Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melanoma Adjuvant; Patients with completely resected stage III or IV melanoma receiving GMV in the adjuvant setting	Biological: Tag-7 gene modified inactivated tumor cells; Patients received GMV once in three weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.
Experimental: Melanoma Therapeutic; Patients with incompletely resected stage III or IV melanoma receiving GMV in the therapeutic setting	Biological: Tag-7 gene modified inactivated tumor cells; Patients received GMV once in three weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.
Experimental: Renal Cell Adjuvant; Patients with completely resected stage III or IV kidney cancer receiving GMV in the adjuvant setting	Biological: Tag-7 gene modified inactivated tumor cells; Patients received GMV once in three weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.
Experimental: Renal Cell Therapeutic; Patients with incompletely resected stage III or IV kidney cancer receiving GMV in the therapeutic setting	Biological: Tag-7 gene modified inactivated tumor cells; Patients received GMV once in three weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events rate	CTC AE v.3 was used for safety assesment	From the fist injection to 3 month after the last injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	To assess the objective response rate (OR) RECIST v1.1 and irRC were used at the final assesment	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
Concentration of MICA in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Concentration of TGF-β1 in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Concentration of IL-10 in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Concentration of VEGF in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Number of T-cells in peripheral blood of patients	Absolute (10^9/L) of CD3+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of T-helper lympocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD4+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of Cytotoxic lymphocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD8+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of NK-lymphocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD16+CD56+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of CD38+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD38+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of HLA-DR+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of HLA-DR+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of CD71+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD71+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of B-lymphocytes cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD71+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Number of CD25+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD25+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
IgA level	IgA (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
IgG level	IgG (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
IgM level	IgM (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Spontaneous lymphocytes migration	Lymphocytes migration (U) without stimulation	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Kon-A stimulated migration	Lymphocyte migration after in vitro stimulation with Kon A (% inhibition of migration)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
PGA stimulated migration	Lymphocyte migration after in vitro stimulation with PGA (% inhibition of migration)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Ingestion rate of monocytes	Ingestion rate (%)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Ingestion rate of neutrophils	Ingestion rate (%)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Circulating immune complex level	Immune complexes (U) in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)

Collaborators and Investigators

• Sponsor: N.N. Petrov National Medical Research Center of Oncology
• Collaborators: Institute of Gene Biology Russian Academy of Sciences
• Investigators: Study Director: Georgy P Georgiev, Institute of Gene Biology of the Russian Academy of Sciences

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2001
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: November 22, 2019
• First Submitted That Met QC Criteria: November 26, 2019
• First Posted (Actual): November 29, 2019

Study Record Updates

• Last Update Posted (Actual): December 6, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; gene modified vaccine; tag-7; tumor cells-based vaccine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Kidney Neoplasms; Carcinoma, Renal Cell; Melanoma
• Other Study ID Numbers: 07-Ген-М

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