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

Study Overview
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Brief Summary
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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
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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,

Official Title
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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

Conditions
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Melanoma, Kidney Cancer

Intervention / Treatment
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* Biological: Tag-7 gene modified inactivated tumor cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed inform consent form. Patients age ≥ 18 years of age at the time of informed consent. Ability to provide and understand written informed consent prior to any study procedures. Histologically confirmed locally advanced or metastatic MM or RCC. Tumor cell culture should be obtained and successfully transfected before inclusion. No evaluable therapy with a proved survival advantage in the current patient setting. The life expectancy of > 3 months as estimated by the investigator Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 -2 at Screening. Exclusion Criteria: 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) History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies Any clinically significant unstable disease Presence of symptomatic or untreated central nervous system (CNS) metastases 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 Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated 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 Malignant disease, other than that being treated in this study 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melanoma Adjuvant<br>Patients with completely resected stage III or IV melanoma receiving GMV in the adjuvant setting | Biological: Tag-7 gene modified inactivated tumor cells<br>* 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.<br>|
| Experimental: Melanoma Therapeutic<br>Patients with incompletely resected stage III or IV melanoma receiving GMV in the therapeutic setting | Biological: Tag-7 gene modified inactivated tumor cells<br>* 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.<br>|
| Experimental: Renal Cell Adjuvant<br>Patients with completely resected stage III or IV kidney cancer receiving GMV in the adjuvant setting | Biological: Tag-7 gene modified inactivated tumor cells<br>* 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.<br>|
| Experimental: Renal Cell Therapeutic<br>Patients with incompletely resected stage III or IV kidney cancer receiving GMV in the therapeutic setting | Biological: Tag-7 gene modified inactivated tumor cells<br>* 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.<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene modified vaccine, tag-7, immunotherapy, tumor cells-based vaccine