Study of Gene Modified Immune Cells in Patients With Advanced Melanoma
Summary
This is a phase 2 study to find the best way to give this new experimental regimen and determine if it can treat metastatic melanoma in humans. In this phase 2 study, the experimental products are given initially to a group of 8 people, and if safe and found to have a significant antitumor activity, it will be given to up to 14 other people, for a total of 22 people in this study.
The study investigators' main aim is to obtain sufficient information about the effects of gene-modified cells in humans. The gene modification of cells is an attempt to direct the patient's own cells to kill melanoma cancer cells. The gene-modified cells studied in this experimental protocol are cells from the patient's blood modified in the laboratory using genetic techniques to express a specific receptor against melanoma cells.
Gene modification of cells involves the transfer of foreign genetic material (DNA) into a cell, in this case immune system cells, using a form of virus that has been modified to express the melanoma specific receptor called MART-1 T cell receptor (or TCR).
This clinical trial has two main study drugs:
- The first study drug is called gene modified MART-1 TCR T cells. T cells are a special type of white blood cells that have the ability to kill cancer cells. They are also called a cytotoxic T lymphocytes (or CTL), which means that they can kill other cells. The CTLs will be obtained from body and taken to the laboratory to grow them and modify their genes. The CTL cells will be gene modified with a virus vector similar to the HIV virus called a retrovirus vector. This retrovirus is called a vector because it has been extensively modified to make sure that it cannot make copies of itself or induce AIDS in patients. The retrovirus vector will allow expression of a protein called the T cell receptor (or TCR). This TCR is specific for a marker on the surface of melanoma cells called the MART-1 tumor antigen. The investigators expect that the insertion of the TCR specific for the MART-1 melanoma marker will allow the CTLs to be redirected to recognize and attack melanoma cancer cells.
- The second study drug is called a dendritic cell vaccine loaded with the MART-1 melanoma protein. Dendritic cells are a type of blood cells that specialize in stimulating the immune system, and will be grown in the laboratory from the patient's own blood cells. The dendritic cells do not directly fight cancer cells. Instead, they teach other cells in the body to look for cancer cells with the MART-1 protein and destroy them, therefore they function as an "on switch" for the immune system. MART-1 is a protein produced by melanoma, which may be recognized by cells of the immune system. The goal of giving the dendritic cell vaccines to the patient will be to further help the ability of the gene modified MART-1 TCR CTLs to attack melanoma lesions in the body.
These two study drugs are given after administering chemotherapy to clear up the patient's immune system before administering the gene modified MART-1 TCR T cells, and the infusion of these cells is followed by 5 days of high dose Interleukin-2, which is an FDA-approved therapy for melanoma that boosts immune system cells.
Description
This is a two-stage phase II clinical trial with the combined primary endpoints to determine the safety, feasibility and antitumor activity of adoptive transfer of peripheral blood mononuclear cells (PBMC) genetically engineered to express the alpha and beta chains of a high affinity T cell receptor (TCR) specific for the HLA-A*0201-restricted MART-1 melanoma tumor antigen to patients with locally advanced or metastatic melanoma.
Patients with MART-1-positive locally advanced or metastatic melanoma who are HLA-A*0201-positive, and HIV, hepatitis B and C seronegative, will receive a non-myeloablative but lymphocyte depleting chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine, and then receive the adoptive transfer of autologous PBMC transduced with the MSGV1-F5AfT2AB retroviral vector, which expresses a high affinity TCR for the MART-1 melanoma antigen (MART-1 F5 TCR). Following adoptive cell transfer, patients will receive MART-126-35 peptide-pulsed dendritic cell (DC) vaccines and high dose interleukin-2 (IL-2).
Study Design
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Conditions
Metastatic Melanoma
Intervention
F5 TCR transgenic cells and MART-1 peptide pulsed dendritic cells, non-myeloablative conditioning chemotherapy
Location
University of California Los Angeles, David Geffen School of Medicine
Los Angeles
California
United States
90095
Status
Recruiting
Source
University of California, Los Angeles
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00910650
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Dendritic Cells, Follicular
Non-hematopoietic cells, with extensive dendritic processes, found in the primary and secondary follicles of lymphoid tissue (the B cell zones). They are different from conventional DENDRITIC CELLS associated with T-CELLS. They are derived from MESENCHYMAL STEM CELLS and are negative for class II MHC antigen and do not process or present antigen like the conventional dendritic cells do. Instead, follicular dendritic cells have FC RECEPTORS and C3B RECEPTORS that hold antigen in the form of ANTIGEN-ANTIBODY COMPLEXES on their surfaces for long periods for recognition by B-CELLS.
Langerhans Cells
Recirculating, dendritic, antigen-presenting cells containing characteristic racket-shaped granules (Birbeck granules). They are found principally in the stratum spinosum of the EPIDERMIS and are rich in Class II MAJOR HISTOCOMPATIBILITY COMPLEX molecules. Langerhans cells were the first dendritic cell to be described and have been a model of study for other dendritic cells (DCs), especially other migrating DCs such as dermal DCs and INTERSTITIAL DENDRITIC CELLS.
Antigen-presenting Cells
A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include MACROPHAGES; DENDRITIC CELLS; LANGERHANS CELLS; and B-LYMPHOCYTES. FOLLICULAR DENDRITIC CELLS are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of IMMUNE COMPLEXES for B-cell recognition they are considered so by some authors.
Dendritic Cells
Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as SKIN and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process ANTIGENS, and present them to T-CELLS, thereby stimulating CELL-MEDIATED IMMUNITY. They are different from the non-hematopoietic FOLLICULAR DENDRITIC CELLS, which have a similar morphology and immune system function, but with respect to humoral immunity (ANTIBODY PRODUCTION).
Lymphoid Progenitor Cells
Stem cells from which B-LYMPHOCYTES; T-LYMPHOCYTES; NATURAL KILLER CELLS; and some DENDRITIC CELLS derive.
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