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Mesothelioma, like many cancers, has several ways to hide from the immune response and keep growing. Ideally, a person’s T cells would recognize the mesothelioma cells when they first become cancerous and kill them. Unfortunately, in some people, their T cells don’t recognize the mesothelioma cells as cancer and the mesothelioma cells continue to divide… and divide… and divide until the person has symptoms.
How T Cells Find and Manage Cancer Cells
As background, T cells see their targets in the context of their own HLA molecules, much like a team uniform. All cells express HLA-A and HLA-B molecules containing small peptide fragments derived from broken down cellular proteins. The cell membranes look like the commercial sponsors plastered on the suits of Nascar drivers.
Each T cell examines just one emblem. The T cell travels around the body and checks all cells, including cells lining the chest cavity (called mesothelium) for its specific emblem X—is it the correct size, placement, spelling, number of them, colors? In scientific terms, some T cells recognize HLA-A2 with peptides from the protein, mesothelin, which is found on cells lining the chest cavity and mesothelioma cells. These mesothelin-HLA-A2 specific T cells check whether cells of the mesothelium express the normal quantity of the normal mesothelin protein (not a larger or smaller mutant protein), and the mesothelin protein has the normal types and levels of glycosylation.
A cytotoxic T cell literally binds to a cell that expresses altered mesothelin proteins (altered emblem X) punches holes in it with perforin, and activates apoptosis (a cell death process) with granzyme, thus killing the cell. The cytotoxic T cell then moves on to the next cell expressing the altered mesothelin protein.
Patients with mesothelioma do not have enough mesothelin-HLA specific T cells to kill the mesothelioma cells. Scientist and clinicians decided to develop methods to reprogram some of the patient’s T cells so they now would target cancer. Several laboratories developed multiple types of chimeric antigen receptors. These chimeric receptors change the target of the T cells. Some engineered T cells would target cancerous mesothelin-expressing cells such as mesothelioma.
“Hunter” T Cells Against Mesothelin-expressing Cells
These T cells newly armed with chimeric antigen receptors that bind to mesothelin-expressing cells seek out the mesothelioma and kill them.
The testing of this approach is in its infancy in mesothelioma. One mesothelioma patient and one patient with pancreatic duct adenocarcinoma were administered their own re-engineered T cells that target mesothelin-expressing cells.1 Several life-threatening adverse events suggest that the treatment using engineered T cells that target mesothelin-expressing cells, like mesothelioma, needs further refinement.1
“Hunter” T Cells Induce High-rate of Remission in Patients with Acute Lymphocytic Leukemia
In contrast, “Hunter” T cells with chimeric antigen receptors specific for CD19-HLA appear to be a very promising treatment for acute lymphocytic leukemia. CD19 is a protein on human B cells. The initial study described that 2 pediatric patients with acute lymphocytic leukemia (ALL) went into remission.2 These researchers recently reported at the American Society of Hematology in Dec 2013 that treatment with CD19-HLA specific T cells attacked sufficient acute lymphocytic leukemia cells to induce remission in 19 of 22 pediatric patients (86%) and 5 of 5 adults.3 However, five pediatric patients relapsed within 2 years and 2 adult patients within 6 months. The tumors of two relapsed patients no longer express CD19.3
Regardless, “Hunter” T cells are a very promising treatment. These therapies are boosting interest in immunotherapy of cancer— enhancing people’s immune response against their cancer.
Beatty, G.L., et al., Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies. Cancer immunology research, 2014. 2(2): p. 112-20.
Grupp, S.A., et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. The New England journal of medicine, 2013. 368(16): p. 1509-18.
Auer, H. Penn Med Team Reports on Study of First 59 Leukemia Patients Who Received Personalized Cellular Therapy. 2013 [cited 2014 June 5]; Available from: http://www.upenn.edu/pennnews/news/penn-med-team-reports-study-first-59-leukemia-patients-who-received-personalized-cellular-thera.