A recent paper* in Science reports that T cells recognizing a mutant protein found only in cancer cells can elicit an anti-tumor response when injected into a patient with end-stage epithelial cancer.
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP). To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations. For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes. They found that a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient. The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation. The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment. The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.
Further work will be necessary to validate this approach in cancer therapy. T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.
*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102
Hosein Kouros-Mehr
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP). To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations. For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes. They found that a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient. The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation. The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment. The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.
Further work will be necessary to validate this approach in cancer therapy. T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.
*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102
Hosein Kouros-Mehr
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