Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer
Background T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors perfor...
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BMJ Publishing Group
2017-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/5/1/22.full |
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| author | Jeffrey Schlom Carl H. June George A. Fisher John J. Nemunaitis Kristen M. Hege Emily K. Bergsland Robert S. Warren James G. McArthur Andy A. Lin Stephen A. Sherwin |
| author_facet | Jeffrey Schlom Carl H. June George A. Fisher John J. Nemunaitis Kristen M. Hege Emily K. Bergsland Robert S. Warren James G. McArthur Andy A. Lin Stephen A. Sherwin |
| author_sort | Jeffrey Schlom |
| collection | DOAJ |
| description | Background T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.Methods Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.Results Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.Conclusion These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity. |
| format | Article |
| id | doaj-art-9301cef97c684c8ba35bd0102a7fc11f |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9301cef97c684c8ba35bd0102a7fc11f2025-08-20T02:12:46ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262017-01-015110.1186/s40425-017-0222-9Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancerJeffrey Schlom0Carl H. June1George A. Fisher2John J. Nemunaitis3Kristen M. Hege4Emily K. Bergsland5Robert S. Warren6James G. McArthur7Andy A. Lin8Stephen A. Sherwin92Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAAff7 0000 0004 1936 8972grid.25879.31University of Pennsylvania Philadelphia PA USAAff4 0000000419368956grid.168010.eStanford University Stanford CA USAAff5 0000 0004 0455 4449grid.416487.8Mary Crowley Cancer Center Dallas TX USAAff1 0000 0004 0408 4133grid.418724.cCell Genesys, Inc Foster City CA USAAff3 0000 0001 2348 0690grid.30389.31University of California San Francisco CA USAAff3 0000 0001 2348 0690grid.30389.31University of California San Francisco CA USAAff1 0000 0004 0408 4133grid.418724.cCell Genesys, Inc Foster City CA USAAff1 0000 0004 0408 4133grid.418724.cCell Genesys, Inc Foster City CA USAAff1 0000 0004 0408 4133grid.418724.cCell Genesys, Inc Foster City CA USABackground T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.Methods Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.Results Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.Conclusion These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.https://jitc.bmj.com/content/5/1/22.full |
| spellingShingle | Jeffrey Schlom Carl H. June George A. Fisher John J. Nemunaitis Kristen M. Hege Emily K. Bergsland Robert S. Warren James G. McArthur Andy A. Lin Stephen A. Sherwin Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer Journal for ImmunoTherapy of Cancer |
| title | Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer |
| title_full | Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer |
| title_fullStr | Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer |
| title_full_unstemmed | Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer |
| title_short | Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer |
| title_sort | safety tumor trafficking and immunogenicity of chimeric antigen receptor car t cells specific for tag 72 in colorectal cancer |
| url | https://jitc.bmj.com/content/5/1/22.full |
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