PT - JOURNAL ARTICLE AU - Kristen M. Hege AU - Emily K. Bergsland AU - George A. Fisher AU - John J. Nemunaitis AU - Robert S. Warren AU - James G. McArthur AU - Andy A. Lin AU - Jeffrey Schlom AU - Carl H. June AU - Stephen A. Sherwin TI - Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer AID - 10.1186/s40425-017-0222-9 DP - 2017 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 22 VI - 5 IP - 1 4099 - http://jitc.bmj.com/content/5/1/22.short 4100 - http://jitc.bmj.com/content/5/1/22.full SO - J Immunother Cancer2017 Dec 01; 5 AB - 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.Abbreviations:99mTc-MAATechnicium Tc 99 m albumin aggragated injectionB72.3murine antibody recognizing a CC49 non-competing epitope of TAG-72)CARchimeric antigen receptorCART72 cellsT cells transduced with the CC49-zeta CARCD3xCD38 beadsanti-CD3 and anti-CD28 antibody conjugated beadsCEAcarcinoembryonic antigenCRCcolorectal cancerCTCAE 2.0Common Terminology Criteria for Adverse Events Version 2.0HAhepatic arteryHAMAhuman anti-mouse antibodyHIVhuman immunodeficiency virusHRPhorse radish peroxidasehuCC49human chimeric antibody directed against TAG-72ICOSinducible T cell costimulatory (CD278)IFNinterferonkat293high efficiency gamma-retroviral transduction systemmuCC49murine antibody directed against TAG-72NHSnormal human serumPBMCperipheral blood mononuclear cellsPCRpolymerase chain reactionRCRreplication competent retrovirusRIAradioimmunoassayscFvsingle chain variable fragmentTAG-72Tumor associated glycoprotein-72TCRT cell receptorULNupper limit of normal