RT Journal Article SR Electronic T1 Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP 22 DO 10.1186/s40425-017-0222-9 VO 5 IS 1 A1 Kristen M. Hege A1 Emily K. Bergsland A1 George A. Fisher A1 John J. Nemunaitis A1 Robert S. Warren A1 James G. McArthur A1 Andy A. Lin A1 Jeffrey Schlom A1 Carl H. June A1 Stephen A. Sherwin YR 2017 UL http://jitc.bmj.com/content/5/1/22.abstract 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