title: Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.
abstract: 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.
  
  
  
  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 1010total 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.
  
  
  
  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 had111Indium-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.
  
  
  
  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.
authors.affiliation: Cell Genesys, Inc, Foster City, CA USA.|Celgene Corporation, San Francisco, CA USA.|University of California, San Francisco, CA USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Hege
authors.affiliation: University of California, San Francisco, CA USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Bergsland
authors.affiliation: Stanford University, Stanford, CA USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Fisher
authors.affiliation: Mary Crowley Cancer Center, Dallas, TX USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Nemunaitis
authors.affiliation: University of California, San Francisco, CA USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.affiliation: Cell Genesys, Inc, Foster City, CA USA.
authors.forename: James G
authors.initials: JG
authors.lastname: McArthur
authors.affiliation: Cell Genesys, Inc, Foster City, CA USA.
authors.forename: Andy A
authors.initials: AA
authors.lastname: Lin
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.affiliation: University of Pennsylvania, Philadelphia, PA USA.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Cell Genesys, Inc, Foster City, CA USA.|University of California, San Francisco, CA USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Sherwin
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002272:Carcinoembryonic Antigen / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D007262:Infusions, Intravenous; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D006023:Glycoproteins; D016898:Interferon-alpha; D011948:Receptors, Antigen, T-Cell; C047052:tumor-associated antigen 72