title: Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.
abstract: OBJECTIVE
  Chimeric antigen receptor-modified T cells (CAR-T) have demonstrated encouraging results in early-phase clinical trials. Successful adaptation of CAR-T technology for CEA-expressing adenocarcinoma liver metastases, a major cause of death in patients with gastrointestinal cancers, has yet to be achieved. We sought to test intrahepatic delivery of anti-CEA CAR-T through percutaneous hepatic artery infusions (HAIs).
  
  
  METHODS
  We conducted a phase I trial to test HAI of CAR-T in patients with CEA(+) liver metastases. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (10(8), 10(9), and 10(10) cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (10(10) cells × 3) along with systemic IL2 support.
  
  
  RESULTS
  Four patients had more than 10 liver metastases, and patients received a mean of 2.5 lines of conventional systemic therapy before enrollment. No patient suffered a grade 3 or 4 adverse event related to the CAR-T HAIs. One patient remains alive with stable disease at 23 months following CAR-T HAI, and 5 patients died of progressive disease. Among the patients in the cohort that received systemic IL2 support, CEA levels decreased 37% (range, 19%-48%) from baseline. Biopsies demonstrated an increase in liver metastasis necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases.
  
  
  CONCLUSIONS
  We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pretreated population with large tumor burdens. Further clinical testing of CAR-T HAIs for liver metastases is warranted.
authors: Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Steven C
authors: SC
authors: Katz
authors: Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Rachel A
authors: RA
authors: Burga
authors: Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Elise
authors: E
authors: McCormack
authors: Department of Pathology, Roger Williams Medical Center, Providence, Rhode Island.
authors: Li Juan
authors: LJ
authors: Wang
authors: Department of Pathology, Roger Williams Medical Center, Providence, Rhode Island.
authors: Wesley
authors: W
authors: Mooring
authors: Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Gary R
authors: GR
authors: Point
authors: Roger Williams Medical Center, GMP Core Facility and Clinical Protocol Office, Providence, Rhode Island.
authors: Pranay D
authors: PD
authors: Khare
authors: Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Mitchell
authors: M
authors: Thorn
authors: Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Qiangzhong
authors: Q
authors: Ma
authors: Department of Radiology, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Brian F
authors: BF
authors: Stainken
authors: Department of Radiology, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: Earle O
authors: EO
authors: Assanah
authors: Roger Williams Medical Center, GMP Core Facility and Clinical Protocol Office, Providence, Rhode Island.
authors: Robin
authors: R
authors: Davies
authors: Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
authors: N Joseph
authors: NJ
authors: Espat
authors: Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts. rjunghans@rwmc.org.
authors: Richard P
authors: RP
authors: Junghans
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary / Q000628:therapy*; D000368:Aged; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000473:pathology / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000637:transplantation*
chemical_list: D011948:Receptors, Antigen, T-Cell