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Clin Cancer Res. 2015 Jul 15;21(14):3149-59. doi: 10.1158/1078-0432.CCR-14-1421. Epub 2015 Apr 7.

Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.

Author information

1
Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
2
Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
3
Department of Pathology, Roger Williams Medical Center, Providence, Rhode Island.
4
Roger Williams Medical Center, GMP Core Facility and Clinical Protocol Office, Providence, Rhode Island.
5
Department of Radiology, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts.
6
Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island/Boston University School of Medicine, Boston, Massachusetts. rjunghans@rwmc.org.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

PMID:
25850950
PMCID:
PMC4506253
DOI:
10.1158/1078-0432.CCR-14-1421
[Indexed for MEDLINE]
Free PMC Article

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