NATIONAL HARBOR, MD – Designer T cells used in immunotherapy for the treatment of liver metastases are well tolerated and reduced tumor burden in a small phase I study, reported an investigator at the annual Society of Surgical Oncology Cancer Symposium.
But the biggest barrier to the success of the therapy may lie in the liver itself, said Dr. Steven C. Katz, a surgical oncologist at the Roger Williams Cancer Center in Providence, R.I.
"Thinking long term, we’re going to have to address the suppressive forces that exist in the liver. I don’t think this is really going to succeed clinically until we find a way to do that," he said.
Genetically modified, designer T-cell technology allows translational science researchers to manufacture and deliver highly potent, specific agents to invoke a desired antitumor response, rather than trying to boost a general host immune response through, say, a vaccine, Dr. Katz said.
The technology has the potential to act against a variety of tumor types, and has been demonstrated to have activity against chronic lymphocytic leukemia, synovial sarcoma, and melanoma, he said.
The technique involves harvesting T cells from patients, activating them in culture, and then transfecting them with a retrovirus to get them to express a highly specific chimeric antigen receptor (CAR).
Dr. Katz and his colleagues are developing a CAR with an immunoglobulin fragment directed against carcinoembryonic antigen (CEA).
"A T cell that expresses this anti-CEA CAR, when it encounters a CEA-positive tumor, ... is activated to divide [and] produce cytokines and is poised to lyse and kill tumor cells in a highly specific fashion, and we demonstrated this in vitro, as have several other groups," he said.
But getting the antigen to the target – CEA-positive liver metastases – is just part of the challenge, he added. Delivering the CAR into the hepatic arterial circulation appears to be the optimal approach for confining the therapy to the target area, thus avoiding possible complications such as colitis that can occur when anti-CEA is delivered systemically.
A second barrier to the therapy is that the liver contains high numbers of suppressive immune cells such as regulatory T cells and myeloid-derived suppressor cells. Coinfusion of cytokines such as interleukin-2 (IL-2) appears to be a necessary step for preventing intrahepatic suppression of therapy, Dr. Katz said.
The investigators have initiated a phase I safety and intrapatient dose-escalation trial of the technology. Patients with CEA-positive liver metastases are given percutaneous infusions of their modified T cells through a femoral artery puncture directly into the hepatic artery. Embolization of the gastroduodenal and right gastric arteries is performed to prevent or limit extrahepatic infusion of the modified cells.
The patients all have unresectable, histologically confirmed CEA-positive liver metastases from colorectal, hepatobiliary, ampullary, or gastric primary tumors; have no extrahepatic disease beyond the lungs; and have had failure of one or more lines of standard systemic chemotherapy.
The first three patients have been treated in a dose-escalation fashion without cytokines. A second cohort of three patients is receiving both designer T cells and a continuous systemic infusion of IL-2 at a relatively low dose of 75,000 IU/kg per day to suppress the liver’s immune response.
"We know that IL-2 is going to be essential for these T cells to survive and do what we want them to do in vivo," Dr. Katz said.
Of the first six patients enrolled, two have been withdrawn from the study: one who had disease progression within the lungs following a second infusion of designer T cells, and one whose designer T cells were discovered to be infected with West Nile virus.
There have been no serious grade 3 or 4 adverse events to date. Adverse events have included grade 2 fevers, a grade 1 fever, and a rash. There has been no significant elevation over baseline in liver enzymes or bilirubin, Dr. Katz said.
Flow cytometry in early testing has shown that the modified T cells appear to be confined to the normal liver and metastatic sites, and have not been detected in significant numbers in peripheral circulation.
To date, only one patient has been treated with designer T cells and IL-2 support; this patient has thus far had a "very favorable" course, with a 40% decrease in tumor burden, although these results are still too early for clinical conclusions to be drawn.
The investigators are exploring additional strategies to circumvent intrahepatic suppression of the therapy by blocking the action of myeloid-derived suppressor cells.
The study was supported by a Society of Surgical Oncology Clinical Investigator Award, an education grant from Genentech, the National Institutes of Health, and the Rhode Island Foundation. Dr. Katz reported having no relevant financial disclosures.