BUFFALO, NY--It appears possible to break immune tolerance to carcino-embryonic antigen (CEA) utilizing a vaccine that is the internal image of CEA, said Kenneth A. Foon, MD, director of the University of Kentucky Markey Cancer Center, Lexington.
CEA is overexpressed on a variety of tumors with minimal expression on normal tissue. It is viewed as a "self-antigen," and thus cancer patients become immunologically tolerant to CEA. The new vaccine consists of specially created antibodies that mimick CEA, so that a patient whose immune system does not recognize CEA may recognize the look-alike antigen and produce antibodies.
"Its been our major interest to use a vaccine approach to augment the survival of colon cancer patients," Dr. Foon said at the first meeting of the Regional Cancer Center Consortium for Biological Therapy of Cancer, hosted by Roswell Park Cancer Institute.
Dr. Foons group created a vaccine that completely prevented the growth of CEA-transduced colon tumors in mice and may be able to do the same for patients, according to preliminary results.
The researchers injected mice with a monoclonal antibody (Ab1) that binds to a unique CEA epitope not found on normal tissue. The mice generated a "mirror image" Ab2 anti-idiotype antibody that binds to the binding region on the original Ab1. This Ab2 antibody was injected into naïve animals who produced an anti-anti-idiotype antibody, or Ab3, that binds to the binding region of Ab2 and also cross-reacts with CEA.
Thus, the researchers were able to generate an anti-idiotype antibody to Ab1. The new anti-idiotype antibody is called 3H1 (CeaVac, licensed to Titan Pharmaceuticals, Inc.).
Mice, Rabbits, and Monkeys
"We vaccinated mice, rabbits, and monkeys, and all three species generated an anti-CEA immune response," Dr. Foon said. "We also demonstrated that vaccination of mice with CeaVac completely prevented the growth of murine colon cancer cells that were transduced with human CEA and therefore expressed CEA on their cell surface."
The first phase I clinical trial involved 24 patients with advanced CEA-positive colorectal cancer. These patients had either failed or refused conventional therapies. Most patients were heavily pretreated with chemotherapy. Each patient received multiple injections of the CeaVac anti-idiotype antibody. Patients were randomized into three groups to receive either 1, 2, or 4 mg doses, rather than an escalating schema. If there was no tumor progression at the end of the fourth injection, monthly injections were continued until tumor progression was noted.
In 16 of 23 patients (one was excluded when diagnosed with a new cancer), an Ab3 response was generated, and 13 of these were genuine anti-CEA responses. There was minimal toxicity, he said, and this cohort had a median survival of 11.4 months, which is comparable to the best results with chemotherapy.
Further trials involved patients with resected disease. Many received fluorouracil(Drug information on fluorouracil)-based chemotherapy in addition to CeaVac. Patients received a 2 mg dose of the vaccine every 2 weeks for four courses and then monthly until disease recurrence.
Among 15 patients to date, 9 have not relapsed: 1 patient with stage II disease and 2 patients with stage IIIA disease have not relapsed; 2 of 4 patients with stage IIIB disease relapsed at 23 months each; 3 of 4 high-risk resected stage IV patients with negative tumor margins relapsed at 6, 10, and 13 months, respectively; and 1 of 4 patients with resected stage IV disease with positive tumor margins relapsed at 14 months.
"Interestingly, those three remaining patients with resected stage IV disease and positive tumor margins continue on study with negative CT scans from 14 to 26+ months," Dr. Foon said.
Also, all 15 patients have generated a high-titer anti-CEA antibody response and an idiotypic T-cell response, with 75% generating a CEA-specific T-cell response. "It is very encouraging for future phase III trials that the immune response to CeaVac was not altered by fluorouracil-based chemotherapy," he said.
A future phase III trial for stage II and III colorectal cancer will randomize patients to a standard fluorouracil-based regimen or the same fluorouracil regimen plus CeaVac, Dr. Foon said.
Additional studies are planned for CeaVac, he noted, and trials with two other anti-idiotype vaccines are either planned or currently underway in breast cancer, ovarian cancer, melanoma, small-cell lung cancer, and neuroblastoma.