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-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.