Different Type of Colon Cancer Vaccine Reduces Disease Spread, Jefferson Scientists Show
Taking
advantage of the fact that the intestines have a separate immune system
from the rest of the body, scientists at the Kimmel Cancer Center at
Jefferson in Philadelphia have found a way to immunize mice against the
development of metastatic disease.
Reporting online Tuesday, June 24, 2008 in the Journal of the National Cancer Institute,
Scott Waldman, M.D., Ph.D., professor and chair of Pharmacology and
Experimental Therapeutics at Jefferson Medical College of Thomas
Jefferson University and his co-workers have shown that mice immunized
with an intestinal protein developed fewer lung and liver metastases
after injection with colon cancer cells than did control animals that
were not immunized. The work may portend the development of a different
kind of cancer vaccine, the researchers say, that may help prevent
disease recurrence.
One
of the reasons that cancer vaccines have been disappointing in many
cases is the lack of immune system-alerting protein antigens that are
specific for tumors only. According to Dr. Waldman, mucosal cells,
which line the intestines (colon cancer arises from mucosal cells, and
mucosal cell proteins continue to be expressed even after they become
cancer) are essentially compartmentalized and possess a separate and
distinct immune system from the body’s general immune system. He and
his group thought that such proteins would be seen as foreign by the
latter system and be useful for anti-cancer vaccines.
Dr.
Waldman, postdoctoral fellow Adam Snook, Ph.D., and their colleagues
engineered viruses – adenovirus, vaccinia and rabies – to express the
protein guanylyl cyclase C (GCC), which is normally found in the
intestinal lining (and in metastatic colon cancer). The researchers
injected the animals with colon cancer cells before or after
immunization.
They
found that the vaccinated animals developed fewer metastases in the
liver and lung – 90 percent and 75 percent, respectively – compared
with control animals. Vaccination also prolonged overall survival, with
a median of 38 days in immunized animals and 29 days in control
animals.
“We
think this identifies a novel class of vaccine candidate targets for
tumors that originate and metastasize from mucosa, like colorectal
cancer,” Dr. Waldman says. “Mucosal cells turn into cancer, invade the
wall of the intestine, breech the compartment and metastasize, carrying
with them all the antigens that typically reside in the mucosal system.
They continue to be expressed by tumors that originate in the mucosa
even when those tumors metastasize into the systemic compartment where
they don’t belong.”
Dr.
Waldman sees GCC as “the poster child” for mucosal antigens.
“Immunizing an animal or person systemically with GCC will be
recognized to some degree as foreign, and the body will mount an immune
response in the systemic compartment,” he explains. “We think that the
immune response will be effective against the cancer but it won’t cross
over into the intestines and cause autoimmune disease.”
As
a result, he says, the immune responses against GCC could be used
both prophylactically and therapeutically. “The target populations for
such a vaccine are patients who have had surgery and adjuvant
chemotherapy and have no evidence of disease. If they have recurrence,
it’s from microscopic disease.”
“This
paper demonstrates the profile of a model cancer mucosal antigen class
that can generate systemic immune responses,” he says. “There is
incomplete systemic tolerance to these antigens, as we predicted, and
that the immune responses have anti-tumor efficacy and the animals are
free of autoimmune disease.”
The
researchers suggest that this approach of using antigens from tumors
originating in immune-restricted sites might be extended to other
cancers that originate from mucosal cells, including cancers of the
head and neck, lung, breast, vagina, and bladder. Adding mucosal
antigens from the same tumor type might also enable the development of
a “polyvalent” vaccine, Dr. Waldman notes.
Media Only Contact:
Richard Cushman
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 6/24/2008