SCIENCE science.org 8 APRIL 2022 • VOL 376 ISSUE 6589 129Some neoantigens reliably appear on
many people’s tumors, however. For in-
stance, pancreatic cancer is almost al-
ways triggered by mutations in a growth
protein called KRAS, which give rise to a
predictable set of neoantigens. This spring,
Johns Hopkins University immunologist
Elizabeth Jaffee and colleague Neeha Zaidi
will begin to safety test a vaccine contain-
ing mutated KRAS peptides in 25 men and
women who haven’t had cancer but are at
high risk because of an inherited mutation
or family history. KRAS is like pancreatic
cancer’s Achilles’ heel, Jaffee says: It’s the
first of several genes to get mutated. As a
result, the team hopes early tumor cells
won’t be able to evade the vaccine by ditch-
ing KRAS and finding another way to grow.
Lynch syndrome cancers also sport a
predictable set of neoantigens. That’s be-
cause patients’ DNA repair problem leads
to “frameshift” mutations, which shift how
a cell’s proteinmaking machinery reads a
gene, scrambling the resulting protein in a
consistent way. A peptide vaccine contain-
ing a few of these neoantigens, which was
developed by a German team, caused no
serious side effects when tested in people
with cancer. A similar vaccine designed for
mice with Lynch syndrome reduced tumor
growth, researchers reported in July 2021
in Gastroenterology.
The vaccine Vilar-Sanchez’s team will
test is more ambitious: It consists of vi-
ruses modified to carry DNA for a whop-
ping 209 frameshift neoantigens found in
Lynch tumors. People’s immune systems
vary in how they respond to specific neo-
antigens, and different individuals’ tumors
won’t all make the same set. “Therefore,
the best [approach] is to have many,” says
Elisa Scarselli, chief scientific officer of
Nouscom, an Italian company developing
the vaccine.
The vaccine is also being developed as
treatment, and in an early test Nouscom
is giving it along with an immunotherapy
drug to patients who have metastatic can-
cers with frameshift mutations like those
in Lynch syndrome. At a meeting in fall
2021, the company reported the treatment
shrank tumors in seven of the first 12 pa-
tients. “We really believe we will see even
more immunogenicity in healthy carriers
of Lynch disease” because they should have
stronger immune systems, Scarselli says.
Vilar-Sanchez’s trial, beginning within a
few months, will give the vaccine to 45 volun-
teers with Lynch syndrome—both people in
remission after cancer treatment and others
who have never had tumors. Investigators
will assess whether the vaccine stimulates
an immune response and has any apparent
effect on polyps or tumor formation.If the results look good, the next step
will be a randomized study of hundreds
of patients over perhaps 5 to 10 years.
“There’s a lot to be gained” if the vaccine
works, Vilar-Sanchez says. “A cancer vac-
cine is not going to reduce the risk to zero,
but it could impact how often we perform
screening.” It could also help patients de-
cide whether to have a hysterectomy to
prevent endometrial cancers, which are
common in people with Lynch syndrome.
All prevention vaccines would face a
long road to regulatory approval if re-
searchers must wait for tumors to appear
to judge the vaccine’s efficacy. So they will
also look for surrogate measures of protec-
tion, such as reduced growth of polyps inpeople prone to colon cancer. For breast
cancer, researchers don’t have biomarkers
yet but hope to find them, perhaps a
change in blood-borne immune cells or
breast tissue, Vonderheide says.
“We have to be smart enough to present
to the FDA [U.S. Food and Drug Administra-
tion] a biomarker of success,” Vonderheide
says. “This is formidable. But we’re inspired
because the impact will be massive.”WHATEVER THEIR PREFERRED antigens, many
scientists expect to model their next pre-
ventive vaccines on the leading COVID-19
vaccines, which use a lipid particle to ferry
mRNA for antigens into cells. mRNA vac-
cines are easier to make and deliver than
DNA or viral vaccines, and the pandemic
has shown they’re generally safe and stim-
ulate a strong response. “The fact that
mRNA vaccines have shown safety in bil-lions of healthy people of all ages makes
[mRNA] a very good platform” for preven-
tive cancer vaccines, Jaffee says.
The White House is gunning for mRNA
vaccines to prevent cancer, too. They are on
the list of potential projects for a reignited
Cancer Moonshot and the new high-risk,
high-reward research agency, the Advanced
Research Projects Agency for Health (ARPA-
H). A concept paper for ARPA-H puts the
goal this way: “Use mRNA vaccines to teach
the immune system to recognize 50 com-
mon genetic mutations that drive cancers,
so that the body will wipe out cancer cells
when they first arise.”
That description raises some eyebrows.
“That would be heroic,” Finn says, because
the vaccine antigens would have to cover
not only a huge number of cancer muta-
tions, but also “the incredible genetic di-
versity” in individuals’ immune responses.
“Not impossible but not simple,” she says.
Clinical geneticist Steven Lipkin of Weill
Cornell Medicine, who works on Lynch
syndrome vaccines, is cautiously optimis-
tic, noting that a vaccine that cut the rates
of the most common cancers “by say one-
third or one-half in a large number of peo-
ple would be a tremendous benefit.”
One team is already testing a multicancer
prevention vaccine—not yet in people, but
in dogs. In a 5-year trial, a team is giv-
ing 400 middle-age dogs a vaccine that
contains 31 antigens from eight common
dog cancers. (Another 400 dogs are get-
ting a placebo vaccine.) It relies on RNA
neoantigens, little-studied molecules that
result from RNA processing errors rather
than mutations in DNA. They are far more
abundant than DNA neoantigens in dogs
and people, and are “highly immunogenic,”
says developer and biochemist Stephen
Johnston of the Biodesign Institute at Ari-
zona State University, Tempe. If they prove
effective, they might make it easier to
reach the White House’s goal of developing
a pancancer human vaccine, he says.
Another proponent of a universal can-
cer prevention vaccine is Johns Hopkins
cancer geneticist Bert Vogelstein. He notes
that sequencing has shown “a relatively
small number of genes are involved in
most cancers,” suggesting a limited num-
ber of antigens could lead to broad protec-
tion. Such a vaccine “seems like science
fiction,” Vogelstein says, but “a concerted
effort by many labs” might succeed. Sei
agrees: “That’s not crazy. That’s possible.”
For Dave Dubin, even a narrower success—
a Lynch syndrome vaccine—“could be
game-changing,” he says, if it meant fewer
cancer screenings and no more major sur-
geries. “The goal would be almost to live a
PHOTO: MD ANDERSON CANCER CENTER normal life.” j
Eduardo Vilar-Sanchez is testing a vaccine
to prevent Lynch syndrome cancers.