Science - USA (2022-04-08)

NEWS | FEATURES

128 8 APRIL 2022 • VOL 376 ISSUE 6589 science.org SCIENCE

the vaccine produced plentiful antibodies,
possibly because the patients’ immune-
suppressing polyps had been removed only
recently. But among the 11 responders, only
three had polyps recur within 1 year of re-
ceiving the vaccine, compared with 31 of
47 participants in a placebo group, Finn’s team
reports in a paper submitted to a journal.
“It was very encouraging,” Finn says.
“When you have no recurrence in respond-
ers, you know the vaccine is working.”
Adding a treatment that blocks immune-
suppressing cells may boost response rates,
she says. Her team now plans MUC1 vaccine
trials for several precancerous conditions.

ONE DRAWBACK of Finn’s vaccine strategy
is that the short proteins, or peptides, it
contains mainly trigger one arm of the im-
mune system: the B cells that make anti-
bodies. “For immunity against cancer we
really need to mobilize T cells,” says can-
cer immunologist Robert Vonderheide,
director of Penn Medicine’s Abramson
Cancer Center. That’s best done by inject-
ing the genetic instructions for the antigen
rather than the antigen itself. Special im-
mune cells then take up the DNA or RNA,
manufacture the antigen, chop it up, and
display bits tailored to that person’s im-
mune system on their cell surfaces. These
antigen-presenting cells then teach T cells
to recognize and kill tumor cells.
Vonderheide’s team is testing a DNA-based
vaccine targeting a different antigen that
marks many tumors: hTERT, a small chunk
of telomerase, an enzyme that protects chro-
mosomes as cancer cells proliferate.
Results of a trial testing the vaccine’s
safety in 93 patients in remission after treat-
ment for various cancers were encouraging.
All but four people made T cells that home in
on hTERT, the team reported in the Journal
for ImmunoTherapy of Cancer in July 2021.
And there was a hint the vaccine was ward-
ing off cancer. Among the 34 people who had
had pancreatic cancer, 41% were still cancer
free after 18 months. In other pancreatic
cancer patients in remission, their tumor
reappears within an average of 12 months.
The Penn team is now studying safety
and immune responses to the vaccine in
16 people in remission from previous can-
cers who have inherited mutations in BRCA1
or BRCA2, relatively common cancer genes
that raise risk for breast and some other
cancers. Next year, the researchers expect
to give the vaccine to 28 people with BRCA
mutations who have never had cancer.
But because hTERT is found on some
normal cells as well as cancerous ones, a
vaccine could trigger an autoimmune attack
on healthy cells, suggests immunologist
Vincent Tuohy of the Cleveland Clinic. He

has devised a breast cancer prevention vac-

cine that may be safer because it contains a

breast cell protein called alpha-lactalbumin

that people only make during late preg-

nancy and breastfeeding. Production of the

protein also occurs in triple negative breast

cancer, an aggressive form of the disease.

Tuohy’s team is testing whether his pro-

tein vaccine can stimulate an immune re-

sponse in 24 women who have been treated

for triple negative breast cancer and have

no plans to get pregnant. The next step, he

says, will be a trial in healthy women with

BRCA1 mutations, who are prone to this

cancer type.

Other teams hope to offer broader pro-

tection against breast cancer. Undeterred

by being called “misguided” in 2012, NBCC

is close to testing a breast cancer vaccine,

initially in healthy breast cancer survivors.

The advocacy group’s president, Fran Visco,

says it set the ambitious goal because it

was “frustrated with the lack of innovation

in breast cancer.” With scientist partners,

it has settled on a vaccine that combines

six tumor antigens, including hTERT and

MUC1. “We don’t know what type of breast

cancer a woman is going to get,” explains

trial leader Keith Knutson, an immuno-

logist at the Mayo Clinic. Multipronged

vaccines “are probably going to be more

effective than vaccines targeting one indi-

vidual protein,” says cancer immunologist

Nora Disis of the University of Washing-

ton, Seattle, who is developing such a vac-

cine to prevent colon cancer.

AS SOME TEAMS are trying to broaden the

immune response triggered by cancer vac-

cines, others want to make it safer and more

precise by targeting neoantigens, only

found on cancer cells. Those efforts have

accelerated over the past decade thanks

to a surge in tumor genome sequencing,

which has revealed a flood of neoantigens.

Some drive cancer growth, whereas oth-

ers have no apparent function. Most are

unique to an individual cancer—an ob-

stacle for developing preventive vaccines,

which have to target markers that can be

predicted in advance. GRAPHIC: V. ALTOUNIAN/

SCIENCE

Antigen-presenting

cells (APCs) take up

antigen and display

fragments on their

surfaces. B cells and

T cells recognize

the antigen and

produce antibodies

and killer T cells.

If tumor cells bearing

the antigen develop,

corresponding

antibodies signal the

immune system to

destroy the cells. Killer

T cells that recognize

the antigen also attack

cancer cells.

Person is

healthy but

at high risk

Vaccines using a tumor of cancer.

antigen can be viral,

messenger RNA, DNA,

or peptide-based.

Healthy cell

Cancer cell

B cell

T cell

Va caccincinesusiusing a tumo

Cancer cell

ell

l

Tumor-associated

antigens or

neoantigens

Ant

ce

ant

fra

sur

T c

APC

B cellB cB cellellell

Killer T cell

Antibodies

ls ls b rinrinrinrin

d

din

s sign

st

c

re

also a

lls.

o a

ls

de

ding

ign

e

cells.

ecog

also a

niz

o a

be

evelop

g

ign

em t

ells.

elop

rin

elo

earin

elop

e

elop

ignal al the

m tm t

p

ignal

m t

g

,

ringg

,

thethe

,

g gg

the

APCAPCAPCAPCAPCAPCAPCAPC

Antiboibodiedie

APCAPC

Ant

APCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPCAPC

TT ceT ceT ceTTTeelleellll AntAntAntAntiboiboiboiboiboiboiboiboiboiboiboiboiboiboibodiediediediedies

o attaaack

Ki

niz

o atta

lle

niz

a

lle

nize

ack

Killelle

oo

Killellellellellellellellellerr

kk

rr

k k

r r

KillerKilKilKilKilKillerler TlerlerlerlerlerlerT Tccccelelllll

TTTTTT

Intercepting cancers

Preventive cancer vaccines deliver proteins known as tumor

antigens, which are scarce on healthy cells but abundant on tumors,

or neoantigens, which are unique to tumors. Immune cells take

up the antigens and produce antibodies and killer T cells that attack

incipient tumor cells, preventing cancer growth.