At both Moderna and BioNTech, the complex logistics of conducting the dozens of different quality-control tests required for each production run falls to algorithms powered by AI.

Before being approved for release, doses of SpikeVax underwent 40 distinct tests that tracked the chemistry, biochemistry, microbiology and sterility of every vial.

With COVID vaccines, the sterility test alone,
which ensures that vials are not contaminated with organisms,
took two weeks.

Refinements have since compressed that test to eight days, Nickerson says.

Ultimately the goal is to shrink it to five days and complete the other tests within that same window.

“The reason it’s hard is we have to design the equipment,”
he explains.

“None of this stuff’s off-the-shelf.”

At the same time, the background science is,
at least in theory,
easily adapted from work that’s already been done.

Lennard Lee,
an adviser to the U.K.’s National Health Service overseeing the rollout of clinical trials for cancer vaccines,
says the pandemic gave regulators there a running start on trials for mRNA cancer vaccines.

In partnership with BioNTech, the NHS launched a program that aims to provide personalized vaccines to up to 10,000 cancer patients in the next five years.

And the NHS and Moderna have invested in a facility that could produce up to 250 million vaccines per year.

In that interval,
as manufacturers work to reduce production times and costs,
clinical trials will evaluate alternative dosage and delivery mechanisms, Lee says.

Although current protocol is for vaccines to target #micrometastases
—small groups of cancer cells that spread to other parts of the body
and linger after cancerous tumors are removed surgically
—there’s no shortage of adjustments that might follow from more data
or improved screening.

Could one deliver a therapeutic vaccine to tackle a tumor before it is large enough to operate on?

Or maybe one could even administer a prophylactic shot that prevents tumor formation in the first place?

With a unified health system and world-class research and manufacturing facilities, Lee says,
the U.K. is well positioned to advance research that would answer such questions.

Fully realizing the potential of personalized mRNA vaccines for cancer, however,
will require more trials in the U.S.,
which has many more cancer research centers than the U.K.

⚠️But the ability of the U.S. to lead this effort is now in jeopardy.

The federal government has long been the dominant source of funding for cancer research in the U.S.

Miriam Merad, a cancer immunologist at the Icahn School of Medicine at Mount Sinai in New York City, says that
in a typical year, funding from the NIH accounts for more than half of the research budget at her institution.

In President Donald Trump’s first term, threatened cuts to the NIH never quite materialized.

Society is not going to let that happen,
Merad thought.

🆘 But just weeks into Trump’s second term, the NIH announced plans to limit indirect contributions to research grants to 15 percent,
-- meaning that for every $100 in funding awarded, only $15 extra would be included for overhead
—a dramatic departure from historical rates in the range of 50 to 60 percent.

“This is an operation,” Merad says,
gesturing to the building where she works,
which is dotted with six-figure pieces of equipment
and has an entire floor dedicated to rearing mice used in research.

“We have to pay salaries;
we have to buy food for the animals.
We have to pay service contracts because we have instruments that need to be serviced all the time.”

These are not expenses that can be easily paused or restarted
based on the fate of a single grant.

Within just a few months of the NIH announcement,
Merad’s department had reduced hires of new postdocs,
and Mount Sinai’s medical school had to shrink the size of its incoming class.

#neoantigens #driver #antigens #passenger #mutations #neoantigens #checkpointinhibitors #WilliamColey #immunotherapy #stroma #MHC

To develop a workable mRNA vaccine, Greenbaum and Balachandran had to both
sequence the DNA of the cancerous tumors they were targeting
and develop a framework for going after the right #neoantigens
—those abnormal proteins that offer clues to a tumor’s underlying mutations.

Neoantigens are made up of short chains of amino acids from proteins with names that look like license plate numbers:
PIK3CA, KDM5C.

One overarching goal of their collaboration is to discern meaningful patterns in the frequency of the sequences
across patients and across cancer types.

What neoantigens survive one mutation after another?

Which ones show up reliably under certain conditions
or look most distinctive to the body’s immune defenses?

Some of these sequences,
from so-called #driver #antigens,
are present in most clones of a given tumor type.

In pancreatic cancer, the driver mutation is often in a gene called KRAS,
but the resulting antigens don’t seem to elicit a reliable immune response in long-term survivors.

Instead, when Balachandran and his colleagues sequenced the blood of such survivors,
the immune cells present in the highest concentrations were those adapted to antigens resulting from one-off,
or “ #passenger,” #mutations.

❌Another threat to personalized mRNA vaccines for cancer was coming into focus:
-- mounting federal hostility to vaccines.

In 2017, at the time that the team published the results of the study, this was a counterintuitive finding.

For decades researchers pursuing vaccines and other immune treatments for cancer had focused on melanoma
-- because melanoma tumors have a high rate of genetic mutations.

“It looks very different to the immune system than many other types of cancers do,”
says Michael Postow,
a medical oncologist at Memorial Sloan Kettering who is involved in clinical trials of mRNA vaccines for melanoma.

“That made it a good target.”

With all the mutant antigens it produces, melanoma should attract the immune system’s attention and trigger it to attack.

The conventional wisdom about pancreatic cancer,
in contrast,
held that it produces so few mutations that it is unlikely to carry passenger antigens that could elicit an immune response.

With the results from the 2017 study of exceptional responders in hand,
Balachandran was able to flip that argument on its head.

Even if vaccines appear to be well suited for melanoma,
there’s always a degree of uncertainty in selecting the right antigens to target.

For starters, the sequencing of a pancreatic tumor biopsy like Brigham’s is really just a snapshot in time.

Come back a few months or a few years later or wait for the patient to experience a recurrence,
and there’s no guarantee the tumor clone that seemed dominant at the time of the initial sequencing will still be a factor in the disease.

Each mutation can also have unpredictable effects,
with the size, shape or biochemistry of the antigen in question shifting dramatically in response to the change of even a single amino acid.

What is more, not every antigen that corresponds to either self or not self is reliably expressed on the surface of the corresponding cell.

A neoantigen that seems characteristic of the tumor might have a profile nearly identical to that of another self-antigen somewhere else in the body.

In that case, a vaccine based on that neoantigen might fail to elicit much of an immune response,
or it could provoke a response against the wrong target.

#neoantigens #checkpointinhibitors #WilliamColey #immunotherapy #stroma #MHC