By May of this year another threat to personalized mRNA vaccines for cancer was coming into focus:

🔥mounting federal hostility to vaccines.

Senate Republicans convened a hearing entitled

“The Corruption of Science and Federal Health Agencies,”

featuring the false claim that as many as three out of four deaths from COVID were caused by mRNA vaccines deployed to stop the pandemic.

(In fact, COVID vaccinations saved an estimated 2.5 million lives between 2020 and 2024,
according to a study published earlier this year.)

In June, Kennedy fired all 17 members of the Advisory Committee on Immunization Practices,
which makes recommendations on federal vaccine policy.

He eventually replaced them with his own advisory committee,
which includes several anti-vaccine stalwarts.

Kennedy has also slashed research funding for mRNA vaccines.

In August he canceled nearly $500 million supporting the development of mRNA vaccines against viruses such as SARS-CoV-2 and influenza.

The move intensified the fears of researchers who want to develop mRNA vaccines for other illnesses,
among them cancer.

After my visit to Memorial Sloan Kettering, Balachandran’s team shared a chart that plotted Brigham’s immune response to her personalized mRNA vaccine.

Along the bottom, triangles marked the dates of her surgery
and each of the nine doses of the vaccine she received over the course of a year.

Above them a cluster of brightly colored lines showed the share of her body’s
T cells targeting the specific mutant proteins in her cancerous tumor.

At first, when Brigham’s tumor was removed,
cells trained to go after each cancer clone were somewhere on the order of one in 500,000 T cells in her blood.

A few months after surgery,
when she’d had four doses of the vaccine,
the lines shot up almost vertically, showing that the most common cancer fighter at that point accounted for around one in 20 to one in 50 T cells
—an increase of more than 20,000-fold.

Those T cells dipped a bit in the months before Brigham’s last booster shot,
given almost a year after her tumor was removed.

But they remained in the same range even three years on.

A phase 2 clinical trial evaluating the safety and efficacy of the vaccine in a larger patient group is currently underway.

The vaccine for Brigham’s cancer was just nine tiny vials of liquid administered through an IV,
a private message that only her immune system was meant to decode.

But the effort that delivered that coded message was a deeply collective enterprise,
one that stretches back through the hundreds of thousands of tissue samples collected,
stored and analyzed at Memorial Sloan Kettering,
-- each one taken from the body of a patient who might not have survived their cancer.

Also in that vaccine were the contributions of generations of taxpayers who never got to see these results.

Perhaps their descendants will be able to beat the disease
—if society continues to support this vital work.

https://www.scientificamerican.com/article/personalized-mrna-vaccines-will-revolutionize-cancer-treatment-if-federal/

#micrometastases #neoantigens #driverantigens
#passengermutations #neoantigens #checkpointinhibitors #WilliamColey #immunotherapy #stroma #MHC

The study revealed a potential liability in a strategy for personalized mRNA vaccines that focused on melanoma:

melanoma’s high rate of mutations gives rise to a large pool of plausible vaccine targets, but it presents just as many chances to guess wrong.

A given tumor could have as many as 10,000 distinct proteins on the surface of its cells;
-- you couldn’t possibly target every one.

But in pancreatic cancer, Balachandran realized, the smaller number of mutations might improve the odds of picking a suitable antigen to target.

That insight underpinned the pitch Balachandran brought to Ugur Sahin,
co-founder and CEO of German biotech company BioNTech.

Their collaboration began before the COVID pandemic,
but in 2020 BioNTech was consumed by the effort to bring the world’s first mRNA vaccine to market.

Together with Moderna, the company demonstrated the vaccine’s safety through billions of doses administered worldwide with very few side effects.

Not only was mRNA safe for vaccine delivery, but,
as Sahin knew from experience,
it is also a flexible platform for genetic information.

Whereas traditional vaccines typically require ongoing production of the exact virus they’re targeting,
most of the genetic information in an mRNA vaccine can stay the same no matter which disease you’re fighting.

BioNTech’s COVID vaccine built on 30 years of work by Sahin and company co-founder Özlem Türeci
that was originally intended for vaccines targeting cancer.

As longtime collaborators who are also a married couple, they had tinkered with the nucleotide sequences on the molecule’s cap and tail
that direct a vaccine to the right part of the cell and tell the immune system what to pay attention to,

and they had improved the mRNA’s stability so that even a small dose of a vaccine could provoke a full-scale immune response.

All that work could be incorporated into vaccines for other diseases;

the only thing that needed to change was the genetic information in the middle of the molecule.

After obtaining positive results for the mRNA vaccine for melanoma,
Sahin agreed to partner with Balachandran to develop an mRNA vaccine for pancreatic cancer.

As global demand for COVID vaccines has slackened,
there has been a mounting rush to apply mRNA technology to a long list of illnesses, including
malaria, flu, tuberculosis and norovirus.

Cancer is a natural target.

Despite treatment advances, it remains broadly incurable and is a leading cause of death
as life expectancies improve across the world.

But because cancer vaccines must be personalized,
the biggest change in approach to developing them for an mRNA platform comes not in development
but in manufacturing.

Both BioNTech and Moderna now confront something like the inverse of the challenge they faced in developing the first COVID shots.

Prior to the pandemic, both companies were upstarts among the giants of the pharmaceutical industry.

Neither had brought a product to market.

Moderna employed under 1,000 people and had manufactured fewer than 100,000 total doses of its clinical-stage vaccines.

Once its SpikeVax received emergency use authorization from the U.S. Food and Drug Administration,
the company quadrupled its workforce
and produced more than a billion doses in just 18 months.

The task facing Scott Nickerson, who oversees Moderna’s manufacturing for individualized neoantigen therapies,
was to reengineer a process perfected for producing mRNA vaccines for millions of people in batches of thousands of liters.

For personalized vaccines, each batch would be a few milliliters at most
and would have to be turned around in weeks.

To get there, Moderna is investing heavily in automation,
partnering with a robotics firm to prepare sterile kits of raw materials for each batch
and thereby minimize operator touch time on the manufacturing floor.

The hope is that rather than following a single large batch of vaccine through the entire manufacturing process,
workers will eventually be able to move from one small batch to the next after setup.

#neoantigens #driverantigens #passengermutations
#immunotherapy #stroma #MHC