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

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

The work that culminated in Brigham’s vaccine grew out of research into a subset of pancreatic cancer survivors known as exceptional responders
—the small percentage of people who make it to the five-year mark after a diagnosis.

“These patients, you know, they’re very rare,”
Balachandran says.

Even at a facility as large as Memorial Sloan Kettering,
which sees tens of thousands of cancer patients a year,
it was possible to study this group with any precision only because of the hospital’s long-standing mandate to save samples of every patient’s tissue.

When Balachandran joined the faculty in 2015, his research on long-term survivors relied on tissue samples taken more than a decade earlier.

In 2017 Balachandran and his collaborators published a study demonstrating that some patients with pancreatic ductal adenocarcinoma had more cells able to recognize the unique proteins that mutant tumor cells produced

and that their immune systems seemed to develop a kind of long-term memory to fight recurrence.

In some cases, immune cells with receptors that could bind to these cancer proteins persisted in the blood for more than a decade after the tumors that spawned them were removed.

What if, Balachandran wondered, we could equip the 92 percent of patients who are not naturally exceptional responders with the same kinds of biological tools?

“If you can teach the immune system to recognize the proteins in, say, pancreatic cancer, perhaps that could provide a blueprint,” he says.

As tumors grow and metastasize, they undergo a kind of compressed evolution
in which normal cells with the host’s DNA accrue mutations that cause them to divide and multiply abnormally,
forming an ever larger group of closely related tumor clones.

Many mutations register in the form of abnormal proteins and protein fragments,
called #neoantigens,
some of which accumulate on the surface of the proliferating tumor cells.

Balachandran compared this growing family tree of tumor clones with new variants in a group of viruses,
like the Alpha, Delta and Omicron variants of SARS-CoV-2,
which emerged as the COVID-19 pandemic wore on.

“You’d want a COVID vaccine to be able to target each different virus in that rapidly evolving clade,” Balachandran says.

For the development of a cancer vaccine, mapping the evolutionary trajectory of a cancerous tumor is equally important,
albeit with a different set of parameters.

The goal is not to distinguish between the presentations of two related pathogens

but rather to understand at what point a disease derived from one’s own body starts to register to the immune system as not self.

“At some point
—we don’t think immediately
—the immune system starts to notice,”
says Benjamin Greenbaum, Balachandran’s colleague at Memorial Sloan Kettering’s Olayan Center for Cancer Vaccines,
who led the computational work behind the vaccine given to Brigham.

In later stages, tumors typically accumulate signs of immune system involvement even if the immune response hasn’t been effective
—changes in the cell makeup of the microenvironment around the tumor,
the display of checkpoint molecules.

These signs can be understood as evolutionary adaptations on the part of the tumor in the race to evade detection,
Greenbaum explains.

“So then the question really became,
Can we try to estimate what the immune system is really seeing in cancer?”

#checkpointinhibitors
#WilliamColey #immunotherapy #stroma #MHC

When the immune system detects a protein from a pathogen,
it’s supposed to dispatch killer T cells to eliminate the invader.

Some cancers can interfere with this process by hijacking the checkpoint proteins that keep our immune system from revving out of control
and using them to turn T cells off.

Starting in the mid-1990s, several research teams found success by treating mice with #checkpoint #inhibitors,
-- then a new class of drugs designed to keep tumor cells from concealing their identity and signaling, effectively, “nothing to see here.”

Thirty years on, checkpoint inhibitors have become a transformative tool in cancer treatment, especially for melanoma.

The research that went into developing checkpoint inhibitors showed conclusively that immune cells detect cancer much in the same way they identify other pathogens:

through differences in protein structure determined by DNA
—a crucial insight.

But as revolutionary as checkpoint inhibitors have been for immunotherapy, they don’t work for everyone
—far from it.

Some 80 percent of patients do not respond to this class of drugs.

Researchers are still trying to understand all the mechanisms that play a role in determining who does respond,
but one key factor is whether the immune system is able to recognize tumor cells on the basis of their mutations.

This is where mRNA vaccines come in.

#Jason #Luke, a melanoma researcher who now serves as chief medical officer of mRNA-medicine start-up #Strand #Therapeutics,
helped to design several ongoing clinical trials of mRNA vaccines for cancer.

He explains that both checkpoint inhibitors and mRNA vaccines build on our deep evolutionary adaptation for fighting pathogens
by identifying the proteins they shed in our bodies.

But checkpoint inhibitors are effective only if the patient’s immune system recognizes the cancer as a threat.

In contrast, mRNA vaccines have the potential to work even in patients whose cancers haven’t spurred much immune response.

The trick, Luke says, is using computational tools to decipher which of a given tumor’s mutations are most likely to be found by the immune system.

#MichaelMemoli
#WilliamColey #immunotherapy #stroma #MHC