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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

Chuck Darwin

@cdarwin@c.im replied · 7 days ago

Much of cancer’s biological power comes from the fact that to the body, it doesn’t always seem like a pathogen.

Because cancer arises from mutations in each patient’s own DNA, the disease complicates our immune system’s central task of differentiating between body and foreign object,
host and invader,
“self” and “not self.”

Physicians long hypothesized that there was a link between cancer and swelling
—a critical sign that the immune system “sees” an enemy to ward off.

In the 1890s #William #Coley,
now known as the father of #immunotherapy,

successfully spurred remission in patients with inoperable tumors by injecting them with bacteria like those that cause strep throat.

But the mechanisms behind Coley’s treatments were poorly understood,
and for decades after his discovery, researchers weren’t sure our immune systems could detect cancer at all.

Because doctors didn’t know exactly how the body perceives and responds to cancer,
early treatments were highly invasive and highly toxic:

The first tactic was major surgery on the organs where cancer was taking root.

That was followed in the 20th century by the development of systemic radiation and chemotherapy to attack cancer cells throughout the body.

Over time oncologists narrowed and refined these approaches incrementally,
using more precise surgery,
more focused radiation
and chemo that killed fewer normal cells as collateral.

Still, the dream was to harness immunotherapy,
which represented a dramatic departure from the usual tactics in seeking to use the human body’s own systems to go after cancer in a more targeted way.

As demand for COVID vaccines has slackened,
there has been a rush to apply mRNA technology to a long list of illnesses.

The first real proof that immune cells are capable of recognizing tumors didn’t come until the 1950s and 1960s.

Gradually, researchers came to understand that cancer deploys a host of tricks to suppress the immune response to growing tumors.

Some forms of cancer use fibrous tissue called #stroma to construct shields that make it difficult for immune cells to penetrate or attack tumors.

Other cancers take advantage of the balancing act our immune systems are always performing when they decide how heavily to invest the body’s defenses in warding off a given threat.

Some tumors produce proteins that can shut down key immune cells.

Tumors may even recruit immune cells to promote the growth of blood vessels that will supply them with oxygen and nutrients.

As scientists learned more about how cancer manipulates the immune system,
they started identifying ways to thwart it.

Inside our cells, proteins are constantly being chopped up into smaller sequences of amino acids,
some of which are then presented on the cell surface as part of what’s collectively known as
the major histocompatibility complex, or #MHC
—essentially the immune system’s tool for differentiating self and foreign molecules.

Chuck Darwin

@cdarwin@c.im replied · 7 days ago

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

Chuck Darwin

@cdarwin@c.im replied · 7 days ago

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