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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 · 6 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.