🔬 Huge long COVID discovery

Hey there,

Welcome to a big biomedical week. We’ve got lots of wild findings out of the pharmaceutical space. With a first-line cancer drug proving efficacy well beyond anyone’s expectations and a diabetes treatment helping clear senescent cells—there’s a lot of really cool plot twists to uncover this week.

Meanwhile—Team Immunology™ is still firing on all cylinders with researchers potentially unlocking new insights into how autoantibodies (potentially) contribute to long COVID symptoms.

There’s so much to cover this week, so let’s jump in without wasting any time:

breath of fresh air

A Lung Cancer Drug Just Proved Incredible Survival Rates

A 5-year study into the efficacy of Lorlatinib achieved 60% survival rates. That is a meteoric jump.

🌬️ Get ready for some truly ground-breaking cancer news.

A new study from the American Society of Clinical Oncology just printed with some brain-breaking results. After 5 years of treatment with Pfizer’s Lorlatinib drug—60% of patients with Non–Small Cell Lung Cancer had demonstrated progression-free survival.

That may not seem like a big deal at first—but patients being treated with a comparable drug had only 8% PFS rates after 5 years.

This is a huge result that runs counter to even the most wildly optimistic expectations for treating NSCLC. Let’s explore how Lorlatinib works and the mechanics behind these great results:

LORLATINIB BASICS:

To keep it short—Lorlatinib is a drug that shuts down a critical receptor inside certain kinds of cancer cells. Inside cells that turn cancerous, a tyrosine kinase receptor called ALK mutates and goes haywire. ALK mutations lead to truly malicious cancers that spread quickly and are hard to treat.

Drugs like Lorlatinib bind to the ATP pocket of these ALK receptors inside cancer cells. This deactivates the receptor and blocks it from working. This slows the progression of NSCLC cancers—giving oncologists a chance to work on other areas of their treatment plan.

This makes ALK-blockers a great first-line treatment for these cancers. But—since cancer is crafty—they’re usually not even close to enough.

JUST MAKE A NEW ALK

First and second-generation ALK treatments don’t work for long because eventually, cancer cells divide enough to mutate a different form of the ALK receptor that doesn't get blocked by the drug. This is why those earlier medications have single-digit 5-year PFS rates.

These Lorlatinab results have potentially flipped the playing field.

LORLATINIB’S BREAKTHROUGH

Lorlatinib rules because it can also penetrate the blood-brain barrier and deactivate cancer cells that have metastisized all the way into those tissues. It is so effective that it appears to not even give these cancers a chance to develop mutations in their ALK receptors.

While there’s still a lot to learn about ALK receptors and how to treat cancers that have them—this Lorlatinib data is incredibly encouraging and opens up really cool new avenues for treatment.

 | Check out the trial data here  |

metabolism all the way down

Inhibiting SGLT2 Pumps Helps Alleviate Aging Symptoms

Another day, another diabetes drug with broad efficacy treating much bigger problems

🧹 Your body needs help clearing out old cells.

This is one of the critical mechanisms that causes diseases related to aging. As you get older and your cells continue to divide—more and more of them hit a limit.

To oversimplify, most of your cells have an internal clock that limits them to a certain number of divisions to help prevent things like cancer. Once cells hit that limit, they enter a state called senescence and stop dividing. When you’re young, your immune system does a pretty solid job of cleaning up these senescent cells and keeping you healthy. However, over time—senescent cells build up and your immune system can’t clear them as well anymore. A big build-up of these senescent cells is associated with a lot of the negative effects caused by aging.

Therefore, a lot of research has explored ways we can help clean up senescent cells without accidentally kicking off a tidal wave of cancer generation.

Which is why it’s completely incredible that a new paper has demonstrated that a type II diabetes medication has demonstrated a strong side affect that helps clean up senescent cells and alleviate some of the negative symptoms associated with aging. It is amazing to see just how much people’s lives improve when these small metabolic dysfunctions get corrected.

Let’s explore what we know so far:

MEET SGLT2

So this isn’t anything like well-known diabetes medications like Ozempic. This class of drug inhibits a pump inside kidney cells called SGLT2. Basically, inhibitors here block glucose from getting reabsorbed by the kidneys and therefore lower blood sugar. This is great if you have type-II diabetes—but how does this help with aging?

INCREASING SENESCENT CELL CLEARANCE

While there is a lot of research still being done to directly pin down the mechanism here—we have some critical clues.

Treating folks with insulin to lower blood sugar doesn’t directly lead to improved senescent clearance in the same way that SGLT2 inhibition does. So it can’t just be lower blood sugar = improved aging symptoms.

The team that did this study noted that SGLT2 inhibitors also upregulate a metabolite called AICAR. AICAR plays a role in a whole bunch of metabolic pathways—and a bunch of metabolic diseases. But the mechanisms that AICAR powers are still being unraveled. It could be that AICAR improves signaling—which in turn helps immune cells find and clear senescent cells.

Either way—this is a potentially massive breakthrough. It’s cool to discover an indirect pathway to help clear senescent cells—and it gives a solid jumping-off point for further unraveling the cellular mechanisms behind aging and age-related diseases.

I found this paper thanks to Friday Links by Niko McCarty

| Read the paper here | 

unraveling long COVID

Antibodies from Long COVID Patients Cause Disease in Mice

In a wild new study—researchers have shed light on the autoimmune nature of Long COVID

 🦠 We’re starting to crack the code of Long COVID.

An alarming number of COVID infections lead to Long COVID—which is a big basket of symptoms that can range from inconvenient to completely debilitating.

With COVID sticking around for the long term—it is critical to unravel precisely what causes Long COVID symptoms so we can better treat this condition.

A new study out of the Amsterdam University Medical Center may help crack that code and prove an autoimmune link causing Long COVID.

The team injected mice with antibodies isolated from Long COVID patients—which resulted in a handful of measurable symptoms in those mice. While these results can’t really prove anything—they suggest a strong autoimmune foundation to Long COVID symptoms.

Let’s break down everything this paper explores:

COVID REACTIONS CAN LINGER

Right off the bat, this paper does a great job of summarizing a bunch of Long COVID biomarkers doctors can now test for. Folks who suffer from Long COVID have massively elevated levels of a fiber protein called GFAP that could be generated by neural inflammation and damage. Other big biomarkers in these patients include proteins like NFL and Tau along with immune signals like type-1 interfereons.

All of these proteins can indicate chronic inflammation associated with auto-antibodies generated by fighting off an initial COVID infection. So, researchers isolated IgG antibodies from Long COVID patients and injected them into mice.

ANTIBODY DISEASES

The team split Long COVID patients into 3 tiers based on serum levels of some of these biomarkers and the severity of their symptoms. Patients suffering from 2 of these 3 cohorts had antibodies that caused mice to become sick when they were injected with them.

The team at AUMC focused on neurological symptoms and found that mice injected with these antibodies displayed measurable increases in hypersensitivity and immobility. This is a critical piece of the Long COVID puzzle.

WHAT COMES NEXT?

There’s still a whole mountain of information researchers need to unravel before we fully can understand and treat Long COVID. However, it’s important to have definitive pieces of data like this study. If Long COVID is exclusively caused by autoantibodies sticking around and wreaking havoc long after the end of a COVID infection—then immunologists have a solid chance of developing treatments to alleviate those symptoms.

Still—it’s important to point out that we’re still in the early days of discovering the mechanics here.

  | Check out the paper here  |

we got games

Biology Connections #6

Test your life sciences cred with this specific take on the NYT connections format.

This section is brazenly adapted from the good folks over at Nerdfighteria’s We’re Here Newsletter

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)