Hi all,
Is it appropriate to start off with a little music?
This is the Car T gene synthesized. Can't see it making the JJJ top 100 though , but it sets the learning agenda.
https://youtu.be/hlRMXiNDxlU?si=Wg0ai5QIcnP4Me3K
I am probably up to part 6 "think tank" on this series. Mr Spock may say fascinating at the end. So much to come.
Onto business :
Cellular pathway for generation 2 Car T therapy.
I have tried to simplify it for understanding, appreciate its complex. It's what our drug does, but I will explain generation 3 cdh17, the massive difference in part 4.
Imagine your immune system has "soldiers" (T cells) that normally find and destroy harmful invaders. CAR T-cell therapy upgrades these soldiers with a special GPS tracker (the CAR) to hunt cancer cells.
Here's how it works;
Scientists take a T cell from your blood and add a lab-made GPS tracker (CAR).The "GPS" has two key parts:Antenna (scFv): A tiny protein piece (from an antibody , the human immune system makes 300 k antibody cells per day, with no antibodies made, we would survive maybe 7 to 14 days before some bacteria or a virus negates us, we shall explore some of them closely (next series) that latches onto CDH17, a marker found on cancer cells.
So imagine a lock and a key mechanism. This scFV is like the key. It fits and locks in.Imagine your body has tiny "detectives" called antibodies that find and grab onto bad guys like viruses or cancer cells.
Scientists can take the most important parts of these antibodies (the "grabby hands") and turn them into a smaller, simpler tool called an scFv (single-chain variable fragment).Think a systems magnet.scFv is like a spy who sneaks into a enemy base to plant a tracker or a bomb, while a full antibody is like a soldier who both fights and calls in airstrikes.
Upgraded T cells are multiplied in a lab, then put back into your body.They patrol your bloodstream, using their GPS to stick to any cell with CDH17.When they lock onto a cancer cell, the alarm triggers the T cell to kill the cancer cell (by punching holes in it or activating self-destruct signals). They then call for backup (by releasing chemicals that rally more immune cells).
These upgraded T cells can multiply inside your body, acting as a "living drug" that keeps hunting CDH17-positive cancer cells over time.
A short documentary.
https://youtu.be/ntk8XsxVDi0?si=54fgCz5O6bRpHHKi
Think of the scFv as a cancer-specific magnet, and the CAR as a battle helmet that turns T cells into "smart missiles" against tumors.CDH17 as a unique cell found on certain cancer cells (like those in stomach, colon, and pancreatic cancers). It's like a international flag. The body knows the pirate flag
The Target (CDH17): This protein is overproduced by cancer cells (like a bright neon sign saying "I'm here!") but barely exists in healthy tissues.
The Magnet (scFv): Scientists design this tool to stick only to CDH17, ignoring normal cells. It’s like a key that fits only one lock.
The Attack: When the scFv latches onto CDH17, it signals immune cells (like CAR-T or CAR-NK cells) to destroy the cancer. We shall look at CAR-NK cells in the future.
Since CDH17 is rare in healthy organs (like the liver), therapies targeting it can focus on cancer cells while sparing normal tissues. This precision reduces side effects compared to traditional treatments like chemotherapy.
Imagine CAR T-cells are like supercharged immune soldiers with a trigger button (the CAR). When they find a cancer cell (via the scFv "magnet"), here's what happens inside them:
The "Trigger Pull":
The CAR's CD3ζ ( CD37 is a key player in how your immune system makes and balances antibodies, the immune system is like a football team we will get to know the players on Chimeric side) domain acts like a starter switch – it sends the first "ATTACK NOW!" signal when the scFv sticks to the cancer
The scFv is the "GPS" that spots cancer cells " flag".
When it sticks to the cancer, it’s like the GPS saying, “Target locked!”
The "Attack Now" Signals CD37 to the zone . CD 37 is like the key forward.
The CD3ζ domain is the button the spy presses to start the car’s engine.
Once the scFv locks onto cancer, CD3ζ sends the first “GO!” signal to the T-cell, telling it to attack.
Why it Matters:
Without CD3ζ, the T-cell wouldn’t know to attack—even if the scFv finds the cancer. It’s the critical first step that turns a “detector” into a “destroyer.”
More players come onto the field. Costimulatory domains (like CD28 ) act as "power boosters battery cells" to keep the T-cell active and alive.
Activated CAR T-cells release tiny "grenades" (perforin) that punch holes in the cancer cell. Then they shoot "poison darts" (granzymes) through these holes. I like that !
The granzymes force the cancer cell to self-destruct (apoptosis), like flipping its "kill switch".
Double Trouble for Cancer:
In some cases, the attack also triggers pyroptosis – a fiery explosion of the cancer cell that alerts more immune cells to join the fight.
CD3ζ starts the fight, while costimulatory domain (CD28) act like a battery .This combination makes CAR T-cells both powerful and persistent against cancer.
Think of cancer cells as rogue factories that grow uncontrollably using two key power switches (Ras/Raf/MEK/ERK and Wnt/β-catenin pathways, we shall explore and simplify the cancer cells defence mechanism next series). CDH17 acts like a security guard keeping these switches turned "ON." Here's what happens when CDH17 is blocked:
"Power Cut" to Cancer Factories:
Ras/Raf/MEK/ERK: This pathway acts like a gas pedal for cancer growth. Blocking CDH17 disables this pedal, slowing cell division.
Wnt/β-catenin: This pathway acts like a survival signal. Blocking CDH17 silences this signal, making cancer cells vulnerable.
Cell-Cycle Arrest: Cancer cells get stuck in "neutral" (G0/G1 phase) and can't multiply.
Apoptosis: Deprived of growth signals, cancer cells self-destruct.
Engineered Cells as "Demolition Crews":
CAR-T/NK cells attack directly (via perforin/granzyme "grenades") while also cutting power to cancer factories by disrupting CDH17's role. This double hit makes tumors collapse faster.
Blocking CDH17 is like cutting electricity to a rogue factory, while CAR-T cells are bulldozers smashing its walls. Together, they starve and demolish cancer cells.
CDH17 is a protein that's normally found in your gut and pancreas, but not in a healthy stomach. When it shows up too much in stomach cells, it becomes a red flag for cancer. Here's what happens in simple terms:
Cancer Link: In stomach cancer patients, CDH17 is overactive in about 74% of cases (nearly 3 out of 4). The more CDH17 there is, the worse the cancer tends to be—it’s often found in advanced tumors that have spread to lymph nodes or other organs.
CDH17 acts like a "glue" that lets cancer cells stick together, move around, and invade other tissues.
Makes tumors grow: It tricks cells into multiplying nonstop by turning on cancer-friendly signals.
Survival Impact: Patients with high CDH17 levels often have shorter survival times because their cancers are more aggressive and harder to treat.
Think of CDH17 as a molecular troublemaker that doctors can detect to predict how serious a stomach cancer is.
Next part we will look at the cancer cell response to generation 2 Car T . I haven't mentioned why I bought yet. I also haven't mentioned our Generation 3 product , so far we have only covered the second generation , the third generation has some really nifty bits and associated pieces, maybe that's part 4. That's where we get into my futuristic theory, the Wagyu steak bit ( vegetarians forgive me)! I can't wait !
Next part is to explain the defences by the cancer cell. Why do we have trouble totally eradicate them considering our immune army with a defence shield of certain drugs we take.
So far I hope I have explained generation 2 Car T therapy. Part 4 will be devoted to where we are in this science . Generation 3. That's when your eyes will open totally I hope,like mine have.
In conclusion, don't things change over 3 years. The imminent author attachment below says the main reason why it's difficult is finding the right antigen. That is so true whilst he was talking about Generation 2 from 3 years ago. The author talks about cytokine release issues causing an effect on the immune system. He can't say that any more with Cdh17.
https://youtu.be/V2wqbn2iFUo?si=Ib3xgjs9qsCRc5qN
Kpax
(20min delay)