The Lab Guru shared some stunning information about the non-responding, sneaky tumor that was surgically removed three months ago. After analyzing it, he now has a theory about why that tumor progressed in spite of TIL therapy! He cautioned that the results haven't been fully proven yet.
First, I want to cover how immunotherapy did work to kill many tumors.
Disclaimer 1: I am neither a doctor nor a scientist.
Disclaimer 2: What follows is my understanding of the details of my own case.
Many Thanks to the brilliant doctors and scientists at NIH who answered loads of questions at virtually every visit (and between times, too!) with patience and competence.
Six tumors in my lungs are now dead, dead, all the way dead. They were killed by my
immune system! Killer T-cells infiltrated my tumors to seek and destroy
cells that harbored the baddest bad guy. This was possible in
part because I inherited a hero HLA allele. It makes a particular protein molecule that worked in concert with killer T-cells to eliminate almost every tumor. HLA has the
ability to mark cells that are "broken". Its job is to grab stuff from inside cells, bind it, and then present that stuff outside, on the cell surface.
More on the good guys, later! The villain in my case is a mutation to a gene called KRAS (KAY rass). The stuff that HLA enlisted to mark my tumor cells for destruction are actually pieces of mutated KRAS proteins (peptides). KRAS itself is vital to our cells, but when mutations happen, trouble begins.
Killer T-cells can't peer
inside a cancer cell (or any other kind) to see what's going on there, but the HLA lives there. If a cell becomes deranged, as happens in
cancer, HLA will grab its evidence (the peptide) that something is way wrong, and
thrust it outside the cell while still holding it in its grasp. This is the only way that a killer T-cell can sense its target; it must be bound to an HLA molecule on the surface of a cell.
Hundreds of types of HLA alleles exist, but each person inherits only a few. Each type creates a molecule that has a unique binding surface. Think of molecule-sized Lego
bricks--if the peptide can snap together with the HLA molecule, the two
form a complex. When this happens, the peptide gets swiftly escorted to the surface, and the courier (HLA) announces to the world outside the cell, "Look what I found!"
Unlike Lego bricks, not all peptides will fit with all HLA molecules. Some won't fit with any. But, happily, it was found that for the mutation that I had, and the HLA type that I inherited, the two did fit together and HLA was able to bind the criminal and set it up for possible detection (and execution!) by my immune system.
Another layer of complexity:
Note the use of the word "possible" above. Just because the tumor cell, thanks to HLA, had the ability to present the mutation to my immune system, it was no guarantee that my immune system could recognize it. Killer T-cells are the immune system's soldiers, but they are highly specific in what they "see." Most types, it seems, are blind to cancer cells.
Each T-cell type is capable of recognizing only one particular antigen (bad guy), which is often referred to as its "target." T-cells sense their target with receptors (TCRs), which are the embodiment of
programmed randomness. We each have millions of unique TCRs. Each one is highly specific to its target and to
no other. Because TCRs are so hyper-focused, we need lots and lots of
varieties of them if we are to remain safe from the constant onslaught
of incalculable numbers of viruses, bacteria, and even cancer cells. Lucky for me (understatement!) my body produces a few different types of T-cells whose target is the baddest bad guy, and I inherited an HLA type that has the ability to show the bad guy to the killer T-cell. When the killer T-cell connects with its target, the HLA-bound peptide, it sends a signal to the tumor cell to self-destruct! Also, when a T-cell finds its target, it replicates itself and can go on to find and kill more tumor cells. Thanks to the Lab Guru's
expertise, 30 million of my mutation-specific T-cells were expanded to 148 billion. These are
the cells that comprised my TIL therapy. These are the cells that killed six known tumors in my lungs.
Tumors are a collection of cells that have lost at least one important
capacity that normal cells have, and that is the ability to die.
As tumors evolve, mutations accumulate. Sometimes, they'll mutate in a
way that gives them an advantage over the immune system.
So, what about that seventh, insidious, tumor?
What the Lab Guru discovered about the recalcitrant tumor is that it was missing one copy--healthy cells have a pair--of Chromosome 6. Chromosome 6 is where the HLA genes live! Since one copy of the chromosome was still there, the theory is that the hero HLA allele must've resided on the copy of the chromosome that went missing. The other chromosome of the pair most-likely did not include that particular allele.
The Sneaky Tumor's Game:
Any tumor cell that was absent the hero HLA was essentially cloaked from my immune system. The killer T-cells could no longer sense their target (even though it was still present) because the hero HLA--the thing with the ability to display the bad guy--was gone! Any cells that were missing that particular Chromosome 6 (either the one from Mom, or the one from Dad) now had an advantage that would help them survive. When they multiplied, those new cancer cells, too, were missing a copy of Chromosome 6. Killer T-cells wouldn't kill those cells, because without that particular HLA complex, the T-cells had no target.
How's that for Science?! "Amazing" doesn't come close.
The End, A Surgeon's Knife:
Similar to the way cancer didn't eliminate just the gene that threatened it but the entire chromosome the gene resided on, my surgeon didn't just excise the sneaky tumor--he removed the entire lung lobe it resided in.
It was a medical necessity to remove the entire lobe, but also something more: Poetic Justice.
Update: Read the Lab Guru's article for the NEJM about my case here.
My friend Tom Marsilje, medicinal chemist/blogger has a unique way of explaining things. Read his take on my case here.
Joan Lunden interviewed me and The Guy for the Today show. Sneak peak on FaceBook here.
Today Show interview here.