Sneaky Tumor

Breaking News!
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 knows how that tumor progressed in spite of TIL therapy! His work was published in the NEJM (see link below).

It may be helpful to understand 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 the NIH who answered loads of questions at virtually every visit (and between times, too!) with patience and competence.

What worked:
Six tumors in my lungs are now dead, dead, all the way dead. (Update 6 years later: my scans show no remnant of any tumor.) They were killed by my immune system! Killer T-cells infiltrated the 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). Pieces (called "peptides") of mutated KRAS proteins are the stuff that my HLA binded with to mark my tumor cells for destruction. KRAS is vital to our cells, but mutations in this gene can lead to cancer.

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 mutated 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 an HLA molecule. 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 term "possible detection" 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 that mutation. Killer T-cells are the immune system's soldiers, but they are highly specific in what they "see." Most types, it seems, are blind and deaf to cancer cells, even when HLA is doing its best to let the T-cells know there is a problem. Why?

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). These receptors are the embodiment of programmed randomness. Our bone marrow churns out millions of T-cells in our lifetimes, each equipped with unique TCRs that are constructed (as far as we know) at random in order to comprise a host of potential future armies against an equally stunning array of potential onslaughts. Each TCR 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 threat 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 (KRAS G12D), and I inherited an HLA type (C*08:02) that has the ability to show that bad guy to the killer T-cell.  

When the killer T-cell connects with its target, the HLA-bound mutant 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, he was able to expand 30 million of my mutation-specific T-cells to 148 billion. These are the cells that comprised my TIL therapy. These are the cells that killed six known tumors in my lungs. Perhaps even more astounding: These are the cells that are still circulating in my system, keeping the KRAS G12D mutation from causing any more tumors for (I pray) the rest of my life.

Tumors are a collection of cells that have lost at least one important capacity that normal cells have--the ability to die. As tumors change over time, mutations accumulate. Tumors can evolve in ways that give them an advantage over the immune system. That is exactly what happened in the case of the one tumor that progressed even after TIL therapy. That tumor's cells developed an advantage that allowed them to escape detection.

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 present, it must mean that the hero HLA allele resided on the copy of the chromosome that went missing from the progressing tumor's cells. The other chromosome of the pair was a different allele; one that doesn't recognize the mutation, and so the sneaky tumor left it alone.

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 the HLA complex to shout, "Look here!" the T-cells passed on by as if those tumor cells were normal, healthy cells.

I can only echo the Psalmist who wrote:

I will give thanks to You, for I am fearfully and wonderfully made; Wonderful are Your works, and my soul knows it very well.
Psalm 139:14 NASB

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.

Links to media:
Read the Lab Guru's article for the NEJM
Three newspaper reporters interviewed me for articles:
New York Times
Wall Street Journal
Philadelphia Inquirer
Joan Lunden interviewed The Guy and me for the Today Show.
Sneak peak for that story on FaceBook here.
Tom Marsilje's blog about my case.