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.

Milestone

Last Friday was the anniversary of "Cell Day". I sent my husband out for a Pepperidge Farm Chocolate Cake just like the one they gave me on the day of the transfusion.

On Sunday we packed up the kids and headed for Frankenmuth, where I was registered to participate in a 5K Walk. That evening, I raised a glass to toast my esteemed immunotherapy fellow, who soon would be turning over my case to someone else. I chose a drink that he likes best. (This was less of a sacrifice than I was expecting!)

We watched fireworks with our kids, and some dear friends. Our youngest was enthralled by the spectacular explosions and declared his appreciation (loudly) after almost every round. As the smoke from the finale cleared, he announced in the darkness of the night that it had been "the best day of (his) life".

The 5K took place the following morning. I was nervous! It seemed to me that all of my health problems began after I ran a 5K in 2011.

Maybe 5K races are bad luck!

My oldest daughter and my husband accompanied me. They kept me to a challenging-enough pace for me, but one slow enough for them to chat effortlessly with each other. Neuropathy in my feet (from stupid FOLFOX) caused some pain, and my lungs...well, they did OK. I wasn't breathing like I felt I needed (wanted) to, but I was breathing adequately, apparently. I could not chat! My lungs would let me walk, or talk, but not both. We walked at about 3.5 mi/h and I finished in 51 minutes.

In movies sometimes a dramatic moment is depicted as happening in slow-motion. That is what happened to me at the finish line. In slow-motion, I saw my foot hit the mark, and it felt like a literal weight had lifted. I could almost hear the woosh as it flew off my shoulders. I've never experienced anything like it before.

When I crossed over the finish line, it felt like a new beginning.

Remembering

Tonight, which is Father's Day in the U.S., we attended the graduation party of the son of dear friends. Last year, also on Father's Day, we attended a graduation party hosted by other dear friends. The difference is that after last year's party, Patrick and I headed straight to the airport. I would be inpatient at NIH starting that night for what would be a nearly month-long stay.

"No tears! No tears!" my friend had said as we left the party. She waved her hands in front of her eyes to keep them away. I did the same. We hugged and I almost made it out of there without crying. Then another friend joined us and I crumpled into a teary mess. We hugged as we cried. They promised me their prayers as I left the building.

My friend's husband called to me just as I reached the parking lot. "Come back! I didn't get to say good-bye!" I did, and cried some more. He promised to send me excruciatingly bad puns every day that I was away (and he did!). I told him that I loved his wife, and he said, "I do too!" and we laughed.

I got into the car then, and stared out the window, still crying. I have never felt so torn as I did that day, leaving my family and friends. Not only was I leaving the kids; I was also taking their Dad away. I felt tremendous guilt over that until I tried seeing the situation from his perspective. In his mind, being with me for as long as he could manage it was his duty, especially since the kids would have adult care-givers. "I have to take care of you," are the words he repeated so often, and always in a way that communicated, "I want to take care of you." He is a gift.

I thought about the risk involved in the clinical trial. I knew beyond a shadow of a doubt that this was my best option, but it made me sad to think that "coming back" might not be a part of this equation. I accepted the uncertainty, but I had to push thoughts of who I was leaving behind out of my mind and try to focus on what lie ahead.

A few days prior, Patrick and I had met with a lawyer to finally get a will in place. This was something we had planned on doing right after our wedding, but never did. As the years went by, one or the other of us would mention something like, "We should really make a will..." but that's as far as it went--just a suggestion. This time was different. This time the gravity of my health urgently demanded that we take action. Surprisingly, none of those preparations made me feel sad; instead I had a sense of well-being.

Driving away from that party though--that was hard.

By the time we arrived at the NIH that evening, it was pretty late. I met the night nurse, who smiled a lot and made sure every single thing was in order. She asked a bunch of questions, explained some of the mortifying practices I'd have to endure, and assured me that I would be well-cared for. Patrick left for the night. I tried to settle in. I had a big room facing the courtyard. I would have no roommate, unlike my previous visit. This was by design. Sharing a room could lead to sharing germs, and that is too big a risk for a neutropenic patient (which is what I'd be once the chemo did its thing).

It was Sunday, and the on-call immunotherapy fellow that night was the one who'd been assigned to my case from the beginning. I found this doctor to be a man of few words, but I was very happy to see a familiar face. I wished him a "Happy Father's Day", and asked how long he would remain on the service. I knew that the fellows were about to rotate out. He assured me that he'd be there on Cell Day. "What's the new guy like?" I wanted to know. He told me his name and instantly brightened. "You'll like him. He's a good guy." I knew that this was the extent of the information I'd be getting from him on that topic. I was uneasy with the knowledge that the one doctor that I was familiar with would be leaving so soon after I arrived. We discussed upcoming events briefly then said good-night.

Then--just as tonight--it was well past midnight by the time I got to bed. I was excited about finally being there, and almost couldn't believe that it was really happening. Monday morning would start early with scans and other procedures. I was on a carefully planned protocol now. I prayed that every step of the way would go as well as it possibly could.

Follow-Up #7

No real news this time, for once!  It's been ten months since I received TIL therapy.  I was back at the hospital for follow-up number seven last week.

First thing on Monday, as usual, I went directly to phlebotomy for a blood draw (only six vials this time).  Later in the day, I had a CT scan.

On Tuesday, I had apheresis. To my immense relief (understatement!) the procedure turned out to be the shorter one. Even better, my research fellow spent some time with me, talking about his work in the lab. The conversation helped to get my mind off of the blood circulating out of and back into...me (gack) and I was very thankful for that.

When the requisite amount of white cells had been collected, my husband and I bolted over to Medical Records to pick up the disk of CT images from the previous day's scan.  I set up the laptop at one of the teensy tables in the atrium.  I was taken aback at how different the scan looks now that I have one fewer lung lobes! I wasn't able to study the images for very long; it was almost time to go to "OP3", where my follow-up would happen.

Even though I expected to hear good news, I had dreaded this appointment for weeks.  It was the last one I would have with my current immunotherapy fellow. It makes me sad to think of someone else as my doctor, but I'm happy that he had (what I hope was!) an interesting and fulfilling year on the service. I consider myself most fortunate to have been in his care over the past year, and I am confident that his future patients will feel the same way.

We stepped into the hallway to review the scans, and I stood there thinking how bizarre they look now.  My right lung lobes have sneaked their way over to where the now-missing left lower lobe had been. My heart is literally in a new place! "Mother Nature will not tolerate empty space," is what I was told. It's so strange-looking to me. Regarding cancer, my fellow saw nothing of concern.  Thank God!

The next morning I met with the thoracic surgeon for follow-up.  He wanted to see how the incisions were healing, first thing.  Little did I know that he would find something that needed attention.  He said that my body was "spitting out a couple of stitches" (gack! again!), and so he removed them.  Actually, his assistant removed them but Ow! OW! QUIT IT!!! After that unpleasantness, he had only good things to tell me, so we left the NIH on a high note.

My follow-ups will get stretched out from now on. I'll go back quarterly for a time, and after that, even less-frequently if all continues to go well.  I am praying that it will!

The Girl Who Lived (apologies to J.K. Rowling)

I am now three weeks out from surgery to remove a progressing tumor and its necrotic neighbor. TIL therapy killed six other tumors, but one remained that did not fully respond to the cell therapy. Instead, it was surgically removed via lung lobectomy.

This inpatient stay lasted one week. On the day I was discharged from the hospital, I asked my doctor to "say the words." He understood exactly what I meant. He obliged by saying the happiest phrase there is for me right now:  "No Evaluable Disease." Hearing those words--from him, especially--filled me with a joy I can't begin to describe.

No
Evaluable
Disease

It is almost incredible to me. Not very many months earlier other doctors--several of them--described my diagnosis as terminal. Yet, a couple of days ago, a written discharge summary arrived via USPS from the NIH which told a better story. As I slowly read the report, my mind absorbed every word, recalling each scene as I had experienced it. My cancer riot was all there--years of uncertainty, painful treatments, and now success--distilled into a few short paragraphs on a couple of sheets of ordinary paper. It was written by the doctor who, to my great benefit,  had seen me through the rigors of the clinical trial, on-going follow-ups, and this most-recent lobectomy. It is this doctor's voice that I hear when I read the report.

COURSE IN HOSPITAL
Ms. Ryan is a 50 year-old female with a history of colon cancer who after undergoing standard therapy, self-referred to the Surgery Branch of the National Cancer Institute
.
.
.
She received 148 billion cells
.
.
.
(she underwent) a left lower lobe resection.
.
.
.
CLINICAL DIAGNOSIS:
Colon cancer metastatic to the lungs, now without evaluable disease.

I read it over and over. I marvel at all that has happened to me:  surgeries, chemotherapy, radiation, and countless needles, transfusions and bone-crushingly painful neupogen injections...the nausea, the fatigue, the waiting--waiting for acceptance onto the trial (2 no's before a yes), waiting to know whether my cells would grow, waiting to know whether they would work... All of it leading up to this one amazing report; this one phenomenal result: Restored Health. No evaluable disease. I cry tears of joy and relief, but then a wave of sorrow hits me as I think of friends who passed away in this same space of time.

I thank God for this life. Always. Always. I thank God for the men and women at the NIH, and for all of the people who prayed for me.

What's Next:
I am scheduled to undergo apheresis again early in May, to facilitate another TIL treatment (one that I may never need).  I had hoped for begged for the shorter apheresis procedure, but no. It will be the longer one, where they circulate my blood volume five times. They say they need more dendritic cells. They also need more "feeders." Bleargh!

"Feeders?!" The word conjurs unpleasant thoughts. I am too squeamish. Instead, I will dwell on the phrase, "No evaluable disease."

I am dreading the 5-1/2 hour apheresis procedure but I will try not to complain.

LIFE IS GOOD!

Will They Let Me Go?

Some drama during what did turn out to be, thankfully, my last night inpatient at NIH had me wondering. The "night thoracic fellow" came in to assess my recovery sometime after 8:00PM. The thinking had been that one more x-ray, the following morning, would be my ticket out of there. Sadly, I seemed to be too puffed up, literally, for it to go that easily.

The thoracic fellow pushed various places around my left chest and side. I could feel the sponginess. After what I thought was quite a lot of him comparing, listening to, and pushing on me, he phoned the thoracic surgeon, "the boss," as he referred to him, to find out what the next step should be.

"The boss" ordered another x-ray for that evening. Off we went. Upon our return, the night nurse offered pain meds, and took vitals. New tonight, and because of the sponginess, she told me that I'd be sleeping "with oxygen." I got to choose between humidified, or non-humidified (humidified, please). She flagged my room as "Do Not Disturb" after she left, and I fell asleep quickly. In the morning, I could tell that the puffiness was worse than it had been the night before. I was at x-ray at 7:00 AM. The tech there recognized me after so many visits, and filled out the sign-in sheet for me.

Shortly after returning to my room, the "daytime thoracic fellow" was there, assessing. She mentioned that they might have to "put in a little chest tube." This was not what I wanted to hear at all. My own fellow came in later, and did his assessment. He advised me to walk around the unit until morning rounds started. This I did, making circuit after circuit. I got light-headed at one point and crashed into my husband's shoulder, unable to move enough air. I thought, "This is it!  They're not going to let me go."

We didn't bother starting to pack up the room. We waited for the doctors to do their rounds. First to round was the immunotherapy team. It was a smallish flock this day, but it did include the principle investigator (The Guy!) The decision about whether I would stay or go was entirely up to the thoracic team. The attending said that the morning's x-ray looked "about the same" as the one from the night before. I didn't know if that was good news or bad news.

A few minutes later, the thoracic surgeon came in with his flock (of one), plus my fellow, to talk to me about how the morning walking went, how I was feeling, and how spongy he felt that I was. After listening to my lungs, and considering for a while, he told me that he was sending me home! Woo Hoo! I am to have a follow-up x-ray at my local hospital in a week, and to mail the disk to NIH.

We were strongly encouraged to include lots of stops during the drive home. The doc suggested that I get out and "do a few laps" every couple of hours. "Walking is the best thing you can do for yourself," he said, and so we did. We stopped five times on our 500+ mile trip.


It's good to be home!

What Happened to Tuesday?

So much of my stay this time is a blur. I've been mostly in my room, with two trips to x-ray (morning, and night). I'm visited by nurses throughout the day. They deliver pain meds, post-TIL treatment meds, and they take vital signs every eight hours. There is very little sleep.

With the chest tube, sleeping happened in spurts. I always woke myself when I'd try to change positions. It hurt a lot when I would move in my sleep.

Breathing was another adventure. I managed to pull 2250 ml on the spirometer (volume of air I can inhale). This was a record for me!

Last night, the thoracic surgeon clamped the chest tube closed. This meant the suction box thingy would no longer be helping me (It was pulling air from the space outside the lung, should any be leaking...pretty sure). By clamping the tube shut, the doc rendered it ineffectual. He would be able to tell by how I responded, over the course of 24 hours, whether it was safe to remove the tube itself. Even though the hose was clamped, I was still attached to the box. I eventually named it, "Beelzebub." It went everywhere I went.

More x-rays last night, and this morning. Then! Then! The thoracic doc decided that I would be O.K. to exist minus the chest tube. He pushed down (hard) around the insertion site while the fellow ripped the tube out. She was not quick at this, I am sad to say. It probably felt quick to her, but to me...notsomuch! It was not exactly painful but the longer a procedure takes, the more likely I am to get nauseous. You'd think I'd get used to this stuff, but apparently not.

I was encouraged to walk as much as possible, and to ask for pain meds. They will no longer keep me on a schedule for those (hurray!) My husband and I took a chilly walk around the hospital wing, and then I decided it was time to put on my own clothes!^†

Tomorrow, I'll have what I hope is the final x-ray during this stay. If it's good, they'll send me home! We have an eight-hour drive ahead of us, but hopefully I'll be able to tolerate it O.K.

† I have since learned that, according to the Patient Handbook, patients are expected to wear their street clothes as much as possible while inpatient. oops.