Sunday, July 19, 2015

Understanding the TIL Clinical Trial in 19 Easy Steps

See the "Key Posts" link on the side bar to navigate to posts about particular steps as I experienced them. This trial is not just for colon cancer patients--they are recruiting patients with other G.I. cancers, as well as patients with other solid cancers. See the trial link below.

Trial ID: NCT01174121
One patient's perspective:

Step 0 (hello, fellow IT people!):  Click the link above, if you're considering this trial.  Read the eligibility criteria carefully. One requirement is that either oxaliplatin or irinotecan has failed to cure you. Note well that word "or." You do not need to try every chemo out there, if you don't want to. When FOLFOX failed me, I applied for this trial. I did not receive irinotecan. (This refers to metastatic colorectal cancer. Other cancer types have different criteria.)
My first contact with NIH was on December 19, 2014. I picked up the phone and dialed (866) 820-4505. I spoke to a friendly, helpful research nurse who got the ball rolling almost immediately.

1:  Tumor harvest.  For the purpose of this trial, at least one tumor must be in an "easily resectable location", and it must be "of sufficient size". The tumor is in a sense a "TIL Factory." The researchers set a size guideline to help ensure they'll have enough material to work with.
My tumor harvest surgery happened on April 1, 2015.


2:  Extract tumor-infiltrating lymphocytes from the tumor.  Note: TIL are the body's natural defense against tumors.  It is because of this step that the protocol requires that a patient commit to a one-month "wash-out" period from chemo before surgery.  If you are unable/unwilling to be chemo-free for one month prior to the tumor-harvesting procedure, this trial is not for you.  The researchers need to harvest a "living" tumor.  They hope to find active TIL in the patient's tumor. Requiring a chemo wash-out prior to harvest surgery gives them a reasonable hope of success at this.
I hadn't had chemo since March 3, 2014, so this was not an issue for me.

3:  Expand the TIL in the lab, using an agent called IL-2. (It is also known as Aldesleukin, or Interleukin-2.) This will be used in development of the final cell product. It will also be given via I.V. after the cell infusion, to promote the optimal environment for the TIL.

4:  Mapping of tumor DNA. (Note the dual purpose for harvesting a tumor:  to collect TIL, and to map the tumor's DNA.) NIH will perform whole exome sequencing on the patient's DNA. This is a far more extensive analysis than you might already have received from companies such as Foundation One.

5:  Mapping of healthy DNA.

6:  Identify the mutations. Mutations are identified by comparing the patient's normal DNA to their tumor DNA.

7:  Choose which mutated genes are significant. Some mutations are innocuous, while others may be oncogenes.

8:  Find out which mutation the patient's TIL most-strongly recognizes. NIH does this by first building a genetic model of the patient's tumor. The model is constructed from pieces of abnormal DNA--the mutations from the previous step. This construct is called a tandem mini-gene. Next, the patient's own dendritic cells (a type of white blood cell) are used to test the TIL for reactivity (see this post for more information on how a T-cell works). Apheresis is the process by which dendritic cells are obtained. My post on my first apheresis is here. I am not a fan of apheresis, but I am a big chicken. I'm sure you'll do fine.
In my case, 61 mutations were incorporated into tandem mini-genes. One of those mutations was the G12D mutation of KRAS.

9:  Identify and expand the active TIL. If some TIL show reactivity against the tumor mutation(s), then those TIL are expanded (multiplied) to large numbers. This becomes the patient's treatment product. It is a highly concentrated collection of immune cells that are targeted to one of a patient's particular tumor mutations.
My cell treatment consisted of 148 billion cells, of which 70% were targeted to mutation G12D of KRAS.

10:  Patient receives "conditioning" chemo.  Chemo (cyclophosphamide, aka cytoxan, and fludarabine) is infused for seven days.  This shuts down the patient's immune system.  The patient is monitored around the clock for side-effects, signs of infection, and receives hydration via continuous I.V infusion. Many difficult things are associated with this stage of the protocol. The breakdown is: two days receiving cytoxan, followed by five days of fludarabine.  This part is difficult.  I may be under-reporting.  If you've read the blog, you have an idea of what this stage was like for me.  In a word:  awful, and I've been told that my side effects were minimal. Keep in mind that everyone responds in their own unique way to chemotherapy, and every patient has their coping mechanisms.  No-one is allowed into this trial unless at least one full regiment of chemotherapy has failed them, so if you're considering this trial, you already have an idea of what you'll be facing with the chemo here.  Bonus: these drugs do not cause neuropathy, however, you will lose your hair.

11:  Cell Treatment. Patient is infused with the TIL. Surgery to harvest my tumor happened on April 1, 2015.  My return to NIH was Father's Day, 6/21/2015, which was ten days prior to "cell day". I received my cancer-killing TIL treatment on July 1, 2015.

12:  IL-2 Infusion. The same agent that was used in the lab to support the proliferation and health of the TIL is now infused into the patient. IL-2 in the doses used by this trial can be a dangerous thing. Normally it comes with a wide range of side effects that could include:  spasms, swelling, fever, chills, and hallucinations. Maybe other stuff. Ask your doctor. This part of the protocol is the one place in the various steps where the number of doses the patient should receive is unknown. The patient is left to decide, for the most part, based on how well (or poorly) they are tolerating the side-effects of IL-2. I had no side-effects from IL-2. One doctor said he had "never seen anything like it," but who knows. I recommend prayer! Lots of it.

13:  More IL-2. IL-2 infusions happen every 8 hours, until the patient or one of the doctors says "stop".  I received 5 doses of IL-2. I was told that this is "about average".

14:  Waiting. The patient is given support meds while neutropenic (neutropenic = bone marrow not producing any white blood cells), hydration as needed, meds for nausea, and any other side-effects of either the chemo and/or the IL-2.  All that is left is to wait for the patient's bone marrow to "wake up" again after the harsh effects of the seven days of chemo. The time it takes for this to happens varies by individual. I was very weak, tired, and nauseated. There were days when even eating seemed like "too much work". I don't mean 'preparing food to eat', I mean the act of eating food that was delivered right to my bedside table. I have a distinct memory of bringing a ravioli-laden fork to my lips exactly one time before deciding that I was too tired for such strenuous activity. Due to the low platelet counts, and neutropenia, the patient is forbidden from any activity that would cause infection or blood loss. This includes tweezing, shaving, and flossing. Getting a tattoo at this point is right out.

15:  Release from hospital. When the patient's platelets reach 50, and absolute neutrophil count (ANC) is at 1,000 for 3 days, or 5,000 for one day, the patient is released from the hospital.  These metrics are the signal that the patient's immune system  is restored enough to allow him to return to society.  Until the bone marrow is fully restored, the patient will take an anti-viral medicine daily, and an antibiotic at 3x/week for many weeks.  I was released on Bastille Day, July 14.  My hospital stay was 24 days. They expect patients on this trial to spend 3 to 4 weeks in the hospital.

16:  First follow-up. This is scheduled for 6 weeks post "cell day." You'll go to the phlebotomy department where many vials of blood will be taken. Later, you'll get scanned (CT and/or MRI). The following day, you will meet with your immunotherapy fellow and an attending physician in the outpatient clinic (aka "OP3") to discuss their findings.

17:  Second follow-up. You will return to NIH a second time--this visit is the teller--around 12-weeks post-cells for scans and labs.

18:  More and more follow-ups. Scans continue periodically, if tumors are not growing, to determine whether tumors are stable or shrinking. If growth is shown two months in a row, the patient is released from the trial to pursue some other course of treatment.  If no tumor growth is shown on the scans, you may be called back for many more follow-ups (let us hope for this!)


If you are considering participating in this trial, understand that it will involve a lot of waiting. It takes several weeks to sequence the DNA, compare it, and to build the tandem mini-genes. You'll be assigned a "fellow" (immunotherapy fellow) who will hopefully be able to answer your questions and keep you informed about how your cells are doing while you wait.

If you do get accepted into the trial, and make it through to "cell day", may I suggest the following for your consideration:

Give up coffee, if possible.  I am a "social drinker" of coffee, so this was not an issue for me, however, I have heard from another trial participant that dealing with caffeine withdrawal was not a pleasant experience.

Say Good-bye to Sleeping
at least for the cyclophosphamide phase. During the two days of this infusion, you are guaranteed to sleep very little. Your bladder will be treated to some protective agent whose name escapes me...  At any rate, they'll be keeping you ultra-hydrated in an effort to protect your bladder, and so you'll be awakened every two hours for a full 48-hours once the Cytoxan infusion begins. Additionally, after the chemo phase is over, nurses will continue checking on you day and night for weeks, sometimes waking you to take vital signs. The beeping and whirring infusion pumps can also be a sleep-stealer until you adapt to the noise. Consider bringing earplugs if noises bother you.

Load up your Amazon Prime account / Netflix / Etc.
  If you are traveling to NIH from far away, like I was, you may spend a lot of time alone in your room. Entertainment could save your sanity.  Set up a Skype account and test it out with friends and family before you leave for the hospital. Bring all of the cords for any devices you plan to use.

Prepare to become bald:
  bring a hat, scarf, wig, or other head covering if you aren't comfortable being seen without hair. Also: newly bald heads are chilly, I've found. One thing I wish I had brought with me was an electric shaver. The clippers left a lot of stubble, and it was painful to sleep on that stubbly scalp for the first couple of nights.

Expect to be taking a lot of pills.
  If pill-swallowing is a difficult experience for you, you might want to get some practice with it before your hospital stay.  While you're neutropenic, you'll be receiving multiple oral meds every day.  Nothing says, "Good Morning!" like a handful of pills.

Most Important:

Remember that you're in a fight for your life.  It won't be easy, but it is worth fighting for, and you've got some incredibly dedicated, caring, and skilled professionals right by your side every step of the way.

6 comments:

  1. Loved the Monty Python reference

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  2. Yes, I'm here reading and hoping for the best possible outcome from this trial.

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  3. I'm reading, I think it's amazing how far you have come! I'm still praying for you. Katie Cavnar

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  4. Hi, I'm Andrea. I've stumbled across your blog and have been reading every entry. I am cheering you on and praying with every post! God bless!

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  5. Thank you for being at the forefront of immunotherapy research akaSleen! I pray that this treatment works for you and also that it opens a path for additional CRC patients to follow! You are a very brave hero in my book! -Tom

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