Dr. Liau and the dendritic cell immunotherapy trial

We met with Dr. Linda Liau to discuss her Phase 2 Dendritic Cell Immunotherapy trial. She was very personable, informative and quite knowledgeable. She was up on many related trials that were being done around the country. Besides being a researcher, she is also a neurosurgeon and is one of the top doctors at UCLA. She looked at Mark's recent mri scans and agreed that they looked fine and that the cavity was getting smaller. She gave us some information about the trial to read and a form of consent to sign.

Here's what we learned about the trial...
Mark would need to be off of temodar for 4 weeks before getting the vaccine. At this point, he would have leukaphereses, which is like giving blood, but just takes the white blood cells and returns the red. They then culture them with some cells from Mark's actual tumor to create an antigen for the tumor. It takes 8-10 days to grow what they need. Vaccine would be every 2 weeks for 3 cycles (total of 6 weeks) then he can go back on temodar. We won't know if we totally qualify for this trial until blood work done because they have to make sure that the immune system is up; however, the mri scan and karnofsky score (100) are good indications that he will qualify. We discussed whether or not to take supplements while waiting to take blood and may be opting to not take anything new before then. There is nothing we can do now until 4 week off of temodar and we will come on 4/17 to gather the blood (leukaphereses) and will have the vaccine injection on 4/26. Since we are getting blood work done already on 4/10 (along with an MRI) Dr. Liau will add on to the order some of the tests that she needs done as well. The injection takes about 10 minutes, but the appointment takes 2 hours (take blood, injection, observation to watch for reaction). The last injection would be on 5/24 and can resume temodar in June cycle.

Questions
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What does the vaccine do?
Basically, we create antigen presenting cells that migrate to the t-cells and the t-cells become activated and become "killer t cells" that are all over your body and can help fight off the tumor cells. (Similar to how your body fights a virus.) It is good to do the vaccine now since there is no regrowth and we can start prepping Mark's tcells to fight of any new bad tumor cells.
How long would treatment be? Every 3 months after initial vaccine.


When is the vaccine taken?
It is first given and then they give a boost every 3 months. With the boosts, they do it in between temodar cycles when immune system is at its best (around day 19). For the boosts they continue with temodar and vaccine together but staggered.

How long does it take to create the vaccine?
10 days from day that we draw blood, but we have to wait until the blood has started its recovery from chemo before we can start growing the vaccine.

Should we worry about regrowth during this period?
It is always a concern, we'll be in contact with Dr. Cloughsey to examine MRIs and discuss as needed.

What if there is tumor regrowth while taking the vaccine?
If MRI shows a growth, they usually recommend going back on a chemo. The vaccine is best taken before there is growth which is why we are taking it now. If there is regrowth, it depends on where it grows and what treatment options are available to remove the new tumor. If there is enough growth to require surgery, they will gather new tumor cells and create a new vaccine. If it is just a little growth, they would go back to standard of care (new chemo) and continue with vaccine. If the growth is too much and they are unable to remove it with surgery, the vaccine isn't of much help because the bad cells would be growing too fast for the killer dendritic cells to fight it.

What happens if you run out of tumor to create the vaccine?
Then we stop. The trial is typically written for a year and we usually stop the boosters at this point. We have Mark's cells in cell culture, so they can be used to create more tumor cells if needed. The fresh tumor will eventually run out, but since Dr. Martin (Mark's neurosurgeon) called Dr. Liau while Mark was in surgery, they were able to culture some of the tumor cells from the beginning so that they can continue to grow some and use if needed in the future.

Does insurance cover this?
No, but it is free and is funded by federal grants. It shouldn't cost us anything.

What kind of results have you seen so far with this trial?
75% of people receiving the vaccine have a median 2 year survival rate (could be longer, but the trial isn't that old yet) they do have a 6 year survivor from a previous trial.

Are there any statistics when regrowth is normally seen after resection surgery?
If there is regrowth, it is usually within the first 9 months, but it depends on the individual and healthy individuals (like Mark) sometimes don't see regrowth for a year. Statistics show median survival of 15 months, the goal of the vaccine is to push that out even further.

How long does it take for hair to grow back after radiation?
It depends on each individual and varies for each.

Other Trials
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We read about a DCVax to treat GBM ?
The description of this one sounds identical to what Linda Liau is doing and looks like it is the same thing. It is the same thing! There is a company that is helping to to fund this research and they had to have a fancy name to publicize it.

Dr Hassenbusch, a neuro surgeon at MD Anderson has combined standard treatment and an experimental vaccine when his WBC count is low from the radiation Every month, he takes a large dose of Temodar for five days. Then, when his white blood cell counts hit rock bottom "about 21 days" he gets the vaccine, which recharges the white blood cells. http://www.virtualtrials.com/news3.cfm?item=3437 Do you know about this?
This approach is the same as what Dr. Liau does. At about day 19 when white blood counts are low and your immune system is starting to ramp back up again (where it is at its prime in educating all of the new cells to recognize the tumor) they give the vaccine. The vaccine that they use at MD Anderson is an EGFR-related vaccine, but since Mark's tumor didn't test positive on the EGFR test with Dr. Mischel @ UCLA, he probably wouldn't respond well to this specific vaccine.

Duke is involved whereby T reg depletion is performed prior to commencing vaccine treatment. The claim is that it potentially enhances the effectiveness of the vaccine?
T regs are the population of cells that are suppressive to the immune system. Temodar suppresses all T cells (fighters and suppressors). This trial tries to just suppress the suppressors tcells more than the non-suppressor cells so that there are more fighter cells out there to fight the tumor. This study has mainly only been done in animals, not available for sanctioned humans trials yet.

Duke does have a similar vaccine treatment to Dr. Liau, but the trial is now closed. Dr. John Samson is the main guy doing the similar trials.

There is a vaccine from Pittsburgh Cancer Institute that doesn't rely on tissue from tumor. Based on approach in which antigen peptides are synthesized and ready to use when needed. Once synthesized, vaccine introduced to glioma cells. Based on 4 different tumor antigens commonly found in glioma tumors. What do you know about this?
There is a trial similar to this being done at UCLA, but it hasn't yet started clinical trials. The limitation is that you have to be of a certain HLA type. Your white cells have a type too (similar to red blood type) in order for a tcell to match an antigen, you have to have a certain type of receptor. These peptides have to match one of these types to be recognized by the dendritic cells in order for it to do its job to activate a tcell to fight the tumor. UCLA does something similar when they don't have any live tumor. When using these peptides, you can only synthesize them a certain way and they have to be just right in order for them to do the job. This HLA will be tested on Mark's tumor and we'll find out on our next appointment when we give the blood. If he has the right HLA type, it is possible that he may qualify for a trial like this in the future; however, it is better that we use the actual tumor cells when we can.

Side Note
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Dr. Liau is going to be on TV on a show called "Miracle Workers"m April 10th on channel 7 at 10pm. She has also been on Dateline twice. Dr. Black used to be at UCLA and was involved in the same research and now he does exactly the same thing over at Cedar Sinai.

What's Next
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03/19/06 - last day of Temodar (round 2)
03/31/06 - Brain Tumor Conference @ UCLA (all day fri/sat)
04/04/06 - blood work
04/10/06 - MRI, blood work & meeting with Dr. Cloughsey
04/17/06 - leukaphereses
04/26/06 - 1st injection of dendritic cell vaccine

first MRI after standard treatment

We met up with the doctors at UCLA to go over Mark's first MRI after completing standard radiation/chemo therapy.

Recap: Missed 6 out of 42 doses of temodar during radiation because of low nutrophyl counts. Everything has been going great. Currently off of dilantin, and on 2000mg of kepra as anti-seizure medication. Did have a small seizure (10 minutes) about a week ago, but was low on the dosage of kepra at the time. No headaches. Has been biking and doing well. Did the normal neurologic tests and did fine. No visual problems.

What are the results of today's MRI?
In the axial cuts, it looks like the blood in the cavity is now gone. Just see a thin rim of contrast, but no dense cottony areas, which means it looks pretty good. There is one area that looks a little questionable at the top, but probably how cavity chose to shrink down. The cavity is shrinking. In the coronal view, there is an area that shows the same difference, but it looks like an artifact from the shrinkage of the tissue, but definitely needs watched. Wants to check again with an MRI in a month. Overall we're happy with the scan. Rest of cavity looks clean and good, everything is dramatically decreased (size of cavity, blood residue, swelling, etc.) Mark also described how he felt that his motor skills were getting back to normal.

I read that there are some imaging features that can correlate to the survival of GBM patients? For example, it stated that there was a survival advantage of brain tumor patients showing nCET on contrast enhancing MR scans? Mark did have some nCET on original tumor scans which may indicate a better survival rate. Not proven, but it is currently in a study and gives us some hope :)

Will be starting back on Temodar at a higher dosage. Will be watching to see how sensitive Mark is to it and will be getting blood tests to watch counts. What if counts go down, would we take some sort of boosting drug? No, don't like to boost wbc counts during chemo. For this round, we will start at a 75% dose (300mg) a day and will check reaction, if blood counts ok, will go to 400mg but no higher than that. Will take in evenings with kytril 5 days out of the month and were given a calendar to track it.

How often should blood tests be taken now? We will take one today and then will take on day 21 and day 28.

Will we need to start up bactrim again? Depends on if lymphocyte count is 600 or lower. Can tell by blood tests.

We had the EGFRvIII and PTEN test finally done on Mark's tumor.
We reviewed these slides.
PTEN: mostly intact (2), but focal area is slightly deficient (1).
vIII: weakly positive (1)
These results of the pten and vIII are not what was considered as meeting the criteria for use of tarceva.
Does this give any indications to avoid anything else? No, this is only a test for tarceva.

Last time we talked about Verinostat (saha) that is a current trial about to open at UCLA that is done in combination with temodar which is a phase 1 study, so we don't know if it leads to strong drop in blood count or what the other side fx are that can be associated with it. Gets evaluated every month. Would we be eliminated if we do dendritic cell therapy? You could not be involved in both trials at the same time and would have to do this trial after dendritic cell therapy. This is a phase 1 study (not open at the moment) that is looking at toxicity of verinostat. If we do this, we can't also do the dendritic cell (phase 2) study, for now, we are choosing the dendritic cell trial.

Last time, you all mentioned that with GBMs, the blood brain barrier is already disrupted. Is this common knowledge? Why do others say it is difficult to get past the blood brain barrier? You can tell if the blood barrier is disrupted just because of the fact that the contrasting fluid can get into the tumor to show up on an MRI. Still need agents to help get drugs past the barrier in other areas of the brain. The tumor does cause a local compromise in the blood-brain barrier.

Questions about recent Trials that we've found -

Have you heard about phase 2 trial at MD Anderson that tests temozolomide alone or in combo with thalidomide and/or Isotretinoin (accutane) and/or Celecoxib (celebrex)for patients that have had radiation in past 5 weeks? UCLA used to give all patients temodar and accutane together, but shown not to be too effective and had lots of sidefx (dry skin, etc) so they no longer do this, we're waiting to see more data about celebrex being effective before committing to use it, thalidomide has a side effect of being too fatigued at the dosage that needs to be given and disrupts quality of life issues so we don't use this drug now either.

I found a trial that used DCVax to treat GBM - The description of this one sounds identical to what Linda Liau is doing and looks like it is the same thing. Her trial is being done at several centers around the country.

Poly ICLC - UCLA had done this one in the past, but not doing it anymore (not open right now)

I read about a UCLA phase 3 trial with Enzastaurin? This one is on its way, but it is for recurrent tumors.

We will be involved in a UCLA research study that compiles medical information, mris, lab tests, pathology information etc. from many current brain tumor patients. The study is designed to compare this information with others with same tumor types to try and find similarities in treatments that are working for specific tumor type or any other useful statistics. It is an anonymous study. Can choose to withdraw from study if desired.

Coming up:
Will be taking chemo 3/15- 3-19
Meeting with Dr. Liau to discuss dendritic cell immunotherapy on 3/22 @ 3:30pm
Will get two blood tests in the next 4 weeks.
Will be scheduling an MRI in 4 weeks.