Dear all,
My son is finishing his second vaccine at IOZK. His tumor is astrocytoma III, H3K27m, low methylation ( our doctor still won't give us the percentage!), clean MRI ( only 4 months since surgery)
Van Gool is against any chemo for now. He wants to do another MRI in three weeks, and he added Accutane and Keytruda this time. Our US oncologist wants to do avastin and then temodar with CCNU. Another well-esteemed Russian NO who is very open- minded ( she was the one who recommended van gool to us) thinks we should continue with temodar while on vaccine since there is a good chance it worked till now. We are very confused - tend to just trust Van gool, but scared to give up chemo even for a month. Any thoughts? thank you!
It has only been 4 months since his surgery, the fact he is doing well could be entirely attributable to the near total resection, or to resection + radiation. There's no way of knowing if TMZ has or hasn't made a difference.
ReplyDeleteA new study showed that in adult gliomas with H3 K27M mutations, MGMT methylation was very uncommon (only 1 out of 21 cases), and I'd be surprised if the same wasn't true in pediatric H3 K27M mutant glioma. I haven't seen any convincing evidence that TMZ is helpful in this tumor type, though there is a real chance it could interfere with vaccine efficacy, considering his blood counts already dropped low during the daily chemoradiation (what is his current lymphocyte count?).
Glad to hear they are adding Accutane and Keytruda, as Accutane (a retinoid similar to all-trans retinoic acid) could help prevent myeloid-derived suppressor cell (MDSC) immune suppression, and Keytruda of course can also help reverse immune suppression.
One thing you might consider would be very low dose daily TMZ (~ 20 mg twice daily) which might not affect the tumor directly, but could also selectively target immune suppressor cells (as suggested by mouse glioma models where very low dose TMZ had beneficial immune effects in combination with a vaccine, see this page for a summary of that study: http://astrocytomaoptions.com/immunotherapy/ )
This very low daily dose of TMZ was used in the following two clinical studies:
http://meetinglibrary.asco.org/content/151704-156
https://www.ncbi.nlm.nih.gov/pubmed/20446016
Thank you, Stephen!
DeleteI'd just want to say that I agree with Stephen. Temodar appears to be of very limited benefit with unmethylated tumors (with GBM, anyway), but it has the potential to interfere with vaccine efficacy. Having gone to the step of getting the vaccine, I think you would generally do best to defer to van Gool's approach in regards to other agents. I agree that a PD-1 agent and Accutane may be promising additions.
ReplyDeletethanks, Steve!
DeleteOlga-
ReplyDeleteNot to confuse you here but...
We have just started a customized "peptide vaccine" in Germany right now for our methylated 5 year old daughter with fully resected and clean MRI for 11 months (flying home tomorrow after 3rd injection). We have been consulting with Darell Bigner at Duke who referred us to the vaccine in Germany. In the course of the planning for this vaccine, Dr. Bigner referred us to his clinical colleague at Duke Gordan Vlahovic in reference to the timing of the peptide vaccine injections and the 5/23 temodar cycles she is doing via MSK in NYC. This was her recommendation that we followed regarding this issue.
Hope this helps and good luck.
_______
High dose 5-day temozolomide induces transient Grade 2 lymphopenia in 100% of adult patients and nadir/lowest lymphocyte count is usually between days 14-21. Furthermore 40% of patients develop transient Grade 3 lymphopenia. John Sampson has been able to induce and maintain potent EGFRVIII-specific immune response in patients with gbm receiving serial cycles of TMZ (Heimberger et al. Neuro Oncol. 2008;10(1):98-103) and vaccine given at the nadir point (lowest lymphocyte count – day 21 of a 5 day temo cycle). As a result in all our studies we use similar schedule which is Vac 1 on day 21+/-a day on a 5 day temozolomide cycle. Vaccines 2 and 3 are given two weeks apart from vaccine 1 and second cycle of temozolomide starts two weeks after the vaccine 3. With each consequent cycle vaccine is given on day 21 +/- a day.
Hope that this helps. Gordana
Gordana Vlahovic, MD, MHS
Associate Professor of Medicine/Oncology
Director, Brain Tumor Immunotherapy Clinical Research
The Preston Robert Tisch Brain Tumor Center at Duke
Duke University Medical Center
Rm. 047 Baker House, Trent Drive
DUMC 3624
Durham, NC 27710
Phone 919-681-4047
Fax 919-684-6674
Dear Winston,
DeleteQuite on the contrary - this is VERY helpful, thank you! This makes me feel even angrier at CHOP that offered absolutely no options/opinions . Where do you guys live? I think I remember seeing that you were from NY, but maybe I am wrong. We are in NJ> I wonder if you could e-mail me at olgaph15@hotmail.com or call 908-392-6030 since we both have pediatric issues.we are in NJ and see a doctor at CHOP, but are seriously considering switching.
Olga, we are doing metronomic schedule of TMZ (20mg BID) with NDV-vaccine just now. If we could help, contact me in any convenient time:
ReplyDeleter.hady@fasie.info, +7(909)4163456, Роман
I saw your words about "well-esteemed Russian NO". That is very interesting for me.
Thanks, Roman! Sending you an e-mail right now
DeleteSince this is the only topic on H3K27M mutations:
ReplyDeletehttps://www.sciencedaily.com/releases/2017/02/170227121258.htm
"This molecule detaches proteins, known as bromodomain proteins, from their binding to a mutant protein, the histone H3K27M, which is present in more than 80 percent of these tumors.
While the molecule itself is not yet available commercially, another similar class of molecules, BET inhibitors, is being tested in clinical trials for pediatric leukemia and other types of tumors. These could be used in a clinical trial for the pediatric tumor, Piunti said."
First time I hear about BET inhibitors, but maybe worth checking it out for this type of tumor?
Study published 2 days ago
DeleteTherapeutic targeting of polycomb and BET bromodomain
proteins in diffuse intrinsic pontine gliomas
http://www.nature.com.sci-hub.cc/nm/journal/vaop/ncurrent/full/nm.4296.html
Your son doesn't have DIPG, but H3K27M mutation...which is often seen in DIPG.
Sorry again for all the spam, it seems I cannot write everything in 1 comment :)
Although this is very interesting, no BET inhibitor has yet been approved, so the most likely way to gain access would be through a clinical trial. I've not yet seen a trial of BET inhibitors for DIPG or midline glioma, but I wouldn't be surprised to see one in the near future.
DeleteI have to keep my eyes open for this one - thank you!
DeleteThank you , Matjaz! You are right, even though he does not DIPG, it is still H3K27 mutated which is a major concern!I need to look into this, thanks!
ReplyDeleteHi, Olga! MAy i ask you also about contact of russian NO ribka2010@gmail.com
ReplyDeleteof course! I am e-mailing you right now
Delete