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ASCO Reading Room | Addition of a Personalized Vaccine to Standard Therapy in Glioblastoma

 

Right to Try (for U.S. patients/advocates)

Hi guys,

I'm wondering if anyone here has pursued the Right to Try law here in the United States? Searching the blog, I couldn't find anything...

My brother is living in Texas where the law has been passed and I've obtained the document provided by the organization website to present to his doctors. (The document is linked here under "How do I initiate a request?" or here is a Google Doc version I uploaded which is the exact same)

James would like to try DCVax-L, if possible.

In order to produce the DCVax-L vaccine, you need to supply fresh or preserved tumor tissue. I've contacted the drug company, Northwest Biotherapeutics https://www.nwbio.com/) and was told:

"In order to manufacture DCVax-L, we usually require 2-3 grams of frozen tumor tissue, although we have worked with less in certain circumstances.  The tissue must be stored frozen without any chemicals or preservatives and not in saline or blocks of paraffin."

I've confirmed that the tissue from his previous resection has now been transferred to paraffin so is unusable.

James's doctors have already said another resection is not advisable due to the location of his tumor progression. However, assuming we could get a biopsy to have some fresh tissue, I'm wondering if this would be a block for his doctors to go ahead and pursue the Right to Try submission to the drug company.

Would they be likely to submit the document and start the legal process if we don't even have the tissue?

It would seem foolish to do a biopsy if we weren't for sure going to be a candidate for the vaccine.

(Again, I'm unsure if a biopsy is possible at the moment but should find out this week.)

Additionally, I requested more information from NWBio about the Right to Try law and she didn't address it with detail, but just assured me that without tissue, nothing could be done.

Does anyone here have experience with kickstarting this Right to Try process? Any tips or advice would be much appreciated.

Link to my first post outlining James's current condition for context.

DCVax Update

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6

Mike B

DCVax-L presentation at ASCO 2017, June 5

The most recent public information on the phase 3 DCVax-L trial was given in the form of a presentation with slides by Dr. Marnix Bosch, chief technical officer of Northwest Biotherapeutics, during the recent ASCO conference in June. The presentation covers both DCVax-L and DCVax-Direct.

The DCVax-L (phase 3 trial) part of the talk is from approximately minute 6 to minute 25.  The most interesting part where new information is presented is from approximately minute 17 to 25.  The remainder of the presentation is devoted to DCVax-Direct.

Watch the video here:
https://www.nwbio.com/dcvax-novel-personalized-immune-therapies-solid-tumors/

Here are some slides from the talk:

We can assume based on this presentation that the threshold for the overall survival analysis to begin has now been reached and is likely underway.  He mentioned that a publication of the preliminary data is in preparation.

The only survival data publicized so far is for the patients who were excluded from the trial due to early progression and were given DCVax on a Compassionate Use protocol, aka the "informational arm".  In the "indeterminate" subgroup of 25 patients within this informational arm who had early evidence of progression followed by a period of stability, 40% have made it to nearly 3 years or more, and 24% have made it to 4 years.

24% surviving at 4 years compares very favorably with the control arm (receiving standard of care) of the recent phase 3 Optune trial, which had 10% surviving at 4 years, and the study arm (standard of care + Optune) of that trial had 4 year survival rate of 17%. 

It would be reasonable to expect survival outcomes in the phase 3 trial to be better than those from the indeterminate group of the "informational arm" given that the latter group was excluded from the trial for at least some form of evidence of early progression, while patients included in the trial had no evidence of progression.

The next step to improve outcomes further is now being taken by UCLA, where a phase 2 trial is slated to open soon combining DCVax-L with nivolumab (anti PD-1), although this trial is for recurrent, rather than newly diagnosed GBM.
https://clinicaltrials.gov/ct2/show/NCT03014804

ERC1671 + avastin

Hi everyone, it's been awhile since I've been on here.  My husband was diagnosed 6/2016 and we are close to hitting that one year mark.  We were looking forward to it as my husband had been getting weekly infusions of MRZ (marizomib-clinical trial) for 3 weeks out of the month and it was  taking a toll on his arms/veins and he could have used a much needed break.  Unfortunately, after monthly MRI's since December, NO suggested surgery as the spot they had been tracking had doubled since the last MRI and was ~14mm.

Up to now, my husband has been doing great and people often comment on how they can't even tell that he is battling brain cancer.  The only issues he had was headaches (which never really stopped) and fatigue.  However, he still continued to work every day and come home to help me with the kids. He even got discharged from hospital after 2 days and looks great!

The pathology report came back and we were hoping that the abnormality was just necrosis, but it's now confirmed that it's indeed recurrence.  I guess the bright side is is that he can now do immunotherapy.  I was wanting him to enter the dcvax clinical trial, but apparently it's closed.  The only thing available for him at his treatment center (uc irvine) is ERC1671 in combination of avastin. Has anyone had any experience with this or can offer any feedback??  Thank you!

On Avastin/TMZ, but looking to future - Abemaciclib potential or DCVax-L/nivolumab therapy

Hi all,

My Dad's story/timeline/cocktail can be seen here:
http://btcocktails.blogspot.com/2017/02/tom-wangerin-cocktail-profile-and.html

He is MGMT methylated, not IDH1 mutated, positive for 1p Deletion, and after recently receiving our genetic testing Foundation One report back (which was completely covered by our insurance!!) shows a "CDKN2A/B loss" - which leads me to my next few topics

• We completed standard chemo-radiation in January 2017 (radiation caused inflammation that has us struggling to get him lower than 4mg/day decadron).

• Has finished (3) rounds of TMZ since.
• His latest Image (March 2017) showed increased inflammation to the point where our NO at UCSF could not really see much, but it was clear the TMZ was not decreasing the tumor size.

• A week ago on April 4th 2017 - My dad received his first Avastin infusion. The thought here is to use the Avastin in short term bursts to not only help with inflammation (lowering decadron dosage), but also clearing up the image for the NO to make a better gameplan moving forward. I want to make sure we are not going to stay on Avastin long enough for the tumor to find new pathways (become "immune") as you see happens so often. Any thoughts on this stradegy?

• Our next image/consultation at UCSF is in a week (4/17/17) to see whether the Avastin infusion made a difference.

Moving Forward

Option 1 - Is anyone familiar with Abemaciclib? I haven't seen any posts on here about this CDK4/CDK6 inhibitor. I bring this up because our NO was surprised to see our Foundation One report mention his "CDKN2A/B loss". He immediately mentioned Abemaciclib and is looking at potential trials or best case getting it off-label in some way or another.

This drug seems to be used more often in breast cancer, but has not shown any spectacular results as far as I can find. Any thoughts?

Option 2 - DCVax-L/nivolumab therapy - Until the last time we met with our NO this was by far our most exciting find. This Phase II trial is soon to be recruiting out of UCLA 

(https://clinicaltrials.gov/ct2/show/NCT03014804?term=immunotherapy+OR+dendritic&cond=glioblastoma+recurrent&state1=NA%3AUS%3ACA&state2=NA%3AUS%3AWA&state3=NA%3AUS%3AOR&rank=1)

DCVax has been spoken about on this forum and appears to be showing better results (and more overall information out there than Abemaciclib). Here are the scary parts of the trial:

• Our NO has said that he has been finding an overwhelming amount of his patients have serious side effect issues with Nivolumab (inflammation being one of them) and he has seen many end there usage. I did find this odd because many on this forum have spoken about it without the negative connotation.
• To be included in this trial my Dad must get below 2mg/day of steroid use, which I'm worried might not be possible. 
• He would need to have a recurrence and it would need to be operable which is scary in itself.... meaning all the stars will need to align for us to get accepted.

Let me know if the community out there has any opinions of our potential options and usage of Avastin.

Thank you all for reading and contributing. 

Ari Wangerin

(Oakland, California)

DCvax-l info for phase 1/2 low grade glioma

Does anyone know the status of these studies? Has any information been released at all? Also, word of a phase 3?

Thank you.

From Musella's website: Immunotherapies for GBM: Tumor Vaccines by Linda Liau, M.D., Ph.D., M.B.A.

Immunotherapies for GBM: Tumor Vaccines by Linda Liau, M.D., Ph.D., M.B.A.         This is a video about the DCVax trial, given by one of my all time favorite brain tumor doctors, Dr. Liau.  This looks very promising. We are hoping to hear the results of the big phase 3 trial soon.  In the earlier trials and in the early progressors which were excluded from this trial but were followed as they took the vaccine,  about 25% of the patients went on to be long term survivors, with many alive and progression free 5-10 years later.  That is unheard of with the standard treatments. Some other immunotherapies have also reported similiar results (although not as long follow up).    We are hoping this large phase 3 trial shows something close to that so it can be approved quickly and all patients can benefit from it.  Best of all it had no serious side effects. Dr. Liau is on the Musella Foundation Medical Advisory Board.  The Musella Foundation has supported Dr Liau's immunotherapy research with $375,000 in grants and we have never received any financial  support from the company developing this treatment, Northwest Biotherapeutics.

Interesting Speech and Presentation

Dr. Linda Liau - Immunotherapy of Glioblastoma.  Very interesting and worthwhile for GBM patients to view in my opinion.

https://www.youtube.com/watch?v=N7lqTt3NIzc

DCVax

Dear friends,
If the DCVax is available at presentation, would this be a favoured option (in addition to standard chemoradiotherapy).  Some are suggesting waiting until relapse, though I don't see the point of waiting.
Thanks for your thoughts
Matthew.

Cancer compass review - PD-1 inhibitors

The following is what was said on the Cancer Compass cocktail thread about PD-1 inhibitors:

page 128:
A: "He mentioned Nivolumab, a PD-1 inhibitor, and essentially said that it would be possible to pay for it out of pocket. My girlfriend doesn't weigh much at this point, and he said paying for 3 administrations of the drug would probably be about $12,000 total. He said that, if he were choosing between Rindopepimut and Nivolumab, he would go for the Nivolumab."


A: "The Nivolumab idea has the potential to be a pretty effective addition at a rather reasonable cost (at least I consider 12k to be reasonable after getting quotes of 150k from the likes of DCVax and such). I'm going to be looking into it a lot now.

He essentially said that he was at a meeting where they were discussing very preliminary results of a study testing a PD-1 inhibitor vs. avastin in recurrent tumors. They were talking about how they were able to radiographically see increased inflammation from an immune response after the administration of a PD-1 inhibitor in a subset of the patients. This included some stable tumors and one that showed some regression."

SW: "I came across an interesting study showing that response to PD-1 inhibitors is correlated with mutational load. The study shows a graph which correlates response rate in various types of cancers to the median frequency of somatic mutations in those types of cancers. For example, melanoma has the highest response rate to PD-1 inhibitors, and also has the highest median number of somatic mutations.

Hypermutated tumors may have a better chance of response to these drugs, at least as single agents. Recurrent tumors previously treated with single agent TMZ are more likely to be hypermutated upon recurrence, but the only way to know if a tumor is hypermutated is with comprehensive genetic testing like FoundationOne. If there are a large number of mutations, plus a mutation in a DNA mismatch repair gene like MSH6, that would suggest a hypermutated tumor.

This is not to say that only hypermutated tumors would benefit from PD-1 inhibitors or CTLA-4 inhibitors, just that they might especially benefit.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937193/

In most cases newly diagnosed tumors won't be hypermutated. Mutations in mismatch repair genes (like MSH6) can be a resistance mechanism following single agent TMZ."

page 134:

A: "I've been doing some research, and some of the upcoming trials are combining Nivolumab with Ipilimumab (Opdivo and Yervoy). This is a PD-1 inhibitor combined with a CTLA-4 inhibitor. The toxicity seems rather large, with something like 50% of patients experiencing grades 3 and 4 adverse events. In melanoma, however, this combination has been very effective.

In mouse studies with glioblastoma, the results of combination PD-1 and CTLA-4 inhibition seems very promising.

What are your thoughts on this combination following 6 adjuvant chemo cycles? In theory, residual tumor burden would be low, and the cells that survived initial treatment might already be expressing a larger number of mutations.

Our NO is the one that initially suggested Nivolumab, which has a lower toxicity profile than Ipilimumab, so I'm not sure that he would even go for the combination. I've priced out 4 doses of the combination, which would be about $44,000. 4 doses of Nivolumab alone would be $16,000."

DS: "Dr. Conrad at MD Anderson (though he recently left MDA) told us that the Nivolumab with Ipilimumab trial had dropped the ipilimumab because it was too toxic and he signed my son up for the Nivolumab alone -- all the ipilimumab portions of the trial documentation were stricken through. We opted not to do the trial as it turned out."

A: "Thank you for that information! I'm surprised they dropped it, as they are combining the two for the treatment of advanced melanoma, and showing a lot of success.

They do note that the toxicity profile is high, but I wonder why they are OK with treating melanoma patients with that protocol and not GBM patients. I now see that the trial is being offered at UVA, so I'm guessing that is how our NO was able to hear preliminary information about some responses."

M: "from what i could determine about the nivo/ipi trial for gbm versus melanoma is this; the mechanism of action causes swelling. greater tumor burden correlates to greater swelling. there is no room for swelling in the brain as opposed to other organs of the body. melanoma patients may tolerate swelling whereas gbm patients would have to go on massive doses of steroids (which might not even help) and that would negate the workings of the immunotherapy."



Download the poster from the 2015 ASCO conference showing the first preliminary results of GBM patients treated with nivolumab alone or nivolumab plus ipilimumab (Yervoy).  Download here.

Surgery.. what to do

Dad got a 3rd opinion on surgery today.  First two surgeons said no.  Surgery is however an option with Dr. Silbergeld at UW (Seattle) but requires that Dad be awake, and that he name items on a powerpoint during the procedure.  Dad was at about 61% ability to name the objects in our EGG yesterday and the cutoff for the Dr. to schedule the procedure is 60%.  This is not an obvious - yes, you should proceed with surgery decision.  There is risk involved.  There are three spots where tumor is present in his brain and this was the only section that was deemed operable, but again is in the speech part of his brain.  It is possible to make it worse, or to get in there, find that dad can't communicate well enough, and have to shut the whole thing down without any tumor resected.  Does anyone have experience with surgery in this area of the brain or with Dr. Silbergeld?  Dr. Berger is booked through the end of October and I don't believe we can wait that long.  BTW we had stopped Celebrex, Aspirin and Fish Oil in anticipation of a possible surgery.