(AVASTIN+CCNU) + Nivolumab after standard chemoradiotherapy?

Hello!

I, like many of you, need optimal treatment for my mother.
My mother has glioblastoma (MGMT methylated). She just finished the standard course of radiotherapy + TMZ. At the moment I'm looking for how to be treated more effectively.

Our doctor advises adding 8 courses of Nivolumab together with AVASTIN + CCNU.
He says that with such a combination, the probability of a complete cure is 30%.
Also, with such a combination, the doctor suggests not using TMZ.
All this seems to me very doubtful!

What would you suggest?

With respect to all and best wishes, Semyon

Immunotherapy and cannabis

Hi,

Does anyone have information on concurrent use of immunotherapy and cannabis? I read that cannabis can have anti-inflammatory effects primarily due to it suppressing the immune system. This seems worrisome if the patient is on immunotherapy. All I could find is one retrospective study on cannabis and opdivo use: http://oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/The-effect-of-cannabis-use-on-tumor-response-to-Nivolumab-in-patients-with-advanced-malignancies

Has anyone's doctor mentioned a possible contraindication?

Thank you.

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

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)

Nivolumab Opdivo infusion and increased seizures?

I was going to ask a question in this post but decided to start a new one instead.

Here's our latest situation:

• My wife has been on Optune for the past seven months, averaging about 69% monthly compliance (two months were 0, the rest were above 85%).
• We started nivo 11 weeks ago.
• Prior to starting her first infusion, there was a new growth, which prompted the nivo in the first place.
• After the third infusion, there was a second new growth.
• My wife just had her fifth nivo infusion this past Monday, March 27th.
• Today, Wednesday, March 28th, she had two light focal seizures - she was conscious the entire time.
• Note that we are not on Avastin nor or Dexa as she doesn't have enough edema to warrant it; at least according to her last two MRIs.

My question:

Are increased seizures a common occurrence when using nivo?

I've not been able to find anything very compelling on the topic.

(Arabinoxylan) Rice Bran improves natural killer white cell activity

Came across this, which is an lengthy advertisement but well cited about how enzymatically modified rice bran (EMRB)/Arabinoxylan substantially increases the cytotoxicity of natural killer white cells.

http://www.lifeextension.com/magazine/2015/1/activate-your-natural-killer-cells/page-01

Here's the NCBI abstract:
https://www.ncbi.nlm.nih.gov/pubmed/25541298

My question is this: If someone is taking a PD-1 inhibitor, would it make sense to also supplement with this or is it akin to putting gas on a fire?

Thoughts?

Agenus vaccine (HSPPC-96) plus pembrolizumab (Keytruda) for new GBM

We've just heard that UCLA will be starting a trial combining DCVax with nivolumab.

NCT03014804   (disregard the references to a "lung tumor" vaccine.  This is a GBM trial and those references were a mistake which should be fixed soon.

Another trial will soon be opening for newly diagnosed GBM testing the Agenus Prophage vaccine (HSPPC-96) in combination with pembrolizumab.  This is a randomized phase 2 trial and unfortunately one arm will be treated with standard of care + pembrolizumab + placebo, while the other arm gets standard + pembrolizumab + vaccine.

Another trial of HSPPC-96 for newly diagnosed GBM reported some results at ASCO 2015.  Patients with high PD-L1 expression had median survival of 18 months, while patients with low PD-L1 expression had an amazing median survival of 44.7 months.  There is thus very good rationale to combine this vaccine with a PD-1 inhibitor such as pembrolizumab.

NCT03018288

Long-term control and partial remission after initial pseudoprogression of glioblastoma by anti–PD-1 treatment with nivolumab

That is the name of a letter published online yesterday in Neuro-Oncology journal.  Click on link to the partial extract here.

I'll be uploading the full one-page letter to the Library.  Immunotherapy folder, Immune checkpoint inhibitors subfolder.

Anecdotal report on PD-1 treatment with nivolumab/Opdivo -- brain edema

On another thread on this blog, the topic came up of PD-1 agents causing brain edema (on the Gamma Delta T-cell thread).  As it wasn't directly applicable to that thread, I thought a new thread might be useful, for the consideration by others who might be considering anti-PD-1 agents (in this case, nivolumab/Opdivo).  Stephen W and I have been unable to find much published information on the incidence of brain edema with such agents, so I'm here publishing an individual experience that might be useful to others.

On my wife's research protocol, nivolumab was started simultaneously with the initial radiation Tx (so, standard /Stupp protocol+experimental nivolumab).  This might make sense in theory, but it made it difficult to distinguish whether her neurologic symptoms were from the PD-1 agent or the radiation.

Over the six-week period of radiation (daily M-F) she had very gradual worsening of neurologic function.  Since there didn't seem to be any obvious exacerbations around the time of her infustions (every 2 weeks), I attributed the changes to the radiation, and presumed she was more sensitive to radiation effects than most.  In retrospect, I was wrong, and the deterioration in function was mostly from brain edema from nivolumab.

The tumor was in the left parietal lobe, close enough to the speech center to cause some language difficulty at initial presentation.  The radiation Tx was "IMRT" meaning heavier radiation near the tumor bed than elsewhere, though no part of her brain was totally free from radiation.  She lost hair over about 60 percent of her scalp, more than I expected.

She developed a gradually worsening R visual field defect, and gradually developed R-sided neglect.  Also, gradually progressive unstable gait, and gradually worsening short-term memory, gradually worsening word-finding, gradually worsening confusion.  The overall picture was similar to early- to mid-course Alzheimer's.

The first post-tx MRI was a month after conclusion of radiation (with Opdivo infusions continuing every 2 weeks).  I was becoming alarmed that she didn't seem to be bouncing back after radiation stopped.
The MRI showed *severe* brain edema, all on the left side (tumor side).  There was uncal herniation, the kind of thing you might see shortly after severe head trauma.  The NO seemed shocked that she could still walk and talk and do reasonably well on a cursory neurologic exam.

A couple of infusions were skipped, and most of her symptoms gradualy improved.  However, focal motor seizures didn't improve.  These were very subtle in the first few weeks, but have become more obvious over time and required increasing Vimpat doses to control.

After skipping a couple of infusions in light of brain edema, she got more opdivo about a week or so ago, and all those symptoms got worse again after about 48 hours post-infusion.  MRI then showed edema similar to to the last MRI, but I'm quite sure edema had improved then worsened again.

So we're out of the study.

Trying to interpret the pattern of edema (all L-sided) is challenging.  It's possible the edema is from nivolumab doing it's job, killing off glioma cells in the left-side of the brain that hasn't showed up on any MRI.  But I don't think so.  I suspect she's having an auto-immune generalized brain effect, and that the edema is all L-sided because the radiation mostly impaired the blood-brain barrier throughout the left brain, allowing higher levels of the nivolumab antibody in all the tissues of the L brain.  It's impossible to know for sure, though.

Possibly, in retrospect, a lesson here might be that nivolumab should be started after the conclusion of radiation, and not concurrently.  Possibly a dose lower then 3mg/kq q 2 weeks would be better.  Nobody will know for sure until there's a lot more research and experience.

For the time being, there's no definite residual tumor tissue at all.  Realistically, she's rather likely to have recurrence at some point in the future.  So we're scoping out other clinical trials to pursue if/when that happens.

At the moment, we're interested in:
https://clinicaltrials.gov/ct2/show/NCT01454596
"CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII"

This is, in part, because NIH/NCI is close to us in Maryland.  We're not yet sure her tumor does express EGFR, but we're pursuing that question.  We're also looking for other promising trials applicable to first recurrence after experimental nivolumab tx, even if geographically distant.  Suggestions welcome.  With any luck, we may have a lot of time before we need to enroll in another study.  Extensive cocktail continues.

Best wishes to the whole community,

Steve
stevemdfp at gmail dot com.

DC vaccine plus PD-1 antibody in GL261 mouse model

A nod to the anonymous commenter who posted a link to this study in the Dendritic Cell Therapy?thread.  This study is the subject matter for my latest update on Astrocytoma Options.

http://astrocytomaoptions.com/immunotherapy/

PD-1 ANTIBODIES (NIVOLUMAB AND PEMBROLIZUMAB)

Late in 2014, the FDA approved two novel drugs for metastatic melanoma. These two drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo) are both antibodies against PD-1, an immune checkpoint found on the surface of immune cells, that leads to anergy (deactivation) or death of immune effector cells when in contact with PD-L1 (ligand for PD-1) expressed on other cells. Though the PD-1/PD-L1 immune checkpoint system evolved as an important means to prevent autoimmunity conditions, the system is clearly co-opted by tumors to escape targeting by host immune cells. As of this writing in July 2016, there are no less than 13 trials currently recruiting glioblastoma patients for therapy involving nivolumab or pembrolizumab, and one trial testing a novel PD-L1 antibody (MEDI4736). The first trial for high grade gliomas to combine a dendritic cell vaccine with a PD-1 antibody is the AVERT trial at Duke University, which opened in early 2016 (NCT02529072). A second trial called CAPTIVE, opened in June 2016, combines the DNX-2401 adenovirus with pembrolizumab (NCT02798406). These two trials are likely the leading edge of the future of immunotherapy: combination of vaccine or oncolytic virotherapy with immune checkpoint blockade.

Preclinical evidence supporting this combination in high grade glioma comes in the form of a study published online in July 2016, by a team of UCLA researchers [1]. In this study, mice were treated with subcutaneous injections of a lysate-pulsed dendritic cell vaccine prepared from murine progenitor bone marrow cells and GL261 mouse glioma cell lysate. Mice were treated with vaccines at either the first day of intracranial GL261 glioma implantation, or at day 3 after tumors were established. Dendritic cell (DC) vaccination significantly increased survival times only in the group receiving early vaccination. In contrast, no prolongation of survival was seen in mice receiving later vaccination, in spite of tumor infiltration by glioma-reactive CD3+ lymphocytes in these mice.

PD-1 was increased on tumor-infiltrating lymphocytes in both untreated and DC vaccinated mice compared to splenic lymphocytes, indicating a localized immunosuppression in the tumor environment. Following DC vaccination, PD-1 was the only marker of immune inhibition increased in the tumor-infiltrating lymphocyte population. All other markers examined, including CTLA-4 (target of the drug ipilimumab) and TGF-beta, were downregulated following vaccination.

These observations led the researchers to treat mice with established gliomas with the combination of DC vaccination plus PD-1 monoclonal antibody (similar in function to the FDA-approved antibodies nivolumab and pembrolizumab). Remarkably, while no survival benefit was observed in mice treated with either vaccine or PD-1 antibody alone, 40% of mice treated with the combination survived at least to day 60 (none of the mice in the other arms survived to day 40).

The survival benefit of the combined therapy was found to be completely dependent on CD8+ cytotoxic T-lymphocytes, as depletion of these cells in the mice wiped out any benefit of treatment. Though mice in both DC vaccine treated, and DC vaccine plus PD-1 antibody treated groups had increased infiltration of CD8+ lymphocytes into their tumors, only combination treated mice had increased proportions of activated CD8+ CD25+ T-cells, showing that PD-1 antibody in addition to DC vaccine was necessary to maintain an activated population of CD8+ T-cells in the tumor environment.

Combination treatment also increased populations of tumor-infiltrating memory T-cells, and when surviving mice from the combination treatment group were re-challenged with a second injection of GL261 glioma cells in the contralateral brain hemisphere at day 60, they again survived significantly longer than untreated controls, though they had no additional treatments beyond the initial treatment at the time of the first tumor cell injections.

GBM samples taken from clinical trial patients before and after treatment with DC vaccines at UCLA showed both abundant expression of PD-L1 (the ligand for PD-1) in the tumor environment, as well as increased PD-1 expression on CD8+ tumor-infiltrating lymphocytes following dendritic cell vaccination. This demonstrates that, as seen in mice, PD-1 expression is a mechanism of immunosuppression following DC vaccination in human patients, a means of tumor resistance to the treatment.

Ex vivo, tumor-infiltrating lymphocytes taken from GBM patients undergoing resection showed greatly increased cytotoxicity against tumor cells when PD-1 antibody was added to the co-culture.

Significance: this study clearly shows that tumor lysate-pulsed dendritic cell vaccination is not sufficient to increase survival in mice with established gliomas, and that additional reversal of local immunosuppression with PD-1 antibody is also required. Human GBM tissue showed the same increase in PD-1 expression following dendritic cell vaccination, as a means of tumor resistance to treatment. Pending demonstration of the safety of combining dendritic cell vaccinations with PD-1 antibodies in current trials for high grade glioma, future vaccine trials should logically include such antibodies (eg. nivolumab or pembrolizumab), especially for patients with significant residual tumor post-resection. This combination treatment is likely necessary to bring the benefits of anti-tumor vaccines to a patient population that otherwise might not significantly benefit – those with significant residual tumor burden.

1. PD-1 blockade enhances the vaccination-induced immune response in glioma. Antonios et al. 2016.
   READ SOURCE DOCUMENT

Nivo dosing

I am curious if anyone that is using Nivo (Opdivo) is on a different schedule than every two weeks.  My son is using Nivo outside of a clinical trial and is scheduled for infusion every two weeks at 240 mg for 4 months, then 480 mg monthly thereafter.  His NO said this is the way Nivo is now being used in clinical trials.  I have not heard of anyone else on this dosing schedule.

Introduction and introductory thoughts

Call me Steve C.  I trained and practiced as a family physician.  Subsequently ended up in administrative work; I don't practice now.  But I've read more research articles about clinical topics than most family docs.

In early May, my wife had a stroke-like episode and was diagnosed with a 4 cm brain tumor, left parietal lobe.  Grade IV glioma = glioblastoma.  Full excision with clinically excellent post-op status, care at Johns Hopkins (to be highly recommended).

She's on the standard Stupp protocol.  However, we were fortunate enough to get into a trial with nivolumab (Opdivo).

The Opdivo is a bit of an immune shotgun approach.  It is a "checkpoint inhibitor," or PD-1 inhibitor.  It tones down some of the body's (including tumor's) ability to avoid being attacked by the immune system.  The main side effects are thus from the immune system attacking tissues other than the tumor.  That may sound like a shot in the dark for killing tumor cells, but some tumors are fairly susceptible to being attacked by the immune system.  Melanoma, for example, is especially "antigenic," and susceptible to being attacked.  An agent very much like Opdivo eliminated Jimmy Carter's metastatic melanoma.  

I recall sadness on hearing about Jimmy Carter's diagnosis of metastatic melanoma.  I was confident that the next news to be heard was to be of his passing away.  I was floored when the next news instead was that he was cancer-free, because of an Opdivo-like treatment.  I knew then that we've entered a whole new era of cancer treatment.

Glioblastoma isn't quite as antigenic as melanoma, but our oncologist tells us that it's more antigenic than most other tumors.  Opdivo may make a huge difference.

Opdivo is an antibody.  She got the first dose (236 mg) by IV yesterday, with no side effects.  She's scheduled to get another dose every 2 weeks *indefinitely*.  Levels should build up steadily over several months (antibodies have a very long lifespan, months, in the bloodstream).  We met another patient on indefinite Opdivo, who looked great and has had no side effects.  We're hopeful.

I've been reading lots and lots of "preclinical" research reports.  An interesting recurrent theme is that many different agents with modest anti-glioma effects in animals seem to have additive effects with other agents against the tumor cells.  This is seen also in the 60 Minutes report, where polio-treated tumors became extremely sensitive to ordinary chemotherapy.

We conclude that an optimum approach would include a wide range of additive adjunctive strategies, to include diet (ketogenic), exercise, mental health, and cautious use of some supplements--those with a reasonably solid base of research to show some evidence of benefit.
Thus, we're still pursing DIY adjunctive approaches.  Among the more promising non-toxic options includes:
http://www.ncbi.nlm.nih.gov/pubmed/27298767
http://www.ncbi.nlm.nih.gov/pubmed/26637846
http://www.ncbi.nlm.nih.gov/pubmed/10902853

I find Pubmed to be an invaluable resource to help sift through promising avenues and avoiding all the snake oil nostrums and charlatanry that dominate the realm of alternatives for cancer treatment.
It's frustrating that we can't rely on the oncologists' assistance with this.  Physicians, especially oncologists, really can't ethically endorse unproven treatments, and so few potential treatments have been adequately studied in humans.  We''ll offer them the opportunity to veto anything they think is hazardous, but we can't expect them to encourage anything.  It was really striking when when we asked their opinion of medical marijuana, whether for symptom relief or for the laboratory-demonstrated anti-tumor effects, and the response was "we have no opinion on medical marijuana."  It's frustrating, but I do respect them for their strict ethical standards here.  I have no doubt that, were they to sit on the other side of the consultation desk, they'd personally be using a range of such agents.

Ipilimumab with Opdivo

Hi All,

Anyone here has had experience with Ipilimumab ( Yervoy) along with Nivolumab ( Opdivo)? I know the earlier study showed severe toxicity but I heard that later on, when the yervoy dose was reduced from 3mg/kg to 1mg/kg, the safety profile became much better and the combination became much better tolerated. Stephen, Any thought on efficacy or on whether it is worth trying in GBM? Many thanks for the help.
Noha

Nivolumab/ Opdivo

Hi everyone,
There's quite a bit of talk on the Inspire forum about Nivolumab. There are trials happening & there are also patients accessing it without cost via the drug company.
We are in Australia and so far Nivolumab is only approved for melanoma and I think it costs about $100,000/ year.
Im wondering if your oncologists in USA/ England etc talk about it at all & if they see it as a promising GBM treatment?
Best wishes to all. Lisa

Response to nivolumab (PD-1 antibody) in hypermutated glioblastoma

Click here for the abstract

Treatment of two siblings with multifocal, hypermutated GBM resulting from "biallelic mismatch repair deficiency" leads to "clinically significant responses and a profound radiologic response."

Find the full paper in the Library.

AVERT trial at Duke now recruiting

Nivolumab With DC Vaccines for Recurrent Brain Tumors (AVERT)

NCT02529072

This is a trial testing

• CMV-targeted dendritic cell vaccine +
• PD-1 antibody (nivolumab)
• a single dose of Td toxoid (tetanus-diptheria) prior to the fourth vaccination

The trial is for first or second recurrence of high grade glioma (grade III or IV), no prior treatment with Avastin (bevacizumab), age 18-80.

DNX-2401 virotherapy plus PD1 antibody trial

Many of you probably already saw this on Al's news blast, but I wanted to post it here too:  a new phase 2 trial will be testing DNAtrix's DNX-2401 virotherapy with Merck's PD-1 antibody pembrolizumab (Keytruda).

http://www.businesswire.com/news/home/20151001005478/en/Merck-DNAtrix-Announce-Phase-2-Immuno-Oncology-Collaboration#.VhMY6vlVikp

This will be the second trial to combine a PD-1 antibody with a second immunotherapy (the other is Duke's trial combining their CMV-targeted dendritic cell vaccine with nivolumab, plus pre-conditioning of the vaccination site with tetanus/diptheria toxoid.

https://www.clinicaltrials.gov/ct2/show/NCT02529072

These are just the sorts of combinations we need!

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.

Chloroquine and immune status

Hi All, Alan isn't having chemo but is on f/n Avastin, Chloroquine, Tagamet, Metformin, DCA and Celebrex plus usual supplements and struggles to keep white cell count within normal parameters, usually it's just below baseline. I thought not having chemo for 6 months or so other than a small stint of 20mg TMZ daily for a few weeks which was 4 months ago would see his immune system back to robust self.  We are doing a dc vax privately and have been trying to hedge our bets by not putting all our eggs in one basket, but don't want to do anything that will impede his immune system. Just a reminder Alan is IDH1 negative and unmethylated so trying to cover all bases.
Chloroquine can be an immune suppressant and taken with Tagamet would increase Chloroquine levels in blood.
 I have been thinking of cutting Chloroquine by half but am really at a crossroads as I feel the chloroquine/avastin combo is what is keeping the tumour stable. Alan has been on Avastin for almost 12 months (2 weeks short of).
Does anyone else have trouble with their white cell count? I would like to know how other chloroquine users immune systems are holding up and would appreciate all thoughts and suggestions.
Thanks,
Linda