Dexamethasone limits benefit of Immune checkpoint blockade

 New study published in clinical cancer research:

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma

https://pubmed.ncbi.nlm.nih.gov/33239433/

from the abstract:

Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival 

Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

The GL261 referred to is a mouse model of glioma.

Major study of hypermutated gliomas published in Nature

Mechanisms and therapeutic implications of hypermutation in gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/32322066
https://sci-hub.tw/10.1038/s41586-020-2209-9  (sci-hub link to the full PDF document)

Unfortunately this study provides negative evidence to the idea that hypermutated gliomas would be more responsive to treatment with PD-1 blockers such as nivolumab and pembrolizumab.

from the study
"MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. "

"Because our prior analyses indicated that patients with hypermutated gliomas might have reduced survival, we used a second set of historical controls to compare the outcome of hypermutated gliomas treated with PD-1 blockade versus other systemic agents. Unexpectedly, we observed a longer median OS for patients treated with other systemic agents when compared to those treated with PD-1 blockade"

However, the mismatch repair deficient, hypermutated tumor cells were sensitive to the chemotherapy agent CCNU (lomustine).

"We next treated native and engineered isogenic MMR-knockout glioma models with temozolomide or the nitrosourea lomustine (CCNU), a chloroethylating alkylating agent that generates DNA interstrand crosslinks and double-strand breaks (Fig. 2c, Extended Data Fig. 8g–i). All MMR-deficient models were resistant to temozolomide and sensitive to CCNU, consistent with the lack of hypermutation in samples from nitrosourea-treated patients"


This confirms advice I've given to patients with temozolomide-driven hypermutated recurrent gliomas: CCNU (lomustine) chemotherapy is probably the best choice in terms of conventional chemotherapy options.  However it argues against advice that PD-1/PD-L1 blockade (drugs such as pembrolizumab or nivolumab) would be the best option.

Irina's mom genomic sequencing report

Dear Stephen! Dear all!

1) Could you please help me with genomic sequencing report!
Probably you could advice any beneficial drugs for our sitation.
Now we use DCA, metformine, chloroquine, celebrex, prozak, boswellia, pterostilbene, EGCG, BroccoMax, berberine, omega 3, milk thistle, cannabioids with high thc - 74%).












Options 1 and 3 have the most pathological nature.

• Option number 1 is located in the KDR gene, which is an oncogene, and involved in tumor angiogenesis processes.
• Option number 3 is in the gene PMS2, which belongs to the tumor suppressor genomes, and is involved in the repair of unpaired
• bases (edits DNA replication errors). Associated with many tumor diseases. This option, as follows from sources (column PMID) often has a germinal nature (is congenital).
• Option number 4 is located in the gene ROS1, which is a proto-oncogene, and encodes a number of tyrosine kinase receptors. He might be both congenital and acquired. 

These mutations currently have no targeted drugs.

Mutation load (Tmb) - high: 3.79 m/Mb (with a threshold value of 0.8 m/Mb)

Microsatellite instability (MSI) - presence (bottom line):

- 11.9% / 12% repeat

- mutations 2 reparation genes of 4

2) How do you think is it worth to try ONK201 drug for my mom if she don't have h3k27m mutation? I read on the forum on face book that many adults with glioblastoma without mutation use it and have positive results. 

Does it really kill tumor stem cells?

Thank you so much!

Baseline corticosteroids reduce activity of PD-L1 blockade

https://www.ncbi.nlm.nih.gov/pubmed/30125216 
Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

http://sci-hub.tw/https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30666-1/fulltext  (summary of study published in the Lancet)

"Baseline corticosteroid use was associated with decreased overall response, and shorter median progression-free survival and overall survival in patients who received the equivalent to 10 mg prednisone or more per day at the start of the PD-L1 blockade."

10 mg of prednisone is equivalent to only 1.6 mg of dexamethasone.

http://clincalc.com/corticosteroids/

Tumor Mutational Burden and response to immunotherapy

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
https://www.ncbi.nlm.nih.gov/pubmed/28835386


This study was a collaboration between UC San Diego, and Foundation Medicine.
Response rate, progression-free survival and overall survival following immunotherapies (in general, or specifically for immune checkpoint inhibitors such as anti-PD-1/PD-L1) was increased in patients with higher tumor mutational burden (as determined by genetic sequencing).


My commentary:
Newly diagnosed gliomas including GBM usually have low tumor mutational burden.  At highest risk for high tumor mutational burden (hypermutation) are likely those with MGMT-methylated tumors that recur following standard TMZ chemotherapy.

Pembrolizumab (Keytruda) is approved by the United States FDA, among other indications, "for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. "

The very high mutational burden sometimes seen in recurrent gliomas following temozolomide chemotherapy is often caused by mutations in one or more of the mismatch repair genes (MHS2, MSH6, MLH1, PMS2).  Having genetic sequencing performed (in North America by Foundation Medicine or Caris, or different companies in other countries) for recurrent post-temozolomide grade IV tumors (especially MGMT methylated tumors) could be a worthwhile way to detect hypermutation/mismatch repair deficiency/microsatellite instability and get access to pembrolizumab outside of a trial.  I can't comment on how easy getting coverage would be (both for the genetic testing as well as the pembrolizumab), as it would in part depend on the policies of the various insurance providers.

Should we get the NGS done? If yes, from where?

Hi folks/Stephen,

Needed a bit of help from you all. My mom is a GBM patient who was diagnosed in Sep 2017. Her cancer is IDH1/2 -ve, methylated and 1p/19q codeletion negative, this is the information that we gauged from the initial gene testing that was done by our hospital post surgery. We are now considering a next generation gene sequencing test done, and I had the following questions on the same:

1. How helpful has the gene sequencing report been for you so far, if you have got one done? What questions should I look at getting answered from this test?

2. Since there is very little tumor tissue that we all have, which is the best place to get the gene sequencing done from? I currently have read and spoken to OncoDNA, StrandAdvantage, RGCC Greece and FoundationOne so far. Which one would you recommend, and why? The recommendation could be different from the mentioned five too.

I read the following doc shared by Stephen in the Brain Tumor library too, but I'm not quite able to figure out on which test is a more appropriate one for what kind of patient. 

https://docs.google.com/spreadsheets/d/1653spmu9DkVCKX16G0_ZUlsTuJOx_Ln2qVysJJI-uoU/edit#gid=0

There are so many genes written in all of them, that it's hard for me to be able to compare and make an informed call :/

Want to know if the gene testing will be of help in further treatment, and the drugs/supplements that we should use for her in the near future.

Her current status

1. Her MRI three months back showed no growth, but had choline elevation at two parts where there was tumor resection. We have her next MRI in about a week from now.

2. She will do her remaining chemotherapy cycles with Temozolomide+Lomustine, her cancer being methylated.

She currently is on ketogenic diet and lot of naturopathic supplements suggested by Nutrition Solutions. 

My plan going forward

After my mom is done with the chemotherapy, I plan to get her immunotherapy (Dendritic cell therapy) done.  Want to know if the gene sequencing will be an add on in this plan.

MDMX and PD-1 inhibitors

So the genetic testing came back on my partner’s tumor (GBM, first recurrence), and while researching the mutations, I found Stephen W’s account of the hyperprogression study linking use of checkpoint inhibitors with accelerated progression in people with certain mutations, including amplification in MDM2 or MDM4.  All 6 of the people in the cohort with MDM2/MDM4 amplifications experienced hyperprogression (across 5 different cancer types, none of which were primary CNS, although several had metastases in the brain; 5 were MDM2 amplified, 1 was MDM4).

My partner’s genetic report includes copy number gain in MDM4.  No indication of the size of the gain; I’ve asked the company if they can clarify.

As it happens, we started pembrolizumab 2 weeks ago.  I figured the worst that would happen was that it was ineffective; it never occurred to me that it might accelerate progression.

The study doesn’t prove that checkpoint inhibitors caused the hyperprogression.  It’s possible that MDM2/MDM4 amplification caused the hyperprogression on its own.   The possible mechanism seems understood: MDM2 suppresses p53, a major tumor suppressor (p53 is mutated in over 50% of all cancers).  I found one study that showed MDM2 amplification is prognostic for poor survival in breast cancer.  On other hand, the chart at the end of the hyperprogression study sure makes it look like acceleration began with the onset of checkpoint therapy.

My partner’s tumor showed high expression of PD-L1 (50%), and also has mutations in NF1 and TERT.  All three of those are correlated with better response to PD-1 inhibitors in other cancers.

The next pembro infusion is scheduled for March 19.  We have to decide by then whether to continue with it or not.  Thankfully we’ll have an MRI that morning.  The tough call will be if there’s no evidence of progression.  I know there’s no clearcut rationale for making a decision either way, but I’m curious if anyone here has any advice.

Other biologically relevant mutations found are TERT, PTPN11, NFE2L2, PTEN, and CDKN2A.  IDH1 is wildtype.  MGMT is reported as unmethylated by sequencing.  The tumor mutational burden increased from 2.05 to 5, and the MSI status is stable (i.e., no mismatch repair defect).  

Our current regimen: CCNU, pembrolizumab, Vitamin D, melatonin, PSK, curcumin (also levetiracetam, Vimpat, Xarelto)

Planned additions: boswellia

Actively considering: ECGC, THC/CBD, Hydro+ALA, celexocib, metformin, everolimus

Thanks,

Brandon

Blood-brain barrier and immune checkpoint inhibitors

Blood-brain barrier and immune checkpoint inhibitors

My partner has a recurrent and unoperable glioblastoma.
He is considering a therapy with immune checkpoint inhibitors (e.g. pembrolizumab or atezolizumab) as his tumor has extremely high mutation burden. Some doctors are in favour but some are not convinced and say that it won't work because of blood brain barrier (BBB).
Is there any research showing immune checkpoint inhibitors don't cross BBB?

(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

Immunotheraphy combo

Do you have any experience or thoughts about this study?
http://www.practiceupdate.com/c/57122/67/12/?elsca1=emc_enews_weekinreview&elsca2=email&elsca3=practiceupdate_braincancer&elsca4=braincancer&elsca5=newsletter&rid=MjMxMDE2NzMzNjcyS0&lid=10332481

Has anyone tried this combo?
Best wishes to all
Brainbutton

GBM treatment options with a moderate budget

My 29 years old husband was diagnosed on 3/26 with a multifocal, thalamic GBM. We are from Hungary. He has undergone surgery on the 5th of April. 80% of the walnut-sized tumor was resected from his thalamus. His other, frontomediobasal tumor seems to be inactive (although it's pretty big, too) so the surgeon didn't resect it and it didn't received radiation either. He has completed SOC and currently is on his first cycle of 5/23 TMZ monotherapy. He has no EGFR amplification. His tumor is IDH negative and indeed very aggressive. Only 3 weeks after surgery he was hospitalized because of edema which was caused by tumor regrowth. So now he has quite a few smaller tumors around his thalamus besides the remaining 20% piece. 

His first post-radiation MR is scheduled for the middle of August. Since I've not yet received the information regarding his MGMT methylation status (long story) I'm constantly worrying and seeking for opportunities in case of tumor progression since in my country there's no protocol for recurrent glioblastoma other than Avastin. I mean no PCV or other chemos, no immunotherapy, no clinical trials, no Optune device (I requested an offer from Germany and it turns out that it costs 30 000 € /months and you need a technical and medical support at home).

I'm aware that we need to manage our finances cleverly in this situation. If you had up to 20,000-30,000 USD which option or options would you go for?

- Immunotherapy in Germany (It seems to me that only Nesselhut Clinic fits into our budget but reviews are not so convincing as nothing in the world of GBM.) 

- Keytruda / Opdivo immunotherapy + TMZ 

In Hungary it's not part of the protocol but hopefully we can find a doctor who will prescribe it at our own expense. As I can see Opdivo has kind of failed; is Keytruda. better? Do we need PD-L1 testing to get it?

- We have gamma knife in Hungary and it can be paid through National Insurance (so patients who qualify don't need to pay for it) but doctors are reluctant to let GBM patients to choose this option. It's usually used for small and simple tumors and for brain metastases. If our NO will advise against it or will be not so eager to help maybe I can search for other European gamma knife possibilities although I can't find too many comments on gamma knife and GBM.

- Neuroblate Laser Ablation. As far as I know it's exactly for problematic tumors, like thalamic ones. I'm planning to send them an inquiry but I have concerns about whether it is an adequate alternative to surgery for inoperable tumors. Can it prolong life or is it just a palliative treatment? How much would be the estimated cost? Has anybody personal experiences with it? Is laser ablation superior to gamma knife? 

Our NO said my husband's thalamic tumor is no accessible for surgery anymore and considering his bad reaction to the first surgery maybe laser ablation or gamma knife wouldn't be the best option for him. What are your thoughts on it? 

- SPMF treatment in India. It's quite cheap but no statistics are available and it's so hard to believe for me that the same effect is achievable with 1-2 hours of treatment for 28 days as with the Optune cap which you need to wear almost all day long up until it works. I've read about a young patient with thalamic tumor on Inspire who had Optune and it didn't do any good for him because of the location. I suppose that the same applies for SPMF, too. 

- I sent an inquiry to Duke's polio virus trial.

My clinical trial applications have been ignored from all over the world so I was tricky enough to mention that "I'm aware that non-U.S. citizens should cover their costs on their own in case of qualifying for a clinical trial and I hope I can manage it with the help of my family. "

I got this answer from doctor Friedman personally "We would not have a trial for you at this time since the surgery was so long ago and the tumor is not growing If it ever does regrow please let us know"

Maybe it was just a polite "no" or maybe this possibility is truly open for us in case of a recurrence but the truth is that I have no idea how much a treatment like this could cost in one of the world's best institutions for cancer. Anybody has any idea about their fees?

- Ask the Brazilian doctor to come to Hungary and teach us to administer Perillyl Alcohol. I've read that the brave persons who tried to make it themselves found it unbearable to use.

Any and all help is very much appreciated. Thank you in advance and sorry for my grammar mistakes.

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?

Temozolomide vs PCV for recurrence

My husband's glioblastoma has recurred.  He is having surgery for the second time (first time was August 2015).  His NO is considering either a second course of TMZ or PCV. Any views on which may be better please?  He is methylated and IDH1 positive.
thanks
Anne Marie

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

dendridic vaccine plus virus

Dear all,
we are planning on getting the vaccine with Van Gool for my 17-year old pretty soon. I know he is using  Newcastle virus with it, but I wonder if this would be the most effective/aggressive option. I have seen mixed reports on its efficacy, so I wonder if tetanus shot or Hilton would be a better option to add to the vaccine. From what I read, tetanus seems a lot more effective. As much as I trust Van Gool's expertise, I still can't fully put my faith into any one treatment if there is a possibility of something working better. I am sure Van Gool would insist on his approach, but I wonder if this is because he truly believes it is better tan others ( such as tetanus) or because this is the only protocol they use at the moment. Would anyone have an opinion on that? Thanks!

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.

Triple combination of dual checkpoint blockade + radiosurgery -> 100% mouse survival

http://clincancerres.aacrjournals.org/content/early/2016/12/04/1078-0432.CCR-15-1535.long

I don't recall seeing a mouse study this successful before.  This study utilized the orthotopic, syngeneic GL-261 mouse glioma model.  Triple combination of PD-1 antibody, TIM-3 antibody, and stereotactic radiosurgery led to 100% mouse survival at day 100, while all untreated control mice were dead by day 30.  Furthermore, the "cured" mice were completely resistant to new tumor formation when re-challenged with glioma cells.  I'll upload this study to the Library, in the Immunology and Immunotherapy folder, Checkpoint inhibitor subfolder.

FoundationOne test now includes "Tumor Mutational Burden" quantification

To my surprise, I just learned that FoundationOne reports now include a quantification of "tumor mutational burden" expressed as number of mutations per megabase of DNA.  This would be the most accurate test for hypermutation.

Foundation One webpage

I believe there is a link between MGMT methylation status, and risk of hypermutated recurrence, which could help explain the increased risk of progression to hypermutated secondary GBM recurrences for IDH1-mutant low grade gliomas (which are usually MGMT methylated) treated with TMZ.

I'd especially recommend FoundationOne for recurrences of MGMT methylated gliomas post-TMZ treatment. This test would tell you if the tumor is hypermutated and therefore if further TMZ could actually make the situation worse.  Unfortunately patients outside the US must self-pay, and the discounted price as of September 2014 was $4600 US.

PD-1/PD-L1 antibodies and hyperprogressive disease in a subset of patients

Sadly, a new study shows that out of a total population of 131 patients with various sorts of tumors treated with anti-PD-1 or anti-PD-L1 monotherapy, 12 of these (9%) had hyperprogressive disease (HPD) following treatment, defined as an increase in tumor growth rate at least 2 times higher than the reference growth rate (before anti-PD-1 treatment).  The subset of patients with hyperprogressive disease were older on average than the rest of the cohort (66 versus 55 years on average).  "At progression, patients with HPD had a lower rate of new lesions than patients with disease progression without HPD".

The mechanism for this increased tumor growth rate in this small subset is currently unknown.

"By RECIST, a total of 49 (37%) 66 (50%) 15 (12%) and 1 (1%) patients exhibited progressive disease, stable disease, partial response or complete response, respectively".  Therefore, stable disease was the most common response overall.

The study was published today (November 8) as an OnlineFirst article by Clinical Cancer Research.

Click here for abstract

I've uploaded the full study to the Library, Immunology and Immunotherapy folder, Immune Checkpoint Inhibitor subfolder