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?
PD-1 is expressed on lymphocytes, while PD-L1 is often expressed by tumor cells. So in theory, PD-1 antibodies could block PD-1 on circulating lymphocytes even if it doesn't cross the BBB.
ReplyDeleteMore than that, we have documented clinical responses and prolonged disease stabilization to both PD-1 and PD-L1 inhibitors (durvalumab) in GBM cases.
See my summaries of abstracts ATIM-35 and ATIM-04 from the SNO 2016 conference:
http://astrocytomaoptions.com/sno-2016-clinical-highlights-scottsdale-arizona/
Also case studies like this:
https://academic.oup.com/neuro-oncology/article-abstract/19/3/454/2760199?redirectedFrom=fulltext
and
Immune Checkpoint Inhibition for Hypermutant
Glioblastoma Multiforme Resulting From Germline Biallelic
Mismatch Repair Deficiency
https://www.ncbi.nlm.nih.gov/pubmed/27001570
What kind of testing did you have done that quantified mutational burden? FoundationOne or Caris or some equivalent testing?
If there is extremely high mutational burden, there is likely a mismatch repair defect as well. Check and see if there are any mutations listed in one of the following genes: MSH2, MSH6, MLH1, PMS2.
If mismatch repair is defective then agents like TMZ or procarbazine will not likely have any effect, though lomustine may still be a valid chemotherapy option if MGMT status is methylated.
In the USA, pembrolizumab is approved for any solid tumor with microsatellite instability or mismatch repair defect, so if you live in the USA you may be able to get access to pembrolizumab. It is the only checkpoint inhibitor approved for all solid tumors with microsatellite instability/defective mismatch repair.
Thank you for your reply. It's FoundationOne testing. There is also a lot of other data suggesting possible therapies and we don't know which one of the would be the best. For example there is also a KRAS mutation and suggested treatment is the MEK inhibitor such as Cobimetinib. My partner was also tested for mismatch repair defect, there is no germline mutation in the classic mismatch repair genes, but there is a POLE mutation. He also had numerous polyps in the colon at the age of 20 years old, some cancerous. Now we know it's PPAP - polymerase proofreading associated polyposis. He took TMZ but we're not sure if it worked. We live in Poland and there is no access to immune checkpoint inhibitor therapy via the national healthcare system and insurence. We would need to pay out of pocket and the cost is around 40k EUR a month. We're looking for clinical trails (preferably in Europe)but haven't found any yet.
DeleteFoundation One doesn't do matched sequencing of healthy tissue, so it's not always clear whether a given mutation is somatic (arose in the tumor), or germline (inherited and present in all the cells in the body). The POLE mutation could certainly account for the high mutational load.
DeleteThere is some literature on efficacy of pembrolizumab etc. in cancer with POLE mutation.
https://www.ncbi.nlm.nih.gov/pubmed/27159395
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109825/
Checkpoint inhibitor trials in Europe for recurrent GBM include:
https://clinicaltrials.gov/ct2/show/NCT02866747
Hypofractionated Stereotactic Radiation Therapy and Durvalumab (anti-PD-L1, France)
https://clinicaltrials.gov/ct2/show/study/NCT02327078?show_locs=Y#locn
Epacadostat Administered in Combination With Nivolumab, United Kingdom
Trials recruiting advanced solid tumors include:
https://www.clinicaltrials.gov/ct2/show/NCT02671435
Durvalumab (MEDI4736) and IPH2201 in Solid Tumors (France, Hungary, Italy, Spain, UK)
https://www.clinicaltrials.gov/ct2/show/study/NCT03084471
Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy (France, Germany, Italy, Netherlands, Switzerland, UK)
https://www.clinicaltrials.gov/ct2/show/NCT02423343
Galunisertib (LY2157299) in Combination With Nivolumab (Spain)
The germline POLE mutation was discovered ealier by prof. Katharina Wimmer in Austria who only tested the blood sample. The High Mutation Burden was reported in FoundationOne report, also around 50 different mutations were listed.
DeleteThank you for checking the clinical trials.
Here is what I found out - maybe will be useful for someone else:
https://clinicaltrials.gov/ct2/show/NCT02866747
Hypofractionated Stereotactic Radiation Therapy and Durvalumab (anti-PD-L1, France) - this is open, but only 1 arm receive Durvalumab, tumor has to be less than 35 mm
https://clinicaltrials.gov/ct2/show/study/NCT02327078?show_locs=Y#locn
Epacadostat Administered in Combination With Nivolumab, United Kingdom
- open, but not recruiting
Trials recruiting advanced solid tumors include:
https://www.clinicaltrials.gov/ct2/show/NCT02671435
Durvalumab (MEDI4736) and IPH2201 in Solid Tumors (France, Hungary, Italy, Spain, UK) - this study is closed to all diagnoses other than Ovarian Cancer
https://www.clinicaltrials.gov/ct2/show/study/NCT03084471
Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy (France, Germany, Italy, Netherlands, Switzerland, UK)
This trial is currently only recruiting for bladder and kidney cancer cohorts.
https://www.clinicaltrials.gov/ct2/show/NCT02423343
Galunisertib (LY2157299) in Combination With Nivolumab (Spain) - hard to find the contact details, no reply yet
We're considering this clinical trial:
https://clinicaltrials.gov/ct2/show/NCT03291314?term=avelumab&cond=Glioblastoma&cntry=BE&rank=1
Just worried if the deep vein thrombosis which was diagnosed in Jan 2017 will not be an issue.
Thanks for these updates. Most of my info on trials comes from clinicaltrials.gov which isn't always up-to-date.
DeleteI systematically check for new trials daily, but somehow I missed the avelumab + axitinib trial, so thanks for finding it. The deep vein thrombosis could exclude him if it persisted within the last 6 months.
I am currently participating in a clinical trial (DNX-2401) which is using pembrolizumab so I am getting infusions of pembrolizumab every three weeks for my rGBM.
ReplyDeleteMarc
Thank you, Marc. How do you feel? how many infusions have you got so far? Are you based in Europe? Is it only pembrolizumab or also some other treatment? I've found the following trial: Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects NCT02798406 which looks interesting.
DeleteI think this is the same trial Marc is in. DNX-2401 is an adenovirus.
Delete