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.

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?

Optimizing TMZ

My 64-year-old husband was diagnosed with GBM in his left temporal lobe after a successful resection in 1/2016. His tumor is unmethylated and IDH negative. He is TMZ-naive and has been on Keytruda and Optune for a year. The tumor was stable until late October, when it extended into a new area.  It is slow-growing according to a PET scan yesterday.

Genomic testing of tissue retrieved from a second resection 11/16 highlighted mutations in NF1, PTEN, ASXL1, HNF1A, MLH1, NOTCH1 and SPEN. My husband's NO suggested Temsirolimus because of the PTEN mutation and TMZ starting in January.

My big research question is how to get the most kick out of TMZ, given his methylation status. It seems that either daily or 7-day/alternating Temodar have better clinical results than the standard protocol. I also wondering how best to sensitize GBM cells to TMZ and potentiate the treatment. Different studies suggest adding:
- Tamoxifen
- MGMT inhibitor O6-benzylguanine (O6-BG)
- Interferon-β (IFN-β)
- oncolytic adenovirus
- excision repair pathway enzyme apurinic/apyrimidine endonuclease/redox factor-1 (APE)
- Prozac/Fluoxetine
- antabuse/disulfiram
-Metformin

This all makes my head swim. Have any of you tried an alternative TMZ dosing schedule along with something to enhance its effectiveness against a unmethylated tumor?

Thanks for all your information and help.