And here we are. "What does anti-PD1 do?" "What does anti-PD1 do in the brain?" "It can't cross the blood brain barrier!" "You don't know!" "What can it do for brain mets?" "What?" "What?" "What?????"
We begin again!!!!
For general info on anti-PD1: background-and-latest-info-on-anti-pd1
I have no idea where the confusion began. Anti-PD1 drugs have never, NEVER, EVER, done ANYTHING to a TUMOR ANYWHERE!!! Ever. Never. Ever. EVER!!!!!!!!!!!! It doesn't hurt tumors. AT ALL! Not in the body. Not in the brain. NO WHERE. Anti-PD1 is NOT chemotherapy. Anti-PD1 is IMMUNOTHERAPY. It does NOT kill cancer. It triggers T-cells. ONLY!!!!!
"What is anti-PD1? In the simplest possible terms: Anti-PD1 drugs are antibodies that block the switch on white cells so that they can now attack melanoma cells. Specifically, programmed death ligand-1 [PD-L1] is produced by the surface of melanoma tumors. That ligand binds to the infiltrating T-cells, down-regulating them. Basically, turning those cells "OFF" to melanoma. ANTI-PD1 blocks that potential interaction, so that the T-cells can now attack melanoma cells."
Anti-PD1 NEVER bothers a tumor...ever...at all...never. ever. ever. Therefore...anti-PD1 doesn't have to cross anything...blood brain barrier...anything. It only has to turn the white cells... confused, mislead, and turned off by the PD-L1 ligand, produced by the melanoma, back ON! Then....voila'....back into fighting form...the T-cells kill the melanoma...wherever it may be....brain, buttocks, buccal mucosa...you get the idea...
Here's some data and pictures:
Just to give you some back ground on immunotherapies and the brain....think about ipi:
Phase II trial of ipi monotherapy in melanoma patients with brain metastases.
Authors: Lawrence, et al.
Ipilimumab, a human monoclonal antibody that blocks CTLA-4 has activity in advanced melanoma. This phase II trial attempted to assess ipi safety and activity in melanoma patients with brain mets. Patients had measurable brain mets with at least one lesion >0.5cm and/or 2 lesions greater than 0.3cm, and none greater than 3cm in diameter. Prior whole brain or stereotactic radiation to non-index lesions were allowed. Ipi 10mg/kg was given IV every 3 weeks for 4 doses. Responding or stable patients could receive maintenance ipi at 10mg/kg every 12 weeks. Total of 72 patients in two arms...arm B still ongoing. No association between brain edema or cerebral hemorrhage and objective response. Of 51 patients in Arm A, at week 12: 4/51 had a partial response, 5/51 had stable disease, with additional unconfirmed responses. Duration of responses ranged from 3 to 12+ months and duration of stable disease ranged from 1-7 months. CONCLUSION: Ipi has a similar level of activity in brain and non-CNS lesions. Ipi worked as well in the brain as it did anywhere else!!!
Tumor-infiltrating lymphocytes and expression of PD-L1 in melanoma brain metastases. Abstract 9055 ASCO 2014, Berghoff, Kiesel, Widhalm, et al.
"The brain is considered an immuno-privileged organ...." But after examining 46 specimens and measuring all the CD8+TILs, PD1 and TILs, etc, etc.... Melanoma brain mets show considerable TIL PD1 infiltrates and PDL1 tumor cells.
Association of tumor-infiltrating lymphocytes with brain edema and overall survival in brain metastases. Abstract 2012. ASCO 2014, Preusser, Berghoff, Fuchs, et al.
"Density of tumor-infiltrating lymphocytes (TILs) has a prognostic impact in various extracrainial solid tumors. We characterized TILs in patients with brain metastases." 118 brain mets of patients with a variety of cancers were examined. They were checked for CD8+ TILs, CD45RO+TILs, CD3+ TILs, and FOXP3+ TILs. Conclusions: "Dense TILs infiltrates are common in brain mets and correlate with the amount of peritumoral brain edema and improved survival prognosis."
When I had a recheck in March, 9 months after finishing my Nivo trial...I learned this:
"Additional Cohort 6 added:
- How this cohort is defined specifically, how many have been enrolled in total, how many may still be enrolled, I do not know, however:
- 5 patients in this cohort were admitted with brain mets.
- 4 were treated (I presume by radiation...though not certain)
- BUT...1 experienced a COMPLETE RESPONSE with just Nivo!!!!! (Awesome, right???!!)"
PERSONAL DATA: When I entered my nivo trial, I had a second brain met...after prior SRS treatment of my first brain met and removal of the right upper lobe of my lung for a met there....YES. I had ANOTHER brain met. When Dr. Weber asked his radiologists to review my scans...I figure the conversation went something like this:
"He tells us to sit tight and that he is going to call a neuro friend of his to look at the scans as well as radiologists to take a look. Off he goes....
Weber pops back in to tell us that he doesn't really know that it is a met at all. He is going to get the other folks to give their opinion.
On his return, he says that the other radiologist/neuro people couldn't definitively say that the lesion in question was a met. He tells us that to his mind, I have "minimal residual disease" and therefore qualify for his study should I wish to participate in it. I figure the conversation went something like this: Weber = Do you think this lesion is a met? Neuro/radiologist = Well, given her history, probably. Weber = Yes, but, on its own. Can you tell me that this is definitely a met? Neuro/radiologist = Well, not definitely."
Bottom line: He lets me in. On scans three months later...after every 2 week dosing of anti-PD1(nivo) and peptide vaccines...the "what's it" in the brain....IS GONE!
Blog post this excerpt was extracted from: melanoma neverland
Anti-PD1 doesn't attack tumors. It sets T-cells straight...and they can go anywhere! Here's old news about how t-cells enter the brain.
I promised pictures:
|This slide is from: Anatomical organization of the brain showing the possible routes of activated T cell entry. From: Autoimmune T cell responses in the nervous system, Joan Goverman, Nature Reviews, Immunology, June 2009|