Monday, June 16, 2014

Anti-PD1 in melanoma: T-cells, the brain, and EVERYWHERE ELSE!!!!

OK...."We begin again!"  For those who know me, or have read this blog closely.....this is a completely stolen phrase...from my professor of favorite college class ever! A small, slightly chubby, ebullient, Indian would look out on his class after a half hour impassioned lecture on this geologic phenom or all the blank, uninterested, unimpressed, lost, confused, attentive faces...and say, "Are you widst me?"  A more searching look, with a pleading quality to his glance, covers us.....  Now, slightly crestfallen, with a small sigh, "I think no." But, with a straightening of shoulders, and a charitable bent wonderful teachers always seem to possess, he would say..."We begin again!"

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 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 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???!!)"
Full post that this was extracted from:   what I learned when my Nivo trial was opened to folks with brain mets

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

  "Activated T cells can enter the subarachnoid space by migrating from blood vessels into the stroma of the choroid plexus and then crossing the blood-cerebrospinal fluid barrier surrounding the choroid plexus stroma, which comprises epithelial cells joined by tight junctions.  Activated t-cells can also enter the subarachnoid space by extravasating through the cell wall of meningeal venules, which consist of endothelial cells connected by tight junctions.  In addition, activated t cells can cross the blood brain barrier surrounding post-capillary venules that penetrate the brain parenchyma, which comprises endothelial cells connected by tight junctions."

So, a lot of noise to try to express simple facts.
1.  Anti-PD1 doesn't kill tumors.
2.  Anti-PD1 unleashes T-cells from the grasp of melanoma so that THEY kill tumors.
3.  T-cells go everywhere.  We have known this for some time.
4.  The latest data regarding melanoma brain mets at ASCO tells us that they are surrounded by TONS of T-cells.
5.  My brain tumor went away after anti-PD1.
6. So did other peoples.
7. T-cells kill melanoma...not anti-PD1.
8. The science does lag behind the theory because folks with brain tumors have historically, not been allowed in anti-PD1 trials...for the most part...or in the expanded access programs as well.

Hope this helps.  Anti-Pd1 doesn't kill melanoma, but the t-cells it releases...DOES! - c

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