This post is prompted by a presentation at the American Society for Radiation Oncology (ASTRO) meeting yesterday.
"To better define the immune landscape of localized prostate cancer, researchers examined 9,393 tumor samples from men who underwent a radical prostatectomy ..." [1]
I'll focus on PD-L1 & PD-L2.
"Programmed cell death protein 1 {PD-1} is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self tolerance by suppressing T cell inflammatory activity." [2]
There are two ligands that bind to PD-1: PD-L1 & PD-L2. PD-L1 has received greater attention. The idea is that by inhibiting PD-L1, T cells will be free to attack tumor cells.
A 2012 trial of Nivolumab (BMS-936558) included 17 men with CRPC [3]:
"No objective responses were observed in patients with ... prostate cancer."
There had been an assumption that PCa cells expressed PD-L1.
A 2016 study [4] reported that:
"some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates anti-tumor immune responses in this disease."
So much for that idea. However, also from 2016, [5]:
"Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml."
"The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer."
Not everyone benefited, but when Xtandi resistance occurs, there may be PD-L1 over-expression & a therapeutic response to a PD-L1 inhibitor.
In a recent paper (2017) [6]:
"We analyzed tumors from 51 patients with {lymph} node-positive prostate cancer ... Patients with at least 1% PD-L1+ tumor cells had shorter metastasis-free survival than those with PD-L1- tumors ..."
...
From yesterday's presentation:
"The analysis of more than 9,000 prostate tumors ... found evidence that PD-L2, not PD-L1, may provide a key route for targeted therapies, such as immunotherapy, to slow disease progression."
"PD-L1, the target of several FDA-approved checkpoint inhibitors, was not associated with outcomes in this study, but PD-L2, which interacts with PD-1 similarly to PD-L1, was associated with worse treatment outcomes. Specifically, higher levels of PD-L2 were associated with greater likelihood for disease recurrence (HR = 1.17 ...), distant metastasis (HR = 1.25 ...) and prostate cancer death (HR = 1.45 ...)."
"“As immune checkpoint blockers have come to market, PD-L1 has received a great deal of attention—but it does not appear to be widely expressed in prostate cancer. PD-L2, however, was much more highly expressed in these tumor samples, and it also was associated with worse outcomes. The understudied PD-L2 ligand may be the better therapeutic target for patients with localized prostate cancer,” said Dr. Zhao."
-Patrick
[1] astro.org/News-and-Publicat...
[2] en.wikipedia.org/wiki/Progr...
[3] ncbi.nlm.nih.gov/pmc/articl...
[4] ncbi.nlm.nih.gov/pmc/articl...
Boron Inhibits Tumor-induced Angiogenesis
