IL-8 with Nivolumab

Hi Tony,

I believe my oncologist at the Abbotsford Cancer Center will also have patients involved in this trial. I seem to be responding to the Nivo maintenance finally so will keep my fingers crossed and keep an eye on this trial.

Best,

Chris

This looks like a really promising trial, Tony.  Here is a report from May….if you haven't seen it:

Phase I trial of BMS-986253, an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors.  

Background: BMS-986253 is a novel fully human monoclonal antibody that binds to and inhibits IL-8, a chemokine that promotes immune escape and tumor progression. High serum IL-8 levels correlate with poor prognosis in various tumors. IL-8 stimulates recruitment of myeloid-derived suppressor cells (MDSCs) and promotes epithelial-mesenchymal transition (EMT) in tumors conferring resistance to immune-mediated killing. We have previously shown the ability of BMS-986253 to reduce mesenchymal features in cancer cells leading to enhanced susceptibility to NK and T cell-mediated lysis, and to decrease the frequency of granulocytic MDSCs in xenograft models. Decreases in serum IL-8 were also associated with response to anti–PD1 therapy in a small cohort of patients with melanoma and NSCLC.

Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with BMS-986253 monotherapy at 4, 8, 16, or 32 mg/kg IV Q2W in a phase I, open-label, 3+3 dose-escalation study. The primary objective was to determine the safety and tolerability and establish the maximum tolerated dose (MTD). Pharmacokinetics and changes in serum cytokine levels including IL-8 were also evaluated.

Results: Amongst 15 patients, no serious treatment-related adverse events (TRAEs) were observed and MTD was not identified through 32mg/kg. TRAEs occurred in 5 pts (33%), and all were Grade 1 except for Grade 2 fatigue, hypophosphatemia and hypersomnia in two patients receiving 32mg/kg. Eleven pts (73%) achieved stable disease (per RECIST v1.1) and 4 patients had progressive disease (27%). The progression free survival rate at 24 weeks for all patients was 73% with two-sided 95% CI [44%, 89%]. Reductions in serum IL-8 levels were observed at all dose levels.

Conclusions: BMS-986253 monotherapy is well tolerated and associated with decreases in serum IL-8 across all doses tested. These data have informed combining this drug with Nivolumab and potentially other agents to evaluate the potential for synergetic activity in selected patient populations. Clinical trial information: NCT02536469.

What's so cool about it is this:  BMS-986253 is a drug that is supposed to inhibit IL-8.  What's so about that?  Well, left to it own devices, IL-8 takes over myeloid-derived suppressor cells (MDSCs), and by doing that allows tumors to resist being killed by immune-mediated processes (whether it is immunotherapy or our own bodies.

Here's how we know that this is important:

We have known for years that fewer MDSC's is a positive sign when dealing with melanoma.  Here's a bunch of posts and data on myeloid derived suppressor cells (MDSCs) and their role in melanoma: 

https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2015/08/markers-for-response-to-immunotherapy.html

 This was a finding from the ratties in my nivo trial that ran from 2010 – 2013:

"There was a trend towards lower baseline MDSC (myeliod derived suppressor cells) levels in non-relapsing patients compared to relapsing patients." 

I wrote this in 2014 based on the report:  "This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though…once again…despite my blood and services having been rendered….I have no idea what my MDSC levels were.  Still…I think this could be a real boon to future patients."  

So I am very hopeful for you!!!!  Ratties ROCK!!!  Keep us posted.  I wish you well.  celeste

Hi Tony,

I don't have any experience to offer you, but I'm writing this to ask you to please keep us informed of your experience. I am scheduled to receive the first of three radiation treatments for a small brain met today. Then if everything is stable in the followup MRI after 30 days I will be screened for the IL-8 trial. Dr. Sharfman tells me that they are very excited about the prospects of this trial. So am I! I hope it goes well for you. I'll be very interested in hearing of your experience.

-Bill

Hi Tony, please keep us posted on this trial, sounds very exciting and its something new, which is what some of us here might need. And Bill, good luck with the radiation and hope you will make this trial too

Best wishes Mark