Replies to post #669295 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Here’s one of the early papers on plx-3397 by Prins/Liau et al. I’ve been around a while. Note: The next SPORE trial in humans will combine DCVax-l + CI + plx-3397 + poly-iclc

flipper44
Member Level
Re: None
Friday, 07/01/2016 8:33:32 PM
I don't think the board has this abstract. Notice the difference between "resected" versus "established." There are, as most of you know, inoperable GBM tumors. This is a pretty hopeful preclinical study. It seems to cover and add to the talk given by Dr. Prins in Seattle recently. (I should add that "C57BL/6" is a common type of laboratory mouse.)

See you after the holidays.

Oral Presentations 2016 AANS Annual Scientific Meeting Chicago, IL • April 30–May 4, 2016
Published online April 1, 2016; DOI: 10.3171/2016.4.JNS.AANS2016abstracts

508. Glioma-infiltrating iAPCs mediate T cell recruitment to and activation in the tumor microenvironment
Joseph Paul Antonios, Horacio Soto, MS, Joey Orpilla, BS, Namjo Shin, Richard Everson, MD, Robert Prins, PhD, and Linda Liau, MD, PhD (Los Angeles, CA)

Abstract

INTRODUCTION:

Tumor lysate-pulsed dendritic cell vaccination has shown efficacy in promoting an immune response in the resected glioma patient treatment setting. However, cure rates are elusive when tumors are well established. We hypothesized that a mechanism of immune regulation exists in the tumor setting; specifically, suppression is dominantly mediated via the PD-1/PD-L1 mechanism by tumor-infiltrating immunosuppressive antigen presenting cells (iAPCs).

METHODS:

To test this hypothesis, we co-cultured T cells with murine glioma in the presence of iAPCs derived from C57BL/6 DC vaccine-treated mice with/without inhibition of the PD-1/PD-L1. T cell cytotoxicity in vitro was then assessed using the xCelligence impedance analysis system. To examine these mechanisms in an in vivo setting, we intracranially implanted mice with GL261 glioma and treated with DC vaccination +/- PD-1 mAb blockade or a small molecule inhibitor of CSF-1R (PLX-3397, Plexxicon) and overall survival was quantified.

RESULTS:

We characterized the tumor infiltrate induced by DC vaccination and showed that there existed a PD-L1+ population of heterogeneous myeloid-lineage cells. This inhibitory antigen-presenting cell (iAPC) population significantly reduced T cell cytotoxicity in in vitro assays; blockade of PD-L1 on these cells recovered T cell cytotoxicity against tumor. In our in vivo model, PD-1 mAb blockade in combination with tumor lysate-pulsed DC vaccination induced a highly significant survival benefit to tumor-bearing mice. Treatment with PLX-3397, in conjunction with DC vaccination, additionally improved the survival benefit beyond that of adjuvant PD-1 mAb blockade.

CONCLUSION:

These findings suggest that an anti-tumor immune response targeted towards glioma is dependent on blockade of iAPC function within the tumor microenvironment.