November 8-12, Oxon Hill, Maryland

                Poster Presentation Date: Friday, November 10, 2017
                Poster Presentation Time: 6:30 – 8:00pm ET

Here's the abstract available online:

Mechanisms of Resistance to Immunotherapy

 

P381 The BET bromodomain inhibitor ZEN-3694 modulates the expression of checkpoint receptors and immune suppressive factors in the blood of mCRPC patients

 

Eric Campeau1, Henrik Hansen1, Sanjay Lakhotia2, Karen Norek1, Laura Tsujikawa1, Sarah Attwell1

1Zenith Epigenetics, Calgary, AB, Canada; 2Zenith Epigenetics, San Francisco, CA, USA Correspondence: Eric Campeau (sattwell@zenithepigenetics.com)

 

Background: Epigenetic regulation of the immune system plays a significant role in the response to immunotherapies. The potential for epigenetic modulators to prime the immune system and increase the duration and frequency of response to checkpoint inhibitors has been supported by both pre-clinical and clinical evidence. ZEN-3694 is an orally available inhibitor of the bromodomain and extra-terminal (BET) domain family of proteins currently in phase I clinical trials in metastatic castration-resistant prostate cancer (mCRPC) (NCT02705469 and NCT02711956). Previously, we have shown that ZEN-3694 modulates multiple checkpoint receptors, immune suppressive factors and cytokines in vitro, and acts synergistically with a PD-1 mAb to inhibit tumor growth in a MC-38 syngeneic mouse model. To follow up with these findings, we examined the ability of ZEN-3694 to modulate the expression of Immuno-Oncology target genes in mCRPC patients at multiple doses in our current phase 1 clinical trial.

Methods: The Nanostring nCounter® PanCancer Immune Profiling Panel was used to measure immune marker expression in patient whole blood RNA taken at 0, 4 and 24 h post dosing with ZEN-3694.

Results: ZEN-3694 modulates multiple checkpoints, suppressive factors and cytokines in peripheral immune cells 4 hours after a single dose. Most of these changes return to baseline at 24 hours, following clearance of the drug. Significant effects were detected at all doses tested, including at well-tolerated doses below the maximum tolerated dose. Multiple checkpoint receptors, including TIM3 and PD-L1, chemokines CCL2/CCR2 and IL-8, and the suppressive factors IDO1 and ARG1, were significantly inhibited 4 h post-dose across 16 patients. These results were also confirmed by real-time PCR for several of these markers. Furthermore, mRNA levels of multiple co-stimulatory markers, including ICOSLG and CD28, were maintained or induced. Several of these markers show a strong dose/exposure response, and Ingenuity® Pathway Analysis suggests that lower doses may be superior to higher doses for cancer immune response modulation.

Conclusions: Taken together, these data suggest that ZEN-3694 has the potential to modulate multiple factors involved in adaptive resistance to therapeutic PD-1 blockade, and therefore may improve response rate and duration in combination with a checkpoint inhibitor. This is the first presented clinical evidence that a BET bromodomain inhibitor can modulate PD-L1 and other relevant immuno-oncology targets in patients at therapeutically well-tolerated doses. Follow up studies to correlate these changes with protein expression, immune cell activation, and tumor-specific targets in patients are underway.