Research Published in Nature Medicine Demonstrates the Immunological Effects of Tomivosertib, Including Inhibiting Production of Checkpoint Protein PD-L1 and Increasing T Cell Infiltration into Tumors
Monday, 14 January 2019
SAN DIEGO, Jan. 14, 2019 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, today announced publication in the peer reviewed journal Nature Medicine of preclinical research demonstrating that tomivosertib (eFT508), the company’s oral, selective, small molecule inhibitor of MNK1/2, selectively inhibits expression of the programed-death ligand 1 (PD-L1), resulting in multiple immune-modulatory anti-cancer effects.The research, conducted in a preclinical model of hepatocellular carcinoma (HCC), showed increased immune activation against tumors, increased immune cell infiltration into tumors, decreased metastasis and prolonged survival as a result of inhibited PD-L1 expression. Furthermore, this research demonstrated that PD-L1 expression is up regulated in the context of oncogene activation at the step of mRNA translation. PD-L1 is an immune-checkpoint protein that inhibits tumor immune suppression by signaling through its receptor on T cells, programed cell death protein 1 (PD-1). The therapeutic benefit of blocking PD-1/PD-L1 signaling has been demonstrated by several FDA-approved inhibitors of PD-1 or PD-L1.
“This report of the molecular mechanism whereby tomivosertib inhibits translation of PD-L1 mRNA further substantiates previously presented results showing that tomivosertib selectively inhibits production of key immunosuppressive factors including PD-1, PD-L1, LAG3, TIM3 and IL-10 through inhibition of a single translation regulator target, MNK1/2,” said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. “We believe that the ability of tomivosertib to down-regulate multiple immunosuppressive factors uniquely complements focused immune checkpoint inhibitor activity such as anti-PD-1 and PD-L1 agents, and may help overcome their common resistance mechanisms, providing support for several of our ongoing clinical trials.”
The article titled, “Translation control of the immune checkpoint in cancer and its therapeutic targeting,” which published today, is from the laboratory of Davide Ruggero, Ph.D., professor, department of urology, and Helen Diller Family Chair in basic cancer research at the University of California, San Francisco, with additional authors from eFFECTOR. This research, conducted in novel mouse models of aggressive metastatic liver cancer, demonstrated that increased expression of PD-L1 in these tumors is due to increased translation rather than increased transcription. It has previously been shown that increased expression of PD-L1 has been associated with increased rates of metastasis and death. However, the mechanism by which this upregulation occurs had not been fully elucidated. This study showed that PD-L1 is regulated at the level of m RNA translation. The paper also showed that treatment with eFT508 results in the selective inhibition of PD-L1 mRNA translation while having no effect on global protein synthesis.
In the study, daily treatment with eFT508 remarkably reduced tumor growth, prevented metastasis and more than doubled the on-treatment survival time of mice.
Taken together, the data provides substantial support for eFFECTORS’s ongoing Phase 2 CPI-A checkpoint combination trial in combination with approved PD-1/PD-L1 inhibitors and the company’s planned Phase 2 trial in combination with Merck’s Keytruda to treat patients with triple negative breast cancer.
*About Tomivosertib (eFT508)*Tomivosertib is eFFECTOR’s wholly-owned, highly selective translation regulator that inhibits MNK1 and MNK2 (MNK1/2) acting at the level of mRNA translation. The oral small molecule drug candidate promotes anti-tumor immune activity by selective down regulation of several immune checkpoint receptors and specific immunosuppressive cytokines. Tomivosertib also has direct action in certain tumor cells, including prostate cancer.
Tomivosertib in being evaluated in multiple ongoing Phase 2 clinical studies in cancers that may respond to MNK inhibition. Patients are actively being recruited into a study wherein tomivosertib is being evaluated as an add-on when patients are experiencing insufficient response to an FDA-approved checkpoint inhibitor [NCT03616834] and into a separate study in castration resistant prostate cancer [NCT03690141]. As part of a clinical collaboration with Merck and Co., tomivosertib will also be tested in combination with pembrolizumab in triple negative breast cancer.
Please visit www.clinicaltrials.gov for further information on ongoing clinical studies of tomivosertib.
*About eFFECTOR Therapeutics*
*eFFECTOR Therapeutics is a clinical-stage biopharmaceutical company at the forefront of an emerging class of therapeutics known as selective translation regulators or STRs. By acting on key biological mechanisms responsible for tumor growth and immune suppression, STRs represent a promising small molecule approach for treating cancer. eFFECTOR’s most advanced program, tomivosertib (eFT508), is currently in multiple Phase 2 clinical trials for the treatment of several types of cancer, both as an immune modulator and as an agent that acts directly on tumor cells. eFFECTOR has entered into clinical collaborations with a strategic alliance between Pfizer and Merck KGaA to study tomivosertib in combination with avelumab and separately with Merck & Co to evaluate tomivosertib in combination with KEYTRUDA. Additionally, the company has an emerging pipeline of promising STR programs targeting well-known oncogenes and intractable targets. eFFECTOR maintains global rights to all of its development programs. For more information visit www.effector.com.
Heidi Chokeir, Ph.D.
You Might Like
Tweets about this