Tumor tackler

The antitumor activity is the result of intratumoral administration of IMO-2125 in combination with an inhibitor of the immunosuppressive enzyme, indoleamine-pyrrole 2,3-dioxygenase (IDO1). IMO-2125 is a synthetic oligonucleotide-based agonist of Toll-like receptor 9 discovered and developed by Idera. IDO is one of several immune checkpoints involved in tumor immune escape, and IDO-1 inhibitors are currently in clinical development, according to the company.

“IMO-2125 is a TLR9 agonist designed as an immune modulator—in this case, an activator of immune response,” explained Robert Doody, vice president of investor relations at Idera Pharmaceuticals. “TLR-9 is expressed in both B cells and plasmocytoid dendritic cells. Intratumoral injection of IMO-2125 leads to interferon-alpha production and activation of dendritic cells. Activation of dendritic cells is a prerequisite for other critical activities, such as T cell infiltration/expansion and Th1 response. These changes in the tumor microenvironment may lead to tumor cell death and eventually to a long-term memory immune response against tumor antigens.”

“There is an extensive body of evidence that demonstrates that modulating the tumor microenvironment is critical to a successful outcome in cancer immunotherapy,” added Dr. Sudhir Agrawal, president of Research at Idera. “In preclinical models, previously we have seen compelling systemic antitumor effects with intratumoral IMO-2125 monotherapy, in combination with inhibitors of CTLA-4, PD-1 and now IDO.”

According to Doody, preclinical studies using IMO-2125 either as a single-agent or in combination with several checkpoint inhibitors—such as anti-CTLA-4, anti-PD-1 and IDO-1 inhibitor—have shown robust tumor regression. This tumor cell killing appears to be CD8+ T cell mediated.

As Doody explained, “Tumor regression was not only observed in the injected tumor but also in the uninjected tumor, essentially creating a systemic response. These studies suggest that IMO-2125 can induce memory T cell responses, leading to a robust systemic antitumor activity. Combination with checkpoint inhibitors will potentiate IMO-2125’s antitumor activity. We are very excited about the potential impact that we may see with our first clinical trial in metastatic melanoma. However, we are also very excited to further understand what other areas we can apply the technology to, such as in tumors that may not be immunogenic and perhaps unresponsive to checkpoint inhibition.”

IMO-2125 was developed several years ago and clinically tested in several human studies, including hepatitis C and a number of different cancers. At that time, IMO-2125 was being delivered in a systemic fashion via subcutaneous injections.

“The results that had been seen via that route of administration were not strong enough to warrant further development,” Doody noted. “In the time since then, the world of utilizing the immune system in the battle against cancer has emerged in a different light. The concept of checkpoint inhibition or other methods of resistance modulation have emerged, as well as, importantly, the concept of intratumoral injections of therapies. The combination of these new discoveries and the underlying mechanism of IMO-2125 merited further consideration, which is what led us to running the preclinical studies that we have published to date and ultimately into the clinical study we are currently running in partnership with MD Anderson Cancer Center.”

Together with the MD Anderson Cancer Center, Idera is currently conducting a Phase 1/2 clinical trial of intra-tumoral IMO-2125 in combination with ipilimumab (CTLA4) for the treatment of pembrolizumab (PD1)-treated refractory metastatic melanoma patients. The study has also recently been amended to include an arm studying the combination of IMO-2125 and PD1 in the same patient population.

Doody concluded, “It’s certainly too early at this point to fully grasp the commercial potential of this technology and approach, but is worth noting that while the approval of drugs such as CTLA4 and PD1 have been incredible advances in cancer care, the overwhelmingly large majority of cancer patients’ needs continue to be unmet.”