IMO-2125 targets tumor microenvironment

Idera presents data demonstrating potent antitumor response from combo treatment with intratumoral IMO-2125

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CAMBRIDGE, Mass.—Targeted toward developing Toll-like receptor (TLR) and RNA therapeutics for patients with cancer and rare diseases, clinical-stage biotech Idera Pharmaceuticals Inc. has announced new preclinical data demonstrating potent antitumor activity in preclinical cancer models with intratumoral administration of IMO-2125 in combination with an anti-PD-1 monoclonal antibody. These promising results have set the wheels in motion for the company’s strategic direction down the road of clinical development of tumor targets, states Sudhir Agrawal, president of research at Idera Pharmaceuticals.  
“The emerging data on preclinical studies with IMO-2125 is continuing to expand the potential of IMO-2125 in immunotherapy of cancer,” Agrawal stated in a news release. “The data we have assembled both in-house and through our academic collaboration clearly demonstrates the impact that intratumoral administration of IMO-2125 is having on the tumor microenvironment and the resulting antitumor activity both in treated and distant tumors.”
IMO-2125 is a synthetic oligonucleotide-based agonist of Toll-like receptor 9 discovered and developed by Idera, he said. Two anti-PD-1 antibodies have been recently approved for the treatment of melanoma and non-small cell lung cancer.  
In Idera’s preclinical studies, treatment with a combination of intratumoral IMO-2125 with anti-PD-1 antibody “showed more potent antitumor activity than either agent alone, with potent antitumor activity observed on treated as well as distant tumors,” according to Agrawal.
Additionally, increased levels of tumor-infiltrating lymphocytes (TILs) and increased PD-L1 and other checkpoint expression was observed in both treated and distant tumors.  
Idera expects to initiate the first clinical study of intratumoral IMO-2125 in combination with ipilimumab in patients with metastatic melanoma before the end of the year.
Robert A. Doody Jr., vice president of  investor relations and corporate communications at Idera Pharmaceuticals, tells DDNews: “Our plan is to clinically develop this program, ourselves,” adding that Idera is “imminently going to be initiating a Phase 1/2 clinical trial of intratumoral IMO-2125 with CTLA4 in metastatic melanoma as part of our strategic research alliance we have with MD Anderson Cancer Center to understand the impact of intratumoral TLR9 agonists in combination with checkpoint inhibitors.”
“This study is the first of several contemplated as part of the alliance,” Doody notes. “We are currently in discussions as to what the next studies may be in terms of which combinations and which tumors to target.”
Doody believes the information discovered from Idera’s preclinical studies is quite significant.
“I think anytime you believe you have found a new opportunity to make a positive impact for patients suffering from cancers, it is incredible news,” Doody says. “The preclinical experiments we have conducted to date have been quite encouraging, and we look forward to seeing if we can replicate those results in the clinical setting.”
He acknowledges that for many people the progress on cancer has seemed slow, and he notes, “As for why it is taking long, I think cancer is a multifaceted disease, which has been difficult to crack. Typically we've seen combinations of different drugs seemingly become more effective. As in our case, we are hopeful by utilizing intratumoral injections of IMO-2125 we are able to change the tumor microenvironment in a manner that will enable the systemic check point inhibitors to become more effective and durable in their treatment of tumors.”
Toll-like receptors (TLRs) are key components of the innate immune system, the body's first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue.  
Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. But checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 are designed to enable the immune system to recognize tumor cells.  
To further potentiate the efficacy of checkpoint inhibitor therapy, intratumoral administration of a TLR9 agonist may create a beneficial tumor microenvironment by increasing the TILs in both the injected tumor and distant tumors.  

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