Better together?

According to the company’s presentation, Idera’s preclinical data showed that cancer immunotherapy with intratumoral injections combining IMO-2055 and ipilimumab demonstrated potent and systemic antitumor activity in multiple preclinical cancer models. IMO-2055 is one of Idera’s synthetic oligonucleotide-based agonists of Toll-like receptor (TLR) 9, and ipilimumab is a U.S. Food and Drug Administration (FDA)-approved checkpoint inhibitor targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).

The findings presented at the meeting summarized several studies evaluating monotherapy with IMO-2055 as well as a combination regimen in which both IMO-2055 and ipilimumab were administered via intratumoral injections. The results of these studies showed that intratumoral injections of IMO-2055 inhibited the growth of treated and distant tumors, measured by tumor volume and histology. Compared to monotherapy with either agent, the combination of the two agents demonstrated increased and sustained systemic inhibition of tumor growth. In addition, the studies identified statistically significant increases in cytotoxic T cells against two tumor-specific antigens (AH1 and β-gal) expressed in treated and distant tumors, respectively, for the combination therapy versus monotherapy with either agent.

“The data showed that IMO-2055 and ipilimumab injections directly into a tumor stimulated a potent immune response and greater inhibition of tumor growth compared to treatment with either agent alone,” says Dr. Sudhir Agrawal, president of research at Idera. “Importantly, these injections into a single tumor also led to a systemic immune response that inhibited the growth of distant, untreated tumors.”

The findings are consistent with Idera researchers’ belief that IMO-2055 and ipilimumab may have complementary mechanisms of action, which would enhance their effectiveness when administered together as part of a cancer immunotherapy regimen. Other combination regimens with IMO-2055 and different checkpoint inhibitors—several of which have been approved by the FDA or are in late-stage clinical trials—also may be effective, Agrawal says.

IMO-2055 is an investigational agonist of TLR 9 discovered and developed by Idera and designed to activate TLR 9 signaling to stimulate an immune response against tumor-specific antigens. TLRs are a class of proteins that play a key role in alerting the body’s innate immune system to invading pathogens as well as damaged or dysfunctional cells such as cancer cells.

Ipilimumab, a compound developed by Bristol-Myers Squibb Co., is approved by the FDA for the treatment of unresectable or metastatic melanoma.

“By targeting regulatory checkpoint pathways such as CTLA-4 or programmed cell death protein 1, checkpoint inhibitors are designed to enable the immune system to recognize tumor cells,” says Agrawal. “A TLR 9 agonist such as IMO-2055 has the potential to enhance the anti-tumor response by activating TLR signaling.”

In simple terms, Agrawal explains, the checkpoint inhibitor is designed to weaken the tumor’s defenses against immune attack, while the TLR 9 agonist is designed to enhance an antitumor immune response.

“We are continuing to conduct preclinical studies of IMO-2055 in combination with various checkpoint inhibitors to further characterize potential cancer immunotherapy combination regimens,” says Agrawal. “In parallel, we are assessing our options to advance an immunotherapy program into clinical development. We look forward to unveiling those plans next year.”

Additional drug candidates based on Idera’s drug discovery platform include IMO-2125 (another synthetic oligonucleotide-based TLR 9 agonist) and IMO-8400, an antagonist of TLRs 7, 8 and 9 designed to inhibit TLR-mediated immune responses. Two Phase 1/2 clinical trials of IMO-8400 are underway in patients with genetically defined forms of B-cell lymphoma in which over-activated TLR signaling has been shown to contribute to the disease process.

Idera Pharmaceuticals’ AACR presentation, titled Intratumoral injection of IMO-2055, a novel Toll-like receptor 9 agonist, with ipilimumab induces a systemic tumor-specific immune response, is available on Idera’s website. Idera’s proprietary technology involves creating novel nucleic acid therapeutics designed to inhibit over-activation of TLRs. In addition, Idera is developing gene silencing oligonucleotides that it has created using its proprietary technology to inhibit the production of disease-associated proteins by targeting RNA.