Following the failure of several OX40 agonist antibody candidates, findings from an early-stage trial suggest a way forward to activate the costimulatory receptor. In the trial, intratumoral injections of mRNA encoding the OX40 ligand yielded favorable immunologic and molecular effects in patients.

Antibody drugs designed to boost antitumor immunity by stimulating the T-cell costimulatory receptor OX40 have largely failed to demonstrate clinical benefit. However, promising early data from candidates with novel therapeutic designs have begun to revitalize industry interest in OX40-directed agents.

One design strategy involves the delivery of OX40-stimulating payloads directly into tumors. DNAtrix, for example, is developing an OX40 ligand–armed oncolytic virus, whereas Moderna is evaluating two lipid nanoparticle–encapsulated mRNA therapies: one, mRNA-2416, encodes just the OX40 ligand; the other, mRNA-2752, also contains the genetic recipes for two proinflammatory cytokines.

At the American Association for Cancer Research (AACR) Virtual Annual Meeting I: April 27–28, 2020, researchers reported that mRNA-2416 was broadly tolerated by patients. It also produced favorable immunologic and molecular effects in solid tumors—including increased OX40-ligand protein expression, elevated PD-L1 levels, and enhanced proinflammatory activity in the tumor microenvironment.

“I was really encouraged by the pharmacodynamics—that's what you want to see,” said trial investigator Ryan Sullivan, MD, of Massachusetts General Hospital in Boston.

However, the clinical impact of the therapy was modest. Overall, 14 of 39 patients achieved stable disease, which lasted for at least 14 weeks in six of them. No patient met the criteria for a partial response, but four patients experienced some shrinkage of their injected tumors.

To augment the cancer-killing activity of T cells, Moderna is now evaluating mRNA-2416 in combination with the anti–PD-L1 drug durvalumab (Imfinzi; AstraZeneca) in solid tumors, mainly advanced ovarian carcinoma. Another phase I study is testing the company's triplet therapy mRNA-2752, which includes mRNAs encoding OX40 ligand, IL23, and IL36γ, in solid tumors and lymphoma.

Ignacio Melero, MD, PhD, of the Clinica Universidad de Navarra in Pamplona, Spain, described the immunomodulator-encoding mRNA design as “extremely elegant—and very fruitful, potentially.” Melero provided outside commentary on the mRNA-2416 trial at the AACR meeting.

“It's likely that, by providing gene expression of the natural ligand, you could be having different costimulatory activity” than with agonistic OX40-targeted antibodies, he said. Such antibody candidates, Melero noted, have demonstrated “almost negligible” clinical efficacy, and little added value when combined with checkpoint inhibitors.

Take GlaxoSmithKline's GSK3174998. In a phase I trial data reported at the AACR meeting, the agonistic OX40 antibody had limited efficacy in patients with advanced solid tumors and did not significantly improve response rate when combined with the anti–PD-1 drug pembrolizumab (Keytruda; Merck). Comparable OX40-directed agents from AstraZeneca, Bristol-Myers Squibb, and Genentech have not fared much better, compelling drug developers to focus on other costimulatory receptor targets, such as ICOS, GITR, and 4-1BB.

When it comes to the clinical failure of OX40 agonist antibodies, some researchers have pointed to suboptimal dosing and scheduling in trials: Giving too much of the drugs or administering them too often, experts say, may have inadvertently overstimulated T cells, triggering exhaustion or cell death.

New dosing schemes may yet salvage the initial crop of monoclonal antibody candidates. Several companies, however, are looking at new drug designs to bolster the activity of OX40-targeted agents.

F-star Therapeutics and Aptevo Therapeutics are nearing first-in-human testing of bispecific antibodies engineered to simultaneously stimulate OX40 and 4-1BB. Others are pursuing bispecific antibodies and fusion proteins that augment OX40 signaling alongside checkpoint blockade.

Alligator Bioscience, for example, is conducting an early trial of a bispecific drug candidate that targets OX40 and CTLA4. According to interim data, the drug is generally safe with no major dose-limiting toxicities; dose escalation is continuing, and preliminary efficacy results are expected next year. –Elie Dolgin

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.