Costimulatory Agonists Start to Bear Fruit in Oncology

Aaron R. Hansen, BSc, MBBS

Costimulatory agents that can trigger a hearty immune system response to tumors constitute a new wave of investigation that is showing positive results. Among the most advanced of these drugs are agonist antibodies that target 4-1BB, which are moving forward in trials and demonstrating efficacy. For an understanding of progress in this regard, OncologyLive^® interviewed Aaron R. Hansen, BSc, MBBS, an expert in the development of immunotherapies for head and neck and genitourinary cancers. Hansen has been involved with several clinical trials of immunostimulatory checkpoint agonists.

OncLive: What are costimulatory immune checkpoints, and why are they so promising?

Where does research stand in terms of human trials?

Which do you think is the most promising of these targets?

What has clinical experience thus far taught us about the use of this type of drug?

What are the most significant unanswered questions relating to the development of stimulatory immune checkpoint agonists?

Amid the promise of costimulatory agents, which are being tested as monotherapy and in combinations, many questions remain, said Hansen, a medical oncologist in the Division of Medical Oncology at the University Health Network Princess Margaret Cancer Centre in Toronto, Ontario, Canada. First, the true workings of these agents are poorly understood, leading to frustrating results in clinical trials. Second, there are still many unknowns in terms of toxicities. Third, knowledge of biomarkers must be expanded so that these treatments can be truly personalized.Hansen: Costimulatory immune checkpoints or receptors, along with inhibitory checkpoints, regulate immune cell function and activity. Costimulatory receptors are expressed on multiple immune cell populations such as T- and B-lymphocytes, antigen-presenting cells, and natural killer cells. The 2 main families of costimulatory receptors are B7/CD28 and tumor necrosis factor receptor. Costimulatory pathways are attractive targets for cancer therapy because they can produce antitumor immune responses.Agonist antibodies have been developed for several costimulatory receptor targets; these include CD27, CD28, CD30, CD40, glucocorticoid-induced tumor necrosis factor—related protein, and the inducible T-cell costimulator OX40 and 4-1BB. These agents are in early phase [I/II] clinical testing to determine dose and schedule, safety, and the pharmacokinetic and pharmacodynamic profiles, in addition to early signals of antitumor activity. They are being studied as both monotherapy and in combination with other immune and nonimmune treatments. To date, no costimulatory agonist has received regulatory approval for use in solid tumors. Although most costimulatory receptor targets are of interest, 4-1BB is the most advanced in terms of de-velopment with agents already in phase II trials. In preclinical human trials of monotherapy and combi-nations with PD-1 inhibitors, 4-1BB antibodies have demonstrated promising clinical activity. Additionally, it is noteworthy that CD-19—targeted CTL019, a chime-ric antigen receptor T-cell therapy, has an intracellular signaling domain of 4-1BB, which highlights the signif-icance of 4-1BB costimulation for antitumor response.In general, costimulatory antibodies are tolerable, with few major adverse events. This makes them excellent partners to combine with other agents. As monotherapies, most agents tend to have limited antitumor activity, but this may change when administered in combination with other drugs.The structural characteristics of an antibody that reliably produce receptor agonism are not defined currently. Antibodies that can mimic the cognate ligand receptor interaction have the potential to produce optimal agonist effects on costimulatory receptors. Hence, full functional testing of each agnostic antibody will be required to demonstrate the presence of desired agonist activity and absence of unwanted secondary effects such as antibody-dependent cellular cytotoxicity. Traditional concepts used for receptor antagonists such as dose schedule, receptor occupancy, and saturation may not apply to the development of antibody agonists, and, thus, new trial designs or approaches are needed to evaluate these agents. Identification of biomarkers or immune profiles that can predict for the patients most likely to respond to costimulatory antibodies would also assist in the future development of these compounds and combinations.