Siwen Hu-Lieskovan, MD
“COMBINATION STRATEGIES are being developed, but the big question is what and how to combine,” said formal discussant Siwen Hu-Lieskovan, MD, of the University of California Los Angeles. “Anti–programmed cell death protein 1 (PD-1) therapy works at the last step of T-cell activation and relies on the patient has to develop an antitumor response. To help T cells to win the race and eradicate tumor cells, we not only need to block the PD-1/PD-L1 stop sign but also help the patient initiate an antitumor response (turn on the engine) as well as improve T-cell function (fuel the tank) and the microenvironment (clearing the road block) to take off the seat belt,” she told listeners.
Closer Look at ASCO Abstracts
DR. HU-LIESKOVAN WAS OPTIMISTIC about using pembrolizumab (Keytruda) to augment chimeric antigen receptor (CAR) T cells in relapsed pediatric acute lymphoblastic leukemia, even though it was a small study. “Possible resistance mechanisms to CAR T cell killing include downregulation of surface expression of target molecules, T-cell exhaustion, immune-mediated elimination, and genetic alterations of the leukemic cells that lead to acquired resistance. Anti–programmed cell death ligand 1 (PD-L1) with pembrolizumab can improve persistence of CAR T cells, and a hypothesis is that it can promote endogenous T-cell antitumor response,” she said.
The second study of the glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist plus nivolumab (Opdivo) was not a “home run” in terms of response, according to Dr. Hu-Lieskovan, but she singled out two cases whose disease have already progressed on PD-1 checkpoint inhibitors and developed a partial response to the combination, showing a benefit of adding the anti–glucocorticoid-induced tumor necrosis factor receptor agonist in selected patients, with a “very favorable” toxicity profile.
“My conclusion [regarding the second abstract] is that the combination with anti-[glucocorticoid-induced tumor necrosis factor receptor] immune agonists has been well tolerated, with a low incidence of severe toxicity. The maximum administrative dose may not be the most effective dose to move forward. Activity has been seen in a wide range of tumor histologies. Further biomarker studies to select likely responders is critical,” she stated.
Some of the points Dr. Hu-Lieskovan made about the second abstract were relevant for the third abstract, which focused on the combination of the indoleamine-pyrrole 2,3-dioxygenase inhibitor navoximod plus atezolizumab (Tecentriq). Again, the toxicity profile was good, with a low incidence of severe toxicity, and the combination showed activity in difficult-to-treat pancreatic and prostate cancers. She noted that in this case as well as in the previous abstract, the maximum administrative dose may not be the most effective dose to move forward, and that identification of biomarkers is key to select likely responders.
Unique Challenges Ahead
DR. HU-LIESKOVAN POINTED OUT that many immunotherapy combination strategies are being studied to overcome mechanisms of resistance to checkpoint inhibitors. These combinations have unique challenges, including the toxicity profile from agent to agent, the timing of immune-related adverse events, the need for more prudent withdrawal criteria from clinical testing since many patients continue to benefit after discontinuation of immunotherapy, and the need for appropriate response criteria that incorporate the stability and durability of response with immunotherapy. Most important is the development of biomarkers for patient selection; which patients may respond to single agent anti–PD-1 or anti–PD-L1 and which ones may require combination therapy, as well as which combination should be chosen for a particular patient? ■
DISCLOSURE: Dr. Hu-Lieskovan reported no conflicts of interest.