Immune checkpoint proteins on immune T cells, like programmed cell death protein 1 (PD1) and its ligand (PD-L1), serve as safety switches that can quiet T cells to prevent autoimmune attacks on healthy tissues. But tumors frequently evolve PD-L1 expression as an immune-evasion mechanism.

Immune checkpoint inhibitors (ICIs) are anticancer immunotherapies designed to block cancer’s manipulation and to thereby unleash immune system attacks on tumors. For a minority of patients, ICIs offer sometimes-remarkable benefits as first- and second-line treatments of lung cancer.

Researchers are working to better understand why many patients with cancer do not benefit and are developing biomarkers to spot which patients are most ― or least ― likely to benefit.

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Others are looking to expand the population of patients who benefit from immunotherapy. They are investigating new combination regimens that might yield untapped therapeutic synergies.1-4

It hasn’t always been smooth sailing.

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“Combining new immunotherapeutic agents with existing treatments such as chemotherapy or tyrosine kinases inhibitors can have both good and bad consequences,” noted Christian Rolfo, MD, PhD, and Evelien LJ Smits, PhD, at the Antwerp University Hospital and University of Antwerp in Belgium.1

Despite early promise for one such combination regimen for patients with NSCLC (EGFR tyrosine kinase inhibitor osimertinib plus the anti-PD-L1 ICI durvalumab), widespread adverse events later emerged.1 (Similarly, adding the anti-CTLA-4 ICI ipilimumab to anti-PD1 nivolumab ICI improved anti-melanoma efficacy but was associated with grade 3/4 toxicities in many patients.2,4)

“The major challenge in oncology today is finding a combination of new drugs and new mechanisms of action that improves the outcomes achieved with the existing standard of care and simultaneously results in fewer toxic effects for patients,” Dr Rolfo and Dr Smits wrote.

Some authors have proposed combining ICIs like nivolumab and pembrolizumab with antiangiogenic agents like bevacizumab or ramucirumab.3 But the search for combination regimens has more frequently focused on combining two different immunotherapy agents that have distinct mechanisms of action, such as interleukin signaling and ICI.2

Dr Rolfo and Dr Smits spotlighted a study published in the same issue of The Lancet Oncology, describing preliminary clinical results from a nonrandomized, open-label phase 1b study of nivolumab (a PD1/PD-L1 ICI) plus ALT-803, an investigational interleukin 15 (IL-15) super-agonist immunostimulant in 21 patients with metastatic NSCLC relapsed or refractory to nivolumab monotherapy ( Identifier NCT02523469).1,2

The results have been “eagerly awaited because both IL-15 and PD-1 or PD-L1 blockers are ranked in the top three classes of immunotherapy drugs that could potentially cure cancer,” Dr Rolfo and Dr Smits wrote. “IL-15 triggers the activation of both innate and adaptive immunity to maximize a patient’s immune response against a tumor [and] IL-15-induced proliferation and activation of both natural killer cells and CD8-positive T cells as effective killer cells.”