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Immune checkpoint inhibitors have transformed the treatment landscape of lung cancers, including both non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Studies show that promising agents have helped some 15-20% of patients achieve sustained benefit for many years. Still, the majority of patients eventually develop primary or secondary resistance to immune checkpoint inhibitors, with median progression-free survival (PFS) ranging from 5 to 10 months.

A review in the most recent addressed ways to enhance the antitumor immune response in lung cancer, including using novel drugs and strategies to overcome resistance to allow more patients to derive clinical benefit.

In the following interview, Shirish M. Gadgeel, MD, division head for hematology/oncology and associate director of Patient Experience and Clinical Care at Henry Ford Health in Detroit, discusses the multiple treatments currently available and the prospects for the future.

What does this article add to the literature about lung cancer treatment?

Gadgeel: In this review, we discuss several inhibitory and activating checkpoints currently being investigated, as well as strategies to activate the antitumor immune response beyond T-cell checkpoints.

The goal was to provide an overview of what to expect in the future in terms of immunotherapy for lung cancer. We include drugs that target co-inhibitory molecules, other immunotherapies, vaccines, cell therapies, and the role of radiation therapy with immunotherapy. Most of the data presented is not regarding standard of care, but how the field can move forward in the management of lung cancer -- in particular in advanced stage disease.

What are some of the novel immunotherapy combinations in development?

Gadgeel: Several drugs to overcome resistance to currently available checkpoint inhibitors are under evaluation, including drugs that target other checkpoints -- both activating and inhibitory -- to enhance effector T cells, natural killer cells, and macrophages in the tumor microenvironment. Many of these agents are being evaluated both as single agents and in combination with currently available checkpoint inhibitors -- in particular, PD-1–directed agents.

Drugs in development in lung cancer to inhibit targets and promote antitumor responses include several antibodies that target LAG-3; the addition of anti-TIGIT antibodies to PD-1–directed agents in both NSCLC and SCLC; anti–TIM-3 agents mainly in combination with PD-1–directed agents; and an anti-CD73 antibody and an anti-NKG2A antibody combined with other monoclonal antibodies.

Active research is ongoing for targeting different pathways of immune recognition to better optimize disease control. 4-1BB is a member of the TNF-receptor superfamily and is a T-cell co-stimulatory receptor. Agonist antibodies to 4-1BB were initially evaluated as both single agents and in combination with other agents, including PD-1–directed agents. 4-1BB has also been used in cellular therapies.

Some chimeric antigen receptor T-cell (CAR T) products use the 4-1BB co-stimulatory domain to activate the CAR T cells. Several agonistic antibodies targeting OX-40 are currently under evaluation in combination with PD-1–directed agents, as well as chemotherapy and radiation therapy. Another innovative method to activate OX-40 is by mRNA-encoding OX-40L.

What is the potential of bispecific antibodies, vaccines, and adoptive cellular therapies?

Gadgeel: Bispecific antibody technology combines different targets in a single antibody compound with the goal of localized synergistic or directed activation. There are multiple potential therapeutic approaches depending upon compound design.

The most advanced in oncology currently is blinatumomab, a bispecific T-cell engager targeting the T-cell receptor CD3. The majority of these bispecific antibodies are not currently used in lung cancer–specific studies, but they are in early development in advanced solid tumors.

Personalized vaccines targeted at an individual cancer's unique neoantigen are in early investigation. There are currently multiple ongoing personalized cancer vaccine studies, either alone or in combination with checkpoint inhibitors.

In the future, we hope to generate a vaccine tailored to the individual patient to provide a more personalized immunotherapy approach.

Current adoptive cellular therapies in lung cancer include approaches using tumor-infiltrating lymphocytes (TILs) or CAR T cells. There are multiple ongoing trials of autologous TIL therapies in NSCLC, alone or in combination with checkpoint inhibitors. Currently, multiple CAR T therapeutic targets are under investigation in NSCLC and mesothelioma in early phases, with mixed activity signals.

What role will radiation therapy play to complement or augment immunotherapies in the future?

Gadgeel: Radiation therapy may augment immunotherapy effects. Some data suggest that an interaction with immunotherapy leads to immune activation. Radiation plus checkpoint inhibitors may turn "cold" tumors into "hot" tumors.

The strongest evidence supporting the use of immunotherapy with radiotherapy has emerged from the trials performed in locally advanced nonmetastatic NSCLC. In the , patients with unresectable, stage III NSCLC without disease progression after platinum-based concurrent chemoradiotherapy were randomly assigned to receive either durvalumab, an anti–PD-L1 antibody, or placebo for 12 months. The median PFS improved from 16.8 months with durvalumab versus 5.6 months with placebo, and overall survival was also significantly prolonged. Analysis after revealed a median overall survival of 47.5 versus 29.1 months and PFS of 16.9 versus 5.6 months

Radiation could be a good partner with immunotherapy. Further studies may tailor fractionation and dosing based on tumor characteristics so radiation promotes an immune response and better efficacy of immune agents.

What is the bottom-line message for practicing oncologists?

Gadgeel: We are at the beginning of immunotherapy in lung cancer. We can expect new agents and see better benefits in patients with current immunotherapy agents, including benefits in those who don't show benefits now. In the future, immunotherapy will be personalized for patients so that they derive a distinct benefit.

Read the review here.