Surreal illustration of lungs filled with glowing immunotherapy particles.

Breathe Easier: Inhaled Immunotherapy Shows Promise for Lung Cancer Treatment

Elliot Brynn in Health & Wellness November 2026 • 4 min read.

"New research highlights the potential of inhaled TLR9 agonists in combination with anti-PD-1 therapy to revolutionize lung cancer immunotherapy."

Lung cancer remains a formidable challenge, often diagnosed at advanced stages where treatment options are limited. Traditional approaches like chemotherapy and radiation can have significant side effects, impacting patients' quality of life. Immunotherapy, which harnesses the body's own immune system to fight cancer, has emerged as a promising alternative, but its effectiveness varies among individuals.

One innovative strategy involves the use of Toll-Like Receptor 9 (TLR9) agonists, which stimulate the immune system to recognize and attack cancer cells. These agonists, when delivered directly to the lungs via inhalation, can generate a localized immune response, potentially minimizing systemic side effects. Recent research has focused on combining TLR9 agonists with anti-PD-1 therapies, which block the programmed cell death protein 1 (PD-1) pathway, further enhancing the immune response against cancer.

This article delves into a groundbreaking study on DV281, a novel C-class CpG-ODN (cytidine-phospho-guanosine oligodeoxynucleotide), and its potential as an inhaled immunotherapeutic for lung cancer. We'll explore the pharmacological profile of DV281 in preclinical models, including mice and non-human primates, as well as its effects on human primary cells. This research highlights the promise of inhaled immunotherapies in revolutionizing lung cancer treatment.

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Stats & Impact

Why Lung Health Matters

The lungs are the body's gas-exchanging organs, providing tissues with a continuous supply of oxygen and removing carbon dioxide from the blood. A typical adult lung weighs about 2.2 pounds (1 kilogram) and measures a little more than 9 inches (about 24 centimeters) during normal breathing. The American Lung Association provides resources for managing conditions including asthma, COPD, lung cancer, and pulmonary fibrosis.

What is DV281 and How Does it Work?

Surreal illustration of lungs filled with glowing immunotherapy particles.

DV281 is a synthetic oligodeoxynucleotide containing CpG motifs, which are specific DNA sequences that activate the TLR9 receptor. TLR9 is primarily found in plasmacytoid dendritic cells (pDCs) and B cells, both of which play critical roles in the immune response. When DV281 binds to TLR9, it triggers a cascade of intracellular signaling events, leading to the production of interferon-alpha (IFN-α) and other cytokines that stimulate the immune system.

The localized delivery of DV281 to the lungs via inhalation is a key aspect of its therapeutic potential. By directly targeting the tumor microenvironment and associated lymph nodes, DV281 can:

Enhance the recruitment and activation of immune cells within the lungs.
Promote the development of a Th1-biased immune response, which is crucial for effective cancer cell killing.
Minimize systemic exposure and potential off-target effects.

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Latest Research

Immune Activation in the Lung

Recent reviews describe combining immune-stimulating agents with checkpoint inhibitors as a strategy for lung cancer immunotherapy. In lung tumor models involving mice and monkeys, a TLR9 agonist combined with an anti-PD-1 agent produced better outcomes, while IFN-γ was noted to upregulate PD-L1 in tumors. The CpG oligodeoxynucleotide DV281 and TLR7/8 agonists are also being studied with immune checkpoint inhibitors to induce cytokine and chemokine responses. In human cell experiments, DV281 promoted IFN-α production in peripheral blood mononuclear cells and increased IL-6 expression in B cells.

Counterpoints

Safety Concerns

A cited study reports that CpG-containing immunostimulatory DNA sequences caused TNF-alpha-dependent toxicity in rodents but not in humans. This finding highlights that immune-stimulating treatments can produce different safety outcomes across species. It also cautions against assuming that promising immune activation in preclinical models will translate directly into human treatment.

Furthermore, the combination of DV281 with anti-PD-1 therapy is designed to overcome the immune evasion mechanisms employed by cancer cells. Anti-PD-1 antibodies block the interaction between PD-1 and its ligand PD-L1, which are often overexpressed by tumor cells to suppress immune cell activity. By blocking this interaction, anti-PD-1 therapy restores the ability of immune cells to recognize and destroy cancer cells.

Looking Ahead: The Future of Inhaled Immunotherapy

The results of this preclinical study provide a strong rationale for further clinical development of inhaled DV281 in combination with anti-PD-1 therapy for lung cancer. A Phase 1b clinical trial (NCT03326752) evaluating the safety and preliminary efficacy of this combination is already underway, marking an important step towards bringing this innovative treatment approach to patients in need. As research continues and clinical trials progress, inhaled immunotherapy holds the potential to transform the landscape of lung cancer treatment, offering new hope for improved outcomes and enhanced quality of life.

What inhaled TLR9 evidence can show

The reported human-cell findings describe immune activity, not whether inhaled DV281 treats lung cancer in people. The evidence also places inhaled TLR agonists at the preclinical stage, so it does not establish clinical benefit.^{[1] [2]}

Local delivery of CpG-ODN can generate immune responses in the lung, while responses to repeated intranasal DV281 in mice were partly to fully reversible after dosing stopped and were absent in TLR9-deficient mice. Together, these findings support a link to TLR9 signaling but do not establish how patients would respond.^[3]

How DV281 fits the wider evidence

A separate review reports better outcomes with a TLR9 agonist plus anti-PD-1 in mouse and monkey lung tumor models, and notes that IFN-γ can upregulate PD-L1 in tumors. These animal-model results are consistent with investigating a combination, but do not establish its effect in people.^[4]

Other reviews describe TLR activation as influencing immune balance in the tumor microenvironment, while a review of inhaled approaches characterizes inhaled TLR9 agonists as promising in preclinical studies. These accounts provide context for the rationale without demonstrating that inhalation improves clinical outcomes.^{[1] [5]}

What remains unresolved for inhaled DV281

Do immune responses observed in human cells translate into meaningful tumor control in patients? The cited human-cell findings report cytokine changes, while the cited efficacy outcomes come from animal lung tumor models.^{[2] [4]}
How durable and clinically relevant are the lung responses to repeated DV281? The reported mouse responses were reversible after dosing stopped, but these observations do not establish the duration of benefit in people.^[3]

Sources

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.intimp.2018.11.019, Alternate LINK

Title: Preclinical Development Of The Tlr9 Agonist Dv281 As An Inhaled Aerosolized Immunotherapeutic For Lung Cancer: Pharmacological Profile In Mice, Non-Human Primates, And Human Primary Cells

Subject: Pharmacology

Journal: International Immunopharmacology

Publisher: Elsevier BV

Authors: Sariah A. Kell, Melissa A. Kachura, Alex Renn, Paula Traquina, Robert L. Coffman, John D. Campbell

Published: 2019-01-01

Everything You Need To Know

What exactly is DV281 and how does it function within the body?

DV281 is a novel C-class CpG-ODN (cytidine-phospho-guanosine oligodeoxynucleotide) that is being investigated as an inhaled immunotherapeutic for lung cancer. It works by activating the TLR9 receptor, primarily found in plasmacytoid dendritic cells (pDCs) and B cells, which are crucial for immune response. When DV281 binds to TLR9, it triggers a cascade of events, leading to the production of interferon-alpha (IFN-α) and other cytokines that stimulate the immune system. This localized delivery to the lungs via inhalation enhances immune cell activity, promotes a Th1-biased immune response, and minimizes systemic exposure.

Why is inhaled immunotherapy, such as DV281, considered significant in the context of lung cancer treatment?

Inhaled immunotherapy, such as that using DV281, is significant because it offers a more targeted and potentially less invasive approach to treating lung cancer. Lung cancer is often diagnosed at advanced stages, and traditional treatments have significant side effects. Inhaling DV281 directly to the lungs allows it to target the tumor microenvironment and associated lymph nodes, leading to a localized immune response. This approach can enhance the recruitment and activation of immune cells within the lungs, promoting a Th1-biased immune response, which is crucial for effective cancer cell killing. The goal is to minimize systemic side effects and improve outcomes for patients.

What is the role of TLR9 agonists in cancer treatment, and why are they important?

TLR9 agonists, like DV281, are important because they stimulate the immune system to recognize and attack cancer cells. TLR9 is a receptor that activates the immune system, and when DV281 binds to it, it triggers a cascade of intracellular signaling events, leading to the production of interferon-alpha (IFN-α) and other cytokines that stimulate the immune system. By delivering these agonists directly to the lungs via inhalation, researchers aim to generate a localized immune response, potentially minimizing systemic side effects, and enhancing the body's ability to fight cancer.

How does anti-PD-1 therapy work to fight cancer, and why is it used in conjunction with DV281?

Anti-PD-1 therapy works by blocking the programmed cell death protein 1 (PD-1) pathway. Cancer cells often use PD-1 and its ligand PD-L1 to suppress immune cell activity, allowing the cancer to evade the immune system. Anti-PD-1 antibodies block the interaction between PD-1 and PD-L1, which restores the ability of immune cells to recognize and destroy cancer cells. Combining DV281 with anti-PD-1 therapy aims to overcome the immune evasion mechanisms employed by cancer cells, further enhancing the immune response against the cancer.

What are the potential implications of this research for the future of lung cancer treatment?

The implications of this research are substantial, especially for lung cancer patients. A Phase 1b clinical trial (NCT03326752) is already underway to evaluate the safety and preliminary efficacy of combining inhaled DV281 with anti-PD-1 therapy. If successful, this approach could transform the treatment landscape, potentially leading to more effective and less invasive treatments, improved outcomes, and an enhanced quality of life for patients. This innovative treatment has the potential to offer new hope.