What are lung cancer vaccines and how do they work?
While vaccines have traditionally been used in the intervention and risk reduction of infectious diseases, there have been attempts to leverage these same vaccine technologies against various cancers over the past 40 years.
All vaccination strategies work by educating a patient’s immune system to recognise and attack a particular target. In the context of the influenza vaccine, the immune system is exposed to proteins found along the surface of the influenza virus, known as antigens. When the body is exposed to the virus the immune system is already trained to recognise and destroy the virus if it is encountered.
Cancer vaccines are not too dissimilar. Many tumours, including in lung cancer and mesothelioma, the cancer cells express cancer associated antigens or neoantigens that are often unique to the cancer cells. A well-known cancer-associated antigen is PSA (prostate-specific antigen) found in prostate cancer. While a neoantigen is a newly formed antigen that arises due to cancer specific mutations or other molecular changes within the cancer cells. With this knowledge, cancer vaccines can be developed to train the immune system to identify cancer cells and remove them.
Figure adapted from Chen & Han (2020). Anti–PD-1/PD-L1 immunotherapy of cancer: current and future strategies. Nature Reviews Immunology, 20, 127–144. https://doi.org/10.1038/s41577-020-0306-5
What types of vaccines exist?
There are several features and properties that can be used to define the type of vaccine.
Different technologies
There are many different technologies that can be used to generate a vaccine, but broadly speaking, they can be defined as one of five categories:
- Peptide–based: Delivers short tumour-specific protein fragments as either free peptides, mounted peptides or encapsulated in nanoparticles.
- Cell-based: Uses whole inactivated, homogenised or modified tumour cells or other host immune cells loaded with the antigen of interest.
- RNA: Introduces messenger RNA (mRNA) encoding tumour antigens, where the host cells translate the mRNA into protein and presents these antigens to activate immunity.
- DNA: Similar to RNA but using plasmid DNA that encodes the tumour antigens.
- Viral: Employs engineered viruses to deliver tumour antigen genes or present the antigens directly to the immune system.
Prophylactic/preventative vs treatment vaccines
Based on the strategy of vaccination, a vaccine can be considered as prophylactic where it is used as a preventative measure to reduce the risk or impact of disease, or a vaccine can be used as a form of treatment.
Prophylactic vaccines are commonly used to reduce the disease burden of infectious diseases. In some cancers, infectious diseases have been associated to cancer incidence. For example, the relationship between HPV and cervical cancer is well established and through a combination of Australia’s HPV vaccination and cervical cancer screening programs, Australia is on track to eliminate cervical cancer by 2035.
In lung cancer, the 2024 LungVax program was announced in the UK that aims to develop a DNA-based prophylactic vaccine targeting common antigens to prevent non-small cell lung cancer (NSCLC) in people at high risk.
Most thoracic oncology vaccine programs are being developed as a cancer treatment, such as MSD and Moderna’s mRNA-4157 also known as V940, and BNT116 under development by BioNTech. Both treatment vaccines are harnessing mRNA-based technologies to treat patients who have a confirmed NSCLC diagnosis.
Personalised vs off-the-shelf vaccines
Another consideration around cancer vaccine strategy is whether the product is personalised or off-the-shelf. The BNT116 vaccine is considered off-the-shelf, where the vaccine encodes for a set of 6 antigens commonly found on NSCLC cells. All patients treated with this vaccine will receive the same product encoding this set of antigens. The off-the-shelf approach offers the benefit of a product that is immediately available to patients, is more cost-effective, and targets cancer antigens that are well-defined and thoroughly profiled.
A personalised vaccine is tailored to an individual’s tumour and accommodates the specific way their cells present tumour antigens (a function of the individual’s HLA-type, which is a kind of frame for antigen presentation at the cell surface). A sample of the tumour is sequenced, machine learning algorithms are generally used to build the tumour mutanome and neoantigen profile, and a unique vaccine is formulated on a patient-by-patient basis. For the V940 vaccine, an individualised neoantigen vaccine is developed that encodes up to 34 neoantigens. The personalised vaccine approach is slower and more expensive than the off-the-shelf approach but is tailored precisely for each patient.
Over time, this strategy would enable machine learning/AI approaches to better understand vaccine design and neoantigen selection, which may improve both personalised and off-the-shelf vaccine development. Clinical trials are still ongoing to determine the efficacy and practicality of both approaches.
Current state of lung cancer vaccines
It is important to highlight that as of May 2025, no thoracic oncology vaccines have been approved and are all undergoing preclinical or clinical development.
In Australia, only the V940 vaccine is currently undergoing clinical trials through the INTerpath-002 (NCT06077760) and INTerpath-009 (NCT06623422) trials. Both are Phase III trials that aim to determine the potential benefit of adding V940 to pembrolizumab in the adjuvant treatment of NSCLC and focus on different patient populations based on prior treatment and pathological response.
Globally there are several key thoracic oncology vaccine trials underway. A notable vaccine candidate is the BNT116 vaccine for metastatic NSCLC either with cemiplimab, a PD-1 inhibitor, in the EMPOWERVAX Lung 1 trial (NCT05557591) or with other drug combinations or as a monotherapy in the LuCa-MERIT-1 trial (NCT05142189).
Further, cancer vaccines are also being explored for mesothelioma. The UV1 vaccine is a peptide-based product in a combination treatment with ipilimumab and nivolumab. The Phase II trial included sites in Australia with the vaccine targeting telomerase, which is dysregulated in 85-90% of all cancers, and has antigenic regions common to several HLA-types, so may offer opportunities across many cancer types and stages. Clinical validation is ongoing, with the UV1 vaccine received Fast Track designation in early 2024 by the U.S. Food and Drug Administration (FDA).
Successes in cancer vaccines outside of thoracic oncology
The enthusiasm towards the latest generation of thoracic cancer vaccines stems from a combination of factors, including the recent developments in vaccine technologies and genetic profiling, but critically, successes and promise observed in other cancer areas.
In melanoma, the V940 personalised neoantigen vaccine has shown promising signals in combination with pembrolizumab in the KEYNOTE-942 Phase IIb trial. The addition of the V940 vaccine prolonged recurrence-free survival versus pembrolizumab monotherapy. This warranted further investigation, with the Phase III INTerpath-001 currently ongoing.
Recently in pancreatic cancer, the autogene cevumeran (BNT122, RO7198457) personalised mRNA neoantigen vaccine containing up to 20 neoantigens jointly developed by BioNTech and Genentech reported on the 3-year follow-up data of a Phase I trial.
While still early in development, of the 16 patients treated, 8 showed T cells responses to the encoded neoantigens. Further, 6 of the 8 patients with an immune response remained disease–free during the 3-year follow-up period of the study. While further investigations are required, with a Phase II currently recruiting, these promising results compare to 7 of the 8 patients without an immune response showing tumour recurrence and pancreatic cancer having an abysmal 12% 5-year survival rate in Australia.
Benefits and Potential Advantages
The recent emergence of mRNA vaccine technology has spurred on a new generation of promising cancer vaccines, with several benefits and advantages compared to previous vaccine technologies.
One of the major advantages is the flexibility of the technology that enables highly personalised vaccines to be tailored to individual cancers, HLA-types and target evolution of disease over time. Once the genetic sequence of a tumour is known, a mRNA vaccine can be designed within days or less and then manufactured within weeks. These timelines are increasingly improving as design and manufacturing pipelines are optimised.
Due the scalability and processes of the mRNA technology manufacturing, product is synthesised recombinantly, relying on enzymatic processes and therefore, do not involve live cells or production of virus, unlike other vaccine technologies.
Due to the cell-free, enzyme-dependent processes in mRNA vaccine manufacturing, vaccine production can be scaled from a single patient through to hundreds or thousands of doses in a single batch. During the peak of the COVID19 pandemic, up to 2.5 billion doses of the Pfizer–BioNTech COMIRNATY COVID19 were reportedly produced in a single year. The combination of flexibility and scalability of this technology allows for mRNA vaccines to be tailored to each individual cancer and to also include multiple antigens.
While in theory, both DNA and peptide-based vaccine technologies could offer these advantages, the manufacturing of peptide-based vaccines is slower, offers less flexibility, and may stimulate all areas of the immune system required to induce an effective anti-tumour response or may require additional immunostimulants to induce a response.
Challenges and Limitations
There are opportunities for optimisation, whether this be in mRNA design such as the mRNA coding sequence, coding and non-coding elements, and nanoparticle formulation, through to clinical considerations such as the ideal drug combinations, use of vaccines as a monotherapy and patient selection.
As noted in the autogene cevumeran vaccine trial, in pancreatic cancer half of the patients did not launch an immune response from the neoantigen vaccine treatment. Further investigation is required to determine which patients are more likely to respond and whether the design of mRNA vaccine technologies can be further optimised to improve these response rates.
The durability of mRNA vaccination remains an open question. The COVID19 mRNA vaccines provide a relatively short-lived vaccination period over several months. Meanwhile, the autogene cevumeran vaccine has shown an average estimated CD8+T cell lifespan of 7.7 years in patients who responded to the vaccine. A further consideration around duration is the period the therapeutic mRNA exists within the body. Generally, synthetic mRNA lasts a few hours to a few days once administered. Emerging mRNA design, such as mRNA chemical modifications, coding optimisation, non-coding mRNA regulatory regents, self-replicating RNA and circular RNA will provide opportunities to prolong the lifetime of these synthetic mRNAs within the body and will address questions around whether mRNA lifetime and treatment durability impacts patient outcomes.
Other clinical priorities and challenges are discussed within the TOGA podcast on cancer vaccines. Despite these current challenges and unknowns, the early data emerging from the last various cancer vaccines is showing some promising evidence on both safety and efficacy. mRNA cancer vaccines are an exciting new class of immunotherapy with a lot of enthusiasm that they could deliver improved and effective thoracic cancer treatments.
Listen to the podcast Vaccines in Thoracic Oncology: The Next Frontier in Immunotherapy
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