New Lung Cancer Vaccines in Development

Types of Lung Cancer Vaccines

mRNA vaccines

The recent success of mRNA-based vaccines against SARS-CoV-2 has highlighted the evolving vaccines field, raising renewed hope that this strategy can be successfully applied for cancer treatment. The success of mRNA-based vaccines against infectious diseases like SARS-CoV-2 has highlighted the potential of this technology for cancer treatment (8).

These vaccines use messenger RNA (mRNA) to deliver genetic instructions to cells, prompting them to produce specific proteins that can trigger an immune response against cancer cells. mRNA allows transient and controlled protein expression while avoiding genomic integration.

mRNA vaccines are also under investigation in NSCLC. The mRNA lung cancer vaccine, BNT116 (FixVac), made by BioNTech, is being trialled in patients to treat NSCLC. The vaccine works by presenting the immune system with tumor antigens from six shared lung cancer associated antigens frequently expressed in NSCLC, aiming to trigger a strong and precise immune response. The vaccine is currently being evaluated in a an ongoing Phase 1 dose confirmation trial in patients with advanced or metastatic NSCLC and in a Phase 2 trial in combination with cemiplimab, a PD-1 inhibitor (7).

The phase 1 clinical trial (LuCa-MERIT-1) is being conducted across 34 research sites in seven countries, including the UK, US, Germany, Hungary, Poland, Spain, and Turkey.

Preliminary results from patients with metastatic NSCLC receiving BNT116 + docetaxel were presented in the AACR conference in April 2024. As of 1 Dec 2023, 20 patients have received BNT116 in addition to docetaxel. The combination demonstrated a manageable safety profile and no signs of additive toxicity. BNT116 + DTX shows encouraging antitumor activity, seven of 20 patients (35%) had a partial response, 10 of 20 patients (50%) had stable disease. The objective response rate was 35% (95% CI: 15.4-59.2) and the disease control rate was 85% (95% CI: 62.1-96.8). Robust antigen-specific T-cell responses and cytokine induction were observed even with the addition of docetaxel.

Personalized Cancer Vaccines

Personalized cancer vaccines or individualized neoantigen therapies are designed to train and activate an antitumor immune response by generating specific immune responses based on the unique genetic mutations present in an individual’s cancer cells. This bespoke approach allows for a more precise and effective immune response against cancer cells. Techniques such as next-generation sequencing and bioinformatics are used to identify the specific mutations in a patient’s cancer, enabling the creation of a vaccine that targets these unique markers.

V940 (mRNA-4157) is a novel investigational mRNA-based individualized neoantigen therapy (INT) consisting of a synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient’s tumor.

The Mobilize trial (NCT05533697) is a phase 1/2 clinical trial evaluating the safety and anti-tumour activity of mRNA-4359 in adults who have confirmed locally advanced or metastatic cancer. The Arm 1a of the study is recruting patients with metastatic NSCLC who have received, and then progressed, relapsed, or been intolerant to, or ineligible for, at least 1 standard treatment regimen in the advanced or metastatic setting. Participants with a known driver mutation like RET patients must have also received or been offered a mutation-directed therapy. Participants must have a tumor lesion amenable to biopsy.

In December 2023 Merck and Moderna started a Phase 3 clinical trial evaluating the mRNA personalized vaccine V940 (mRNA-4157) in combination with immune checkpoint blockade pembrolizumab for resected stage II, IIIA or IIIB NSCLC. The trial is called INTerpath-002 (NCT06077760) (9).

Also the KEYNOTE-603 study (NCT03313778) evaluates the the safety, tolerability, and immunogenicity of mRNA-4157 alone and in combination in participants with solid tumors including resectable NSCLC A recent study of of mRNA-4157 in NSCLC patients showed generation of de novo and enhancement of existing neoantigen-specific T-cell responses in patients with resected solid tumors (10).

Also, the results of the Phase 2b clinical trial of mRNA-4157 plus pembrolizumab in patients with resected high-risk melanoma showed efficacy and a manageable safety profile (11).

In addition to this, the Jaime Leandro Foundation (JLF) is a private nonprofit organization that is assisting in the development of personalized vaccines leveraging the FDA’s Expanded Access rule. The JLF process involves different phases for the development of a personalized therapeutic vaccine that will take approximately 4-5 months. More info here.Cell-Based Vaccines

Cell-based vaccines are designed using patient’s own immune cells (dendritic cells) aiming to kill cancer cells. The dendritic cells are cultured with lung tumor antigens, and subsequently the antigen-loaded dendritic cells are reinfused into the patient. Some pilot studies using neoantigen peptide-pulsed autologous dendritic cell vaccine were conducted showing feasibility for this new approach for treating lung cancer. However, some dendritic cell-based immunotherapy studies has shown low response rates in lung cancer patients pointing out some limitations of this approach (1-4). Various strategies including the combination with other immunotherapies, are being developed to improve the effectiveness of dendritic cell vaccines.

Peptide-Specific Vaccines

Peptide-based vaccines mimic the epitopes of the antigen that triggers an anticancer immune response, specifically targeting cancer cell proteins. Peptide vaccines are based on in vitro–synthesized peptides known to be highly immunogenic. The peptide vaccines could limit significantly the chances for allergenic and other complications but they require carriers or adjuvants to counterbalance the low efficiency.

Several peptide/protein-specific vaccines have been investigated in NSCLC, including MAGE-A3 (MAGE expression is found in 30–50% of NSCLC samples, being more frequent in squamous cell lung cancer. Treatment with the MAGE-A3 vaccine did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on these results, further development of the MAGE-A3 vaccine for use in NSCLC has been stopped (5).

Studies are investigating the treatment of therapeutic vaccine against epidermal growth factor (CIMAvax-EGF) for NSCLC patients. Different trials are evaluating the activity of the vaccine in combination with anti-PD1 immune checkpoint inhibitor (NCT02955290)(6).

Preventing Lung Cancer with Vaccines

Lung cancer remains a leading cause of cancer-related deaths worldwide. While current treatments can be effective, they often come with significant side effects. Cancer vaccines offer a promising alternative for preventing lung cancer by stimulating the immune system to recognize and attack abnormal lung cells before they develop into full-blown cancer.

Some successful vaccine approaches have been developed such as Gardasil for preventing human papillomavirus-driven cervical, vaginal, and vulvar cancers.

Researchers at the University of Oxford, the Francis Crick Institute and University College London have been granted £1.7 million of funding from Cancer Research UK and the CRIS Cancer Foundation to develop a lung cancer vaccine. The study will be called LungVax and there will be a Phase I dose-escalation and Phase II prevention trial of ChAdOx2-lungvax-NYESO vaccination for patients at risk of new or recurrent NSCLC. This vaccine targets specific cancer mutations to activate a robust T cell response to recognize and kill cancer cells.

Vaccines for Oncogene-Driven NSCLC

• ALK rearrangement is found in approximately 5–6% of NSCLC, and an ALK vaccine has shown promise in preclinical studies. The vaccine produce effective immune responses that eradicated primary tumors and metastatic in mice (14). The investigators are conducting a small, phase 1 clinical trial in 20-25 humans to confirm the safety and efficacy of the new vaccine (15).
• KRAS mutations can occur in 20-30% of NSCLC. KRAS mutation-based cancer vaccines have shown encouraging results at preventing relapse of KRAS-mutated cancers in a Phase I trial led by researchers at MD Anderson Cancer Center (16). Also a mucosal vaccine against KRAS demonstrated the ability to induce local immune responses in the lung and resulted in reduced tumor growth (17).

Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells. One of the main limitations is the complexity of identifying specific target tumor antigens shared by multiple tumor types. One of the significant challenges is the heterogeneity of lung cancer patients, which complicates the development of universally effective vaccines (17).

• Cancer vaccines aim to exploit the body’s immune system to activate long-lasting memory against tumor cells.
• Different vaccine approaches are currently under investigation for the prevention and treatment of NSCLC patients.
• mRNA vaccines are currently being tested for NSCLC treatment including BNT116 and the personalized vaccine V940 (mRNA-4157). With ongoing clinical trials and funding, lung cancer vaccines may transform lung cancer survival globally.