Application of KRAS Vaccine in the Treatment of KRAS-mutated Malignancies

Safety and Efficacy of KRAS Vaccine in the Treatment of KRAS-mutant Malignancies

The goal of this study is to evaluate the safety and efficacy of mRNA vaccine for the KRAS mutation malignant tumors.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most prevalent oncogenes in humans and plays a pivotal role in tumor initiation and progression. KRAS mutations are observed in various cancers, particularly in non-small cell lung cancer, colorectal cancer, and pancreatic cancer. Mutations in the KRAS gene activate multiple signaling pathways, such as MAPK/ERK and PI3K/AKT, which regulate cell proliferation, survival, and migration, thereby driving tumor progression and the development of drug resistance. Due to its critical role in cancer, KRAS has emerged as a key therapeutic target. However, the structural characteristics of KRAS mutants have historically rendered direct inhibition of the KRAS protein extremely challenging, leading to its designation as an "undruggable" target over the past decades. Consequently, patients with KRAS-mutated malignancies face limited treatment efficacy and a lack of precision therapeutic options. In recent years, advances in scientific technologies have enabled the successful development and marketing of several drugs targeting specific KRAS mutations. Nevertheless, most existing therapies exhibit suboptimal efficacy, necessitating further exploration of treatments for broader mutation types and larger cancer populations.

mRNA vaccines represent a highly promising novel approach in oncology. Preliminary reviews of global clinical trials investigating tumor-related mRNA therapeutics reveal that current research primarily focuses on malignancies such as melanoma, prostate cancer, colorectal cancer, acute myeloid leukemia, and breast cancer, with most studies in Phase I/II. Published data demonstrate that mRNA-based cancer therapies exhibit significant potential in anticancer immunotherapy and favorable safety profiles. Given the promising antitumor efficacy of mRNA therapeutic vaccines targeting KRAS mutations in KRAS-mutated tumors, coupled with the limited treatment options and poor outcomes for most KRAS-mutated cancer patients, monotherapy with mRNA therapeutic vaccines or their combination with immune checkpoint inhibitors may offer substantial clinical benefits. Accordingly, the research team plans to conduct an "Exploratory Study on the Application of mRNA Vaccines Targeting KRAS Mutations in KRAS-Mutated Malignancies."

Key Inclusion Criteria:

• Male or female participants ≥18 years of age.
• Participants with solid tumors confirmed to carry KRAS mutations.
• At least one measurable lesion according to RECIST 1.1 criteria.
• ECOG physical condition score: 0-1 point.
• Adequate organ and bone marrow function.
• Ability to understand and voluntarily provide written informed consent before trial participation.

Cohort-specific Inclusion Criteria:

Cohort 1:

• Failure of prior standard therapy, intolerance to standard therapy, ineligibility for standard therapy, or absence of a standard treatment regimen.
• Life expectancy ≥3 months.

Cohort 2:

• Newly diagnosed, treatment-naïve lung adenocarcinoma confirmed by pathology (histology/cytology).
• Resectable disease classified as stage IB-IIIA per AJCC 9th edition criteria.
• KRAS G12C/G12D/G12V/G13D mutation-positive by genomic testing.

Exclusion Criteria:

• Patients with a history of other malignancies.
• Presence of primary central nervous system (CNS) tumors, active CNS metastatic tumors, or carcinomatous meningitis, either historically or identified during screening.
• Uncontrolled moderate to massive serous cavity effusion.
• Confirmed presence of other classic gene variants.
• Known cardiac clinical symptoms or diseases that are poorly controlled.
• Unstable thrombotic events (e.g., deep vein thrombosis, arterial thrombosis, pulmonary embolism) requiring therapeutic intervention within 6 months prior to screening.
• Any active autoimmune disease or a history of autoimmune disease.
• Uncontrolled clinical disorders, psychiatric illnesses, or other significant diseases as assessed by the investigator that may interfere with informed consent, compromise interpretation of trial results, pose risks to participants, or otherwise hinder the achievement of trial objectives.
• History of interstitial pneumonia or suspected interstitial pneumonia; or pulmonary abnormalities that may interfere with the detection or management of suspected drug-related pulmonary toxicity during the trial.
• Hypersensitivity to the investigational drug (including any excipients).
• Patients who received anti-tumor therapy within 4 weeks prior to the first dose, or those with unresolved adverse reactions (except alopecia) from prior anti-tumor therapy (NCI CTCAE > grade 1).
• Systemic use of corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressants within 14 days prior to the first dose.
• Participants who received drugs of the same class within 6 months prior to the first dose.
• Prior organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis infection.
• Active tuberculosis (TB) or a history of active TB; or severe acute/chronic infections requiring systemic treatment.
• Pregnant or lactating women.
• Any other factors deemed by the investigator to render the participant unsuitable for trial participation.