A groundbreaking phase II randomized clinical trial is evaluating the combination of personalized neoantigen peptide vaccines with precision radiotherapy for patients with advanced malignant tumors who have exhausted standard treatment options. This multicenter study represents the first clinical investigation to combine these two therapeutic modalities for stage IV pan-cancer treatment.
The trial employs an innovative open-label, two-arm design that randomizes patients 1:1 into either a control group receiving conventional treatment plus radiotherapy, or an intervention group receiving personalized tumor peptide vaccines combined with conventional treatment and radiotherapy. A unique crossover feature allows control group patients to transition to vaccine treatment upon radiologically confirmed disease progression, creating treatment opportunities for a broader patient population while maintaining scientific rigor.
Treatment Protocol and Design
The study protocol follows a carefully sequenced approach, with precision radiotherapy administered first, followed by individualized neoantigen peptide vaccination one week later. The radiotherapy component utilizes Critical Lesion Eliminating Radiation Therapy (CLERT), delivered in three sessions over one week using either high-dose (8-10 Gy × 3) or low-dose (2 Gy × 3) stereotactic body radiation therapy regimens.
For neoantigen identification, the research team employs three independent prediction platforms - TruNeo®, ImmuneMirror, and a Bayesian-based model - to enhance prediction reliability. The top 20 overlapping mutant peptides identified by at least two algorithms are selected as vaccine targets, ensuring higher accuracy and minimizing the risk of selecting non-functional peptides.
The personalized vaccine treatment extends over five months, beginning with a "prime phase" involving vaccinations on days 1, 4, 8, 15, and 22, followed by "booster phase" treatments at weeks 12 and 20. Each vaccination consists of up to four injection pools containing up to five peptides each, with individual peptides dosed at 0.3 mg and mixed with Poly I:C adjuvant.
Patient Population and Endpoints
The trial targets patients aged 18-80 years with advanced or recurrent malignant tumors who have failed standard treatments and currently lack effective first-line options. Eligible patients must have at least one radiologically measurable lesion, an expected survival time of three months or more, and an ECOG performance status of 0-2 points.
The primary endpoint is progression-free survival, evaluated using RECIST 1.1 criteria with FDG-PET/CT inclusion. Secondary endpoints include the incidence and severity of adverse events, overall survival, objective response rate, in-field response to local radiotherapy, and distant response rate.
Scientific Rationale and Innovation
The combination approach is based on emerging evidence that radiotherapy can enhance neoantigen presentation and immune activation. High-dose radiotherapy exceeding 8 Gy promotes immunogenic cell death and T cell activation, while also increasing regulatory T cells and myeloid-derived suppressor cells. Low-dose radiotherapy below 2 Gy reshapes the tumor microenvironment with lower toxicity, enabling multi-site irradiation while maximizing immunomodulatory effects.
Preclinical studies have demonstrated that radiotherapy induces neoantigen release, and when combined with neoantigen vaccines, leads to expansion of neoantigen-specific CD4+ and CD8+ T cells, significantly enhancing anti-tumor effects. The trial design allows investigation of how different radiation doses impact vaccine immunogenicity and clinical outcomes.
Sample Size and Statistical Considerations
Based on statistical calculations assuming a median progression-free survival of 4 months in the control group versus 8-10 months in the vaccine group, the study aims to enroll 154 patients with 77 subjects in each group to achieve 80% statistical power. An interim analysis at 6 months with 40 patients will provide preliminary efficacy data to determine whether to continue recruitment.
The crossover design addresses ethical considerations while maintaining statistical integrity, as progression-free survival analysis will be based solely on data collected prior to crossover. Advanced statistical methods including rank preserving structural failure time and inverse probability of censoring weighting will adjust for treatment switching effects.
Broader Implications
This trial addresses a critical unmet need for patients with advanced cancer who have limited treatment options. The response rate for radiotherapy or neoantigen vaccines alone in advanced tumor patients is approximately 30%, highlighting the potential for synergistic effects when combined.
The study also explores the concept of shared neoantigens across different cancer types, potentially enabling development of universal vaccines for patients harboring specific genetic mutations such as TP53, KRAS, or EGFR. This approach could particularly benefit rare tumor populations lacking new treatment options.
Patient recruitment began in January 2024, with enrollment expected to continue over the next 2-3 years. The trial has received support from the Global Collaborative Oncology Group and is registered under identifier GCOG0028, representing a significant step forward in personalized cancer immunotherapy.
