Revolutionary Study Demonstrates Safety and Efficacy of Neoantigen DNA Vaccines in Breast Cancer

Cancer neoantigens refer to polypeptide or amino acid sequences that are modified in a tumor to which the immune system can mount a response. The past decade has also seen advances in cancer sequencing and other biotechnologies which have greatly enhanced the capacity to delineate cancer neoantigens. We undertook one of the first preclinical studies aimed at assessing the possibility of identifying neoantigens by employing an immunogenomics approach.   

A recent study published in Genome Medicine showed that cancer neoantigens are important targets of cancer immunoediting and established the initial proof of concept that cancer exome sequencing and epitope prediction algorithms can reveal cancer neoantigens. In later studies on human clinical trials, we showed that the vaccination with a neoantigen-containing vaccine could elicit CD8 and CD4 T cell responses which are specific to the target neoantigen, resulting in the induction of anti-tumor immunity. 

The clinical protocol was reviewed and approved by the Institutional Review Board at Washington University School of Medicine. Patients were consented over a period of 35 months from June 2015 to February 2018. Patients with persistent TNBC following neoadjuvant chemotherapy were eligible for participation. Patients with evidence of metastatic breast cancer or autoimmune disorders were excluded. Subjects enrolled in the protocol provided germline (peripheral blood) and tumor DNA samples, and consent for tumor/normal exome sequencing and data sharing in a controlled access database (dbGaP).  

Tumor/normal exome sequencing as well as tumor RNA sequencing were employed to identify expressed somatic mutations. Can sarcomas be vaccinated by designing the neoantigen processes using pVACtools software? To manufacture the vaccines in an academic GMP facility, there was a need to identify and rank cancer neoantigens employing the algorithms. Electroporation was used to deliver the neoantigen DNA vaccines in conjunction with following surgical excision of the primary tumor and after completing standard care treatments. The safety and immune responses to the vaccines were evaluated using ELIspot, flow cytometry for intracellular cytokine production, and TCR sequencing. 

All participants received 4 mg of the neoantigen DNA vaccine at baseline, day 29±7, and day 57±7. Each neoantigen DNA vaccine was delivered intramuscularly using the TriGrid™ electroporation device (ICHOR Medical Systems, San Diego, CA). Each subject underwent monitoring through follow-up visits at weeks 11, 24, and 52, and additional follow-up visits or a telephone contact yearly thereafter. The main purpose of this clinical trial was to find out the safety of the neoantigen DNA vaccine strategy.

Safety was thoroughly evaluated following vaccination with eight or more clinical and laboratory assessments conducted in the first 6 months of the trial. 18 subjects received three doses of neoantigen DNA vaccine, where one patient on average had 11 neoantigens (range 4-20). The vaccination procedures were generally tolerated with relatively few adverse events. Neoantigen–specific T-cell responses were recorded in 14 out of 18 Subjects by ELISpot and flow Cytometry. With a median follow-up at 36 months, the recurrence-free survival in the cohort of vaccinated patients was 87.5% (95% CI: 72.7 – 100%). 

The present study showed the earliest neo-vaccine study conducted on patients suffering purely with TNBC, has demonstrating the viability and promise of this vaccine therapy for this patient group. Previous studies have predominantly targeted cancers of the head and neck, glioblastoma, lower airway lung cancer, muscle-invasive bladder cancer, and severe cutaneous melanoma all of which are high mutation burden cancers. In contrast, our trial seeks breast cancer, which is considered a low mutational burden tumor. 

Despite of the small number of alterations it was nevertheless feasible to determine between 4 and 20 cancer neoantigens for each TNBC patient and most of them are in our trial elicited neoantigen-specific immune responses. Majorly using ELISpot as the readout, the antigen-specific immune response was detected in 14 of the 18 patients vaccinated. 

It is essential to acknowledge the benefits and disadvantages of using historic controls in clinical trials. A few notable limitations that include a selection of bias regarding who is enrolled in the trial, differences in patient demographics like where historical data is obtained from, the patient population in the study, and changing patient care considerations over time. However, the good clinical results seen following the administration of neoantigen DNA vaccination, which have a strong rationale for conducting further trials of neoantigen DNA vaccines in patients with TNBC.  

These results support further study of the neoantigen DNA vaccine platform in TNBC and other low mutation burden cancers. 

Reference: Zhang X, Goedegebuure SP, Chen MY, et al. Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients. Genome Med. 2024;16:131. doi: 10.1186/s13073-024-01388-3