Vaccines are not oblivious, especially in 2021, but when we say ‘vaccine’ we usually refer to something that can prevent an infection. Have you ever heard of therapeutic vaccines? One revolutionary therapeutic vaccine for melanoma, a new personal neoantigen vaccine called NeoVax, was developed by Ott et al. and its early clinical outcome was published in 2017 Nature letter. There they determined that NeoVax is ‘safe and immunogenic in patients with high-risk melanoma´. Now, four years later, Hu et al. from the same research group published a follow up paper on the extended performance of the given vaccine. Up until this article, immune response studies in neoantigen-targeted vaccines had not extended over one year. Hu et al. studied patients after 4 years and proposed that vaccine administration induced differentiation of T cells to memory T cells which is beneficial for treatment of late stage cancers.
Melanoma is cancer of pigment producing skin cells (melanocytes); a type of skin cancer mostly caused by UV radiation. The peptide vaccine- NeoVax targets 13 to 20 new proteins per patient, called neoantigens, that cancer cells develop through mutations and it is personified specifically to induce immune response against the individual’s tumour while sparing the surrounding tissue and developing a long-lasting immune memory. In addition to the peptide vaccine there are whole-cell cancer vaccines and direct loading of tumor material or tumor antigen to autologous antigen presenting cells ex vivo.
The study by Hu et al. followed up patients included in the 2017 study, after almost 4 years. Those patients had curative surgery of stage 3 melanoma (where cancer cells have spread to nearby lymph nodes and not to distant organs) or stage 4 metastatic melanoma (where cancer cells have spread to distant organs, most often lungs). The scientists performed pre- and post-vaccine tumor specimens evaluation and reported that 96% of mutations encoding for the neoantigens (contained in the vaccine) were still present, suggesting that immune-editing of vaccine targets was not severe.
Hu et. al. reported long term persistence of both helper CD4+ and cytotoxic CD8+ T cells 4 years after vaccination, which are both important for long term tumour control. When looking at the cytokine profile of post-vaccination tumor samples, Hu et al. noticed the upregulation of IL-2 which is involved in T cell proliferation and differentiation and indicated that T cells are entering their effector state earlier than usual.
Prior to vaccination, neoantigen-specific T cells displayed ‘naive’ phenotype, but soon after administering the vaccine, these T cells displayed cytotoxic and AICD (activation induced cell death) signatures and had loss of effector function because of prolonged antigen stimulation. After the last vaccine booster most cells had ‘memory-like’ phenotype crucial for future immune response.
Next, the scientists discovered that following an immune check point therapy drug, pembrolizumab, a shift in T cell receptor (TCR) cells occurs. However, on measuring TCR repertoire kinetics in relation to vaccination, the researchers found that these neoantigen-specific T cells were already present at the beginning of the pembrolizumab therapy, suggesting that NeoVax might have caused the shift.
But that is not all, the study also led to another exciting finding. ‘Epitope spreading’ was detected early after vaccination- these T cells can recognize other neoantigens and tumor associated antigens (TAAs) expressed by tumor which were not already present in the vaccine. This phenomenon persists for a long period of time and is consistent with tumor progression-free survival.
Since, developing long-term immunity is a hallmark of cancer immunotherapy, persistence of neoantigen specific T cells even after 4 years of vaccination, is very encouraging. Unfortunately, NeoVax alone may not be enough of a solution for antitumor therapy, especially for patients with cancer recurrence. Does that mean there is no hope for patients with metastatic tumors? Combinatorial therapy is the way to go. In combination with immune-checkpoint therapy NeoVax could be the future of putting metastatic tumors (not only melanoma!) under control. In future, we are excited to see how cancer immunotherapy and vaccines can target heterogeneous tumors.
Article author: Ines Poljak. Ines is a MSc student at University of Copenhangen and works on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
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