Speciality Chemicals Magazine MAR / APR 2024 | Page 52

Neoantigen peptides for novel immunotherapy in pancreatic cancer

Dr Guotao Li , director of peptide R & D at GenScript Biotech , offers an overview of an emerging class of peptides

Pancreatic cancer is one of the most lethal malignancies , characterised by a dismal prognosis and limited treatment options . Conventional therapies , such as surgery , chemotherapy and radiation , have shown limited efficacy in improving patient outcomes .

The emergence of immunotherapy as a promising approach for cancer treatment has led to the exploration of novel strategies , including the use of neoantigen peptides . These are tumour-specific antigens that arise from somatic mutations in cancer cells , making them attractive targets for immunotherapy .

Role of neoantigens

Neoantigen peptides are derived from tumour-specific mutations and have the potential to elicit a robust immune response . The immune system recognises them as foreign entities , leading to the activation of cytotoxic T cells and the generation of an antitumour immune response .

The specificity of neoantigens for cancer cells makes them an attractive target for immunotherapy , as they have the potential to selectively target and destroy tumour cells while sparing normal tissues . Moreover , they can overcome the immunosuppressive microenvironment of pancreatic cancer , providing a promising avenue for overcoming the immune evasion mechanisms employed by the tumour .

Despite this promising potential , several challenges exist in harnessing them for immunotherapy in pancreatic cancer . One of the major hurdles is the identification and validation of neoantigens that are truly

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immunogenic and can elicit a potent anti-tumour immune response .

The complexity of the tumour mutational landscape and the heterogeneity of neoantigens across different patients present significant challenges in personalised neoantigen-based immunotherapy . Additionally , the development of effective delivery systems and adjuvants to enhance the immunogenicity of neoantigen peptides is crucial for their successful application in clinical settings .

Unexpected preclinical discoveries

The untranslated regions ( UTRs ) in the mRNA play a crucial role in its translation , degradation and localisation , despite not coding for the final protein . The 5 ' UTR contains upstream open reading frames

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( uORFs ) that can interfere with translation initiation , affecting the main open reading frame of the gene .

However , recent research has found that some uORFs can be translated into peptides with unexpected functions . A team from Sun Yat-Sen University discovered that the uORF of the RNF10 gene could serve as an antigenic epitope , supporting the development of a novel immunotherapy ( Figure 2 ). 2

The RNF family of E3 ubiquitin ligases is essential in maintaining cellular functions , with dysregulation observed in various diseases , including pancreatic cancer . The researchers screened the expression levels of RNF family members in the CT26 cancer cell line and found that RNF10 was most abundant . The uORF region of RNF10 was found to produce a neoantigen peptide ( uPeptide ) that

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