A preclinical study has provided in vitro and in vivo evidence for using mutated KRAS epitopes as a viable target for neoantigen-based immunotherapy against solid cancers.
KRAS mutations in solid cancers
In recent years, immunotherapy has transformed the cancer treatment landscape. It has proven to be a success in improving the survival outcomes of patients who ae resistant to traditional therapies. However, not all patients have responded positively to these existing immunotherapies, especially those with advanced solid tumours. As a result, there is great interest in discovering new immunotherapeutic targets to expand the benefits to more patients.
KRAS mutations are some of the most common mutations in human cancer. They are predominately found in pancreatic, lung and colorectal carcinomas where they drive tumour development and growth. Over 75% of KRAS protein alterations occur at the G12 site, therefore making it an ideal drug target.
However, only one small molecular inhibitor has been successfully developed for a specific KRAS G12 mutation that is found in lung cancer. There are currently no available treatments targeting G12 variants that are prevalent in other types of tumours.
Neoantigen-based immunotherapy
Recently, researchers from the Abramson Cancer Centre at Penn Medicine developed a neoantigen-based immunotherapy against KRAS–mutated cancers. The preclinical study was published in Nature Communications.
Neoantigens are cell-surface proteins expressed by cancer cells as a result of mutations in the tumour genome. They represent tumour-specific antigens (epitopes) targeted by T cell receptors (TCRs) on T cells during the anti-tumour immune response. For T cells to be activated, the TCRs must also recognise the specific human leukocyte antigen (HLA) expressed by host cells. HLAs present epitopes as an epitope-HLA complex to specific TCRs and are thus indispensable for T cell-mediated immune responses. HLA is also highly variable within the human population.
There has been much interest in developing neoantigen-targeted cancer vaccines and adoptive T cell therapies. Such treatment is considered to be highly personalised as somatic tumour mutations are often unique to patients. The high prevalence and conserved mutational profile of KRAS may allow for a broadly generalisable neoantigen-based therapy. However, KRAS epitopes are poorly characterised as an immunotherapeutic target.
KRAS as an immunotherapeutic target
Using a multi-omics approach, the researchers identified mutated KRAS G12 neoantigens presented on HLA types commonly expressed by cancer patients. They employed computational epitope prediction, biochemical assays of HLA binding and stability, and proteomics analysis.
To induce the production of neoantigen-reactive TCRs, the researchers co-cultured selected neoantigens with cytotoxic T cells derived from healthy donors. They isolated three TCRs each directed towards a specific mutated G12 epitope in combination with a particular HLA type.
The researchers further showed that engineered T cells armed with these TCRs exhibited cytotoxicity against in vitro tumour cell lines. Importantly, the cells did not react to wild-type KRAS peptides. Even more promisingly, the adoptive transfer of the T cells into a mouse model of metastatic lung cancer prolonged survival and led to tumour eradication.
Future directions
This preclinical study has supported KRAS as a clinical target for immune-based therapies. Given the ubiquity and recurrence of KRAS mutations, it is a feasible target for treating lung, colorectal and pancreatic tumours.
These findings have laid the foundation for a pending clinical trial for a vaccine targeting pancreatic cancers with both the KRAS mutations and specific HLA types identified in the current study. If successful, the vaccine would benefit up to 10% of pancreatic cancer patients. The trial is expected to launch in 2022, subject to regulatory approval, at Penn’s Abramson Cancer Centre.
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