EACR25-2222
Cancer immunotherapy revolutionized cancer treatment paradigms. Yet, only around 20% of the patients respond to immunotherapy. Neoantigens have emerged as promising targets in cancer immunotherapy since they are tumor-unique and can mediate an effective tumor-directed T-cell response. Recurrent neoantigens, derived from hotspot mutations, are becoming increasingly attractive targets for immunotherapy as they are shared among large groups of patients and may pave the way toward “off-the-shelf” cancer therapies. However, identifying immunogenic ‘HLA-peptide’ pairs represents a significant challenge. HLA genes are the most polymorphic region in the human genome and are highly variable. Our study aimed to uncover recurrent neoantigens presented by HLA class I molecules, focusing on genes linked to treatment resistance. This research is crucial because new approaches that generate long-lasting therapeutic responses are critically needed, especially for cancer patients with tumors that have evolved resistance to existing therapies.
We have developed a novel analysis pipeline, SpotNeoMet, emphasizing the identification of recurrent, clonal, driver mutation-derived neoantigens specifically presented on metastatic tumors resistant to specific targeted therapies. Analysis of large patient cohorts from the Hartwig Medical Foundation dataset and the Cancer Genome Atlas followed by systematic HLA immunopeptidomics.
In this study, using SpotNeoMet, we discovered three recurrently presented novel neo-peptides derived from the Androgen Receptor (AR) H875Y mutation, the most common castration-resistant prostate cancer mutation. We validated these neoantigens as highly immunogenic and isolated their cognate T-cell receptors (TCRs) from healthy donor PBMCs. Further characterization revealed that these TCRs are highly sensitive and specific to their targets, demonstrating remarkable efficiency in recognizing and eliminating prostate cancer cells presenting these neo-peptides.
The emergence of resistance to targeted treatments in metastatic cancer patients underscores the urgent need for innovative therapeutic approaches. Our study introduces SpotNeoMet, and using AR H875Y mutations as a proof of concept, we demonstrate the robustness of our pipeline in developing a T cell-based immunotherapy. SpotNeoMet promises a systematic method to uncover 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers. Importantly, our data suggest that resistance drivers can be transformed into therapeutic opportunities through various immunotherapy modalities.