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Neoantigen Detection Platform Picks up T-Cell Responses to Tumor Mutations

NEW YORK – Investigators at the La Jolla Institute for Immunology (LJI) and the University of California, San Diego, have developed a platform for systematically profiling tumor-specific neoantigens that the immune system uses to defend against somatic mutations found in tumors — an advance that is expected to help uncover potential immunotherapy targets or treatment-related biomarkers.

The team described its "identify-prioritize-validate" (IPV) approach for finding and validating CD4-positive and CD8-positive T-cell-targeted neoantigens in a study appearing in Science Translational Medicine on Wednesday.

The strategy combines bioinformatics approaches with tumor mutation and transcriptomic profiles generated from tumor and matched normal peripheral blood samples, along with autologous peripheral blood mononuclear cell (PBMC) culturing and synthetic peptic response assays.

While many neoantigen identification strategies proposed in the past have focused on predicted peptide alterations expected to impact human leukocyte antigen (HLA) molecule presentation on tumor cells, the IPV strategy picks up neoantigen targets of CD4-positive and CD8-positive T cells in an HLA-independent manner by incorporating functional validation steps to investigate neoantigen responses by an individual's own immune cells.

"IPV validates, rather than predicts, neoantigens," co-senior and co-corresponding authors Stephen Schoenberger, a cellular immunology, hematology, and oncology researcher affiliated with LJI and UCSD's Moores Cancer Center, and Bjoern Peters, an infectious disease and vaccine research and medicine researcher affiliated with LJI and UCSD, said in an email.

They noted that in vivo T-cell response generation "is a complex multistep process that isn't easily subsumed into a set of computational algorithms designed to model any specific feature of HLA class I presentation from endogenously expressed proteins."

In contrast, the IPV prioritization algorithm relies on bioinformatics to systematically assess all expressed mutations, together with an individual's blood sample-based peripheral T-cell repertoire, to find and continuously refine its predictions by focusing on mutation-associated sequence features with known immune effects.

When they used the IPV platform to search for and validate CD4-positive and CD8-positive T-cell-targeted neoantigens in a case of metastatic pancreatic ductal adenocarcinoma, for example, the investigators uncovered 16 suspicious mutations in 15 genes that were subsequently translated into 33 candidate 20-mer peptides to culture alongside cultured T cells from patient PBMCs.

Through pooled peptide experiments, the team narrowed in on nine neoantigen peptides linked to six tumor mutations that prompted T-cell responses — results that were subsequently explored in more detail using cytokine capture assays and neoantigen-specific T-cell library sequencing.

Likewise, the researchers tracked down previously unappreciated T-cell response-promoting neoantigens when it used the platform to assess 13 additional cancer cases spanning several tumor types, including a handful of cases profiled by targeted panel sequencing rather than exome sequencing.

"IPV has identified neoantigens across all tumor types so far tested," Schoenberger and Peters explained, "including many with tumor mutational burden (TMB) levels that are below thresholds required for most purely predictive algorithms."

Based on their findings, the researchers suggested that the IPV platform may help uncover clinically relevant neoantigens. This approach may particularly enable the development of personalized cancer vaccines, Schoenberger and Peters explained. That possibility is now being explored in preclinical studies and a UCSD Moores Cancer Center Phase Ib clinical trial focused on low tumor mutational burden cancer cases.

"[W]e are preparing to extend these efforts to next-generation vaccines that synergistically coordinate neoantigen-specific CD4-positive and CD8-positive T-cell responses in a manner analogous to that used by the immune system to control microbial pathogens," they said, adding that the team is "also exploring whether the IPV platform can provide predictive biomarkers for response to immune checkpoint blockade in hopes of extending that lifesaving approach to more patients."

Together with their collaborators at LJI and UCSD, they have established a company to further develop the platform for personalized immunotherapy. A patent on the IPV platform was submitted by LJI and UCSD listing Schoenberger, Peters, and other study authors as inventors.