An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Neoantigens are key targets for antitumor T-cell responses in cancer immunotherapy.
• Current in silico methods for neoantigen prediction have limitations in capturing the complexity of T-cell recognition.

Purpose of the Study:

• To develop and validate the ATLAS bioassay for empirical identification of neoantigens.
• To investigate the nature of T-cell responses (stimulatory vs. inhibitory) to neoantigens.
• To assess the therapeutic potential and safety of ATLAS-identified neoantigens in cancer treatment.

Main Methods:

• The ATLAS bioassay involves expressing patient-specific tumor mutations in E. coli, pulsing dendritic cells, and testing T-cell recognition.
• Profiling of T cells from lung cancer patients and evaluation in a murine melanoma model (B16F10).
• Clinical study involving a personalized vaccine with ATLAS-identified stimulatory neoantigens and poly-ICLC adjuvant.

Main Results:

• Profiling revealed both stimulatory and inhibitory T-cell responses to individual neoantigens.
• In mice, immunization with stimulatory neoantigens conferred protection, while inhibitory neoantigens accelerated tumor growth.
• A clinical study showed the personalized vaccine was well-tolerated, eliciting robust CD4+ and CD8+ T-cell responses to 99% of vaccinated antigens.

Conclusions:

• Empirical neoantigen screening via the ATLAS bioassay provides a more nuanced understanding of T-cell responses than in silico prediction.
• The bioassay identifies potentially deleterious inhibitory responses that can impact immunotherapy design.
• The ATLAS assay is a valuable tool for uncovering pre-existing, patient-relevant neoantigen T-cell responses for improved cancer immunotherapy strategies.