A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer

• Main Authors: Spencer D. Martin, Darin A. Wick, Julie S. Nielsen, Nicole Little, Robert A. Holt, Brad H. Nelson
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2018-01-01
• Series: OncoImmunology
• Subjects: neoantigen; immunotherapy; adoptive t cell therapy; mutations; t cells; mini-line; ovarian cancer
• Online Access: http://dx.doi.org/10.1080/2162402X.2017.1371895

Mutated cancer antigens, or neoantigens, represent compelling immunological targets and appear to underlie the success of several forms of immunotherapy. While there are anecdotal reports of neoantigen-specific T cells being present in the peripheral blood and/or tumors of cancer patients, effective adoptive cell therapy (ACT) against neoantigens will require reliable methods to isolate and expand rare, neoantigen-specific T cells from clinically available biospecimens, ideally prior to clinical relapse. Here, we addressed this need using “mini-lines”, large libraries of parallel T cell cultures, each originating from only 2,000 T cells. Using small quantities of peripheral blood from multiple time points in an ovarian cancer patient, we screened over 3.3 × 106 CD8+ T cells by ELISPOT for recognition of peptides corresponding to the full complement of somatic mutations (n = 37) from the patient's tumor. We identified ten T cell lines which collectively recognized peptides encoding five distinct mutations. Six of the ten T cell lines recognized a previously described neoantigen from this patient (HSDL1L25V), whereas the remaining four lines recognized peptides corresponding to four other mutations. Only the HSDL1L25V-specific T cell lines recognized autologous tumor. HSDL1L25V-specific T cells comprised at least three distinct clonotypes and could be identified and expanded from peripheral blood 3–9 months prior to the first tumor recurrence. These T cells became undetectable at later time points, underscoring the dynamic nature of the response. Thus, neoantigen-specific T cells can be expanded from small volumes of blood during tumor remission, making pre-emptive ACT a plausible clinical strategy.