We aimed to determine how many cancer-specific antgiens (neoantigens) need to be targeted by how many different TCRs for eradication of naturally heterogeneous solid tumors.

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B957
Abstract ID: 6238

Presenting Author:
Steven Wolf , Postdoc at Univ. of Chicago

Abstract:

Recognition of mutant tumor-specific antigens (neoantigens) seems to be essential when checkpoint blockade or adoptive transfer of TILs are effective. Cures remain challenging. We therefore aimed to determine how many neoantigens and how many different TCRs are needed for eradication of solid tumors. Adoptively transferred TCR-engineered autologous T cells were used to target naturally expressed (autochthonous) neoantigens. The targeted tumors were derived from primary autochthonous cancer cell cultures resembling the original heterogeneous tumor. Such heterogeneity is regularly found in humans. Tumors to be treated were established for at least three weeks. Relapse after CD8TCR-therapy alone was common in heterogeneous tumors, even when targeting multiple different autochthonous neoantigens. CD8TCR-therapy was only effective against tumors made artificially homogeneous. By contrast, large and established solid tumors of natural heterogeneity were eradicated by a combination of CD8TCR-therapy with CD4TCR-therapy, each targeting an independent neoantigen. While direct cancer cell recognition by CD8TCR-therapy was essential for cure. CD4TCR-therapy targeted a mutant neoantigen on tumor stroma was essential as well and required for CD8TCR-therapy to be effective. Thus, two cancer-specific TCRs can be essential and sufficient for effectively targeting heterogeneous solid tumors expressing unmanipulated, autochthonous neoantigens.