Journal Article

DKFZ-2024-00809

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication.

Wolf, S. P. ; Anastasopoulou, V.DKFZ* ; Drousch, K. ; Diehl, M. I. ; Engels, B. ; Yew, P. Y. ; Kiyotani, K. ; Nakamura, Y. ; Schreiber, K. ; Schreiber, H. ; Leisegang, M.DKFZ*

2024
AACR Philadelphia, Pa. [u.a.]

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Please use a persistent id in citations: doi:10.1158/1078-0432.CCR-23-2905

Abstract: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells.Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans.Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells.Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Keyword(s): Humans (MeSH) ; Antigens, Neoplasm (MeSH) ; Neoplasms: pathology (MeSH) ; CD8-Positive T-Lymphocytes (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; CD4-Positive T-Lymphocytes (MeSH) ; Antigens, Neoplasm ; Receptors, Antigen, T-Cell

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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