One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication.
Clin Cancer Res
; 30(8): 1642-1654, 2024 Apr 15.
Article
in En
| MEDLINE
| ID: mdl-38190111
ABSTRACT
PURPOSE:
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. EXPERIMENTALDESIGN:
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.RESULTS:
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.CONCLUSIONS:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antigens, Neoplasm
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Clin Cancer Res
/
Clin. cancer res
/
Clinical cancer research
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article
Country of publication: