Lymph Node-Targeted Vaccine Boosting of TCR T-cell Therapy Enhances Antitumor Function and Eradicates Solid Tumors.

Autor:	Drakes DJ; Elicio Therapeutics, Boston, Massachusetts., Abbas AM; Elicio Therapeutics, Boston, Massachusetts., Shields J; Elicio Therapeutics, Boston, Massachusetts., Steinbuck MP; Elicio Therapeutics, Boston, Massachusetts., Jakubowski A; Elicio Therapeutics, Boston, Massachusetts., Seenappa LM; Elicio Therapeutics, Boston, Massachusetts., Haqq CM; Elicio Therapeutics, Boston, Massachusetts., DeMuth PC; Elicio Therapeutics, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2024 Feb 02; Vol. 12 (2), pp. 214-231.
DOI:	10.1158/2326-6066.CIR-22-0978
Abstrakt:	T-cell receptor (TCR)-modified T-cell therapies have shown promise against solid tumors, but overall therapeutic benefits have been modest due in part to suboptimal T-cell persistence and activation in vivo, alongside potential tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and function of TCR T cells through combination with Amphiphile (AMP) vaccination including cognate TCR T peptides. AMP modification improves lymph node targeting of conjugated tumor immunogens and adjuvants, thereby coordinating a robust T cell-activating endogenous immune response. AMP vaccine combination with TCR T-cell therapy led to complete eradication and durable responses against established murine solid tumors refractory to TCR T-cell monotherapy. Enhanced antitumor efficacy was correlated with simultaneous in vivo invigoration of adoptively transferred TCR T cells and in situ expansion of the endogenous antitumor T-cell repertoire. Long-term protection against tumor recurrence in AMP-vaccinated mice was associated with antigen spreading to additional tumor-associated antigens not targeted by vaccination. AMP vaccination further correlated with pro-inflammatory lymph node transcriptional reprogramming and increased antigen presenting-cell maturation, resulting in TCR T-cell expansion and functional enhancement in lymph nodes and solid tumor parenchyma without lymphodepletion. In vitro evaluation of AMP peptides with matched human TCR T cells targeting NY-ESO-1, mutant KRAS, and HPV16 E7 illustrated the clinical potential of AMP vaccination to enhance human TCR T-cell proliferation, activation, and antitumor activity. Taken together, these studies provide rationale and evidence to support clinical evaluation of combining AMP vaccination with TCR T-cell therapies to augment antitumor activity. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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