Abstract
While T cell receptor (TCR)-modified T cell therapies have shown promise against solid tumors, overall therapeutic benefits in clinical practice have been modest due in part to suboptimal T cell persistence and activation in vivo, alongside the possibility of tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and activation 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-priming endogenous immune response. Vaccine combination with TCR-T cell therapy provided simultaneous in vivo invigoration of adoptively transferred TCR-T cells and in situ priming of the endogenous anti-tumor T cell repertoire. The resulting induction of an adoptive and endogenous anti-tumor effect led to durable responses in established murine solid tumors refractory to TCR-T cell monotherapy. Protection against recurrence was associated with antigen spreading to additional tumor-associated antigens not targeted by vaccination. Enhanced anti-tumor efficacy was 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 anti-tumor activity. Taken together, these studies provide rationale and evidence to support clinical evaluation of the combination of AMP-vaccination with TCR-T cell therapies to augment anti-tumor activity.
Summary AMP-vaccination targets the lymph nodes to enhance TCR-T cell therapy resulting in solid tumor eradication and durable protection against recurrence.
Competing Interest Statement
All authors are employees of Elicio Therapeutics and, as such, receive salary and benefits, including ownership of stock and stock options from the company. D.J.D. and P.C.D. have an Amphiphile-peptide boosting of TCR-T Cells patent pending to Elicio. The authors declare no other competing interests.