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

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.

ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a prototypical sero-negative autoimmune disease that affects millions worldwide. Single nucleotide polymorphisms in the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene have been linked to AS via GWAS studies, however, the exact mechanism as to how ERAP1 contributes to pathogenesis of AS is not understood. We undertook µCT imaging and histologic analysis to evaluate bone morphology of the axial skeletons of ERAP1-/- mice and discovered the hallmark skeletal features of AS in these mice, including spinal ankylosis, osteoporosis, and spinal inflammation. We also confirmed the presence of spontaneous intestinal dysbiosis and increased susceptibility to Dextran Sodium Sulfate (DSS)-induced colitis in ERAP1-/- mice, however the transfer of healthy microbiota from wild type mice via cross-fostering experiments did not resolve the skeletal phenotypes of ERAP1-/- mice. Immunological analysis demonstrated that while ERAP1-/- mice had normal numbers of peripheral Foxp3+ Tregs, they had reduced numbers of both "Tr1-like" regulatory T cells and tolerogenic dendritic cells, which are important for Tr1 cell differentiation. Together, our data suggests that ERAP1-/- mice may serve as a useful animal model for studying pathogenesis of intestinal, skeletal, and immunological manifestations of Ankylosing Spondylitis.