Background Clinical results from TCR-T Cell therapies demonstrate anti-tumor efficacy, although therapeutic benefits remain transient due to suboptimal T Cell functional persistence and tumor infiltration alongside antigen escape mechanisms.1 2 3 4 5 Amphiphile (AMP) vaccines improve lymph node targeting of cancer immunogens, stimulating an enhanced endogenous anti-tumor response.6 7 We describe an approach to generate robust and durable anti-tumor responses by combining AMP lymphatic targeting with TCR-T Cell therapy. AMP cognate peptides traffic to lymph nodes and improve TCR-T Cell activation, persistence, and function compared to soluble (SOL) peptide vaccination or TCR-T Cells alone, inducing a superior anti-tumor effect.
Methods C57BL/6J mice were subcutaneously implanted with B16F10 10 days prior to transduced pmel-1 T cell transfer or 75 days after T cell treatment for rechallenge experiments. Tumor-bearing mice received 5 doses, 2x/week of AMP-GP100/AMP-CpG, SOL-GP100/SOL-CpG, or PBS by tail-base vaccination. Caliper measurements determined tumor progression and overall survival. TCR-T Cell persistence was assessed bi-weekly through retro-orbital bleeds. Tumors and lymph nodes from treated mice were excised and analyzed by Nanostring for differential gene expression and flow cytometry for TCR-T Cell functional persistence and T cell epitope spread. Human T Cells (HTCs) and Dendritic Cells (DCs) were isolated from autologous PBMCs, transduced with KRAS-specific TCRs, and cultured with AMP-KRAS-peptide pulsed DCs before assaying T Cell boosting.
Results We demonstrate that AMP vaccination expands tumor specific TCR-T Cells in vivo up to 46-fold while enhancing the activation, cytokine secretion, and pro-inflammatory gene expression of tumor-infiltrating TCR-T Cells. Endogenous tumor-infiltrating T cells from AMP vaccinated mice produced up to 17-fold greater cytokine secretion following re-stimulation with non-targeted tumor epitopes. These results correspond to the eradication of established B16F10 tumors and a resistance to secondary tumor challenge in cured mice. Providing clinical relevance, HTCs transduced with KRAS-specific TCRs and boosted with AMP-KRAS-peptide pulsed DCs exhibited enhanced T cell activation, Th1 cytokine secretion, and cytolytic capacity compared to HTCs exposed to unlabeled DCs.
Conclusions AMP vaccination delivers cognate peptides to lymph nodes providing in vivo activation of tumor-specific TCR-T Cells which amplifies anti-tumor potency of such adoptively transferred cells. AMP vaccination significantly enhanced TCR-T Cell anti-tumor response and led to durable cures of solid tumors in an established, syngeneic tumor model. Additionally, AMP-peptide pulsed autologous DCs enhanced the function of clinically relevant KRAS-specific TCR-T cells in vitro. Taken together, these studies provide direct rationale and evidence for the combination of AMP vaccination with TCR-T Cell therapies to augment clinical responses.
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