Lymph node-targeted vaccine boosting of TCR-T cell therapy enhances anti-tumor function and eradicates solid tumors

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.

Current advances in cancer vaccines targeting NY-ESO-1 for solid cancer treatment

“…As a monotherapy, cancer vaccines have not yet been demonstrated to show outstanding clinical results in malignant tumor treatment. Recently, there has been a growing interest in the integration of cancer vaccines with ACTs to combat tumor evasion of immune surveillance and resistance ( 77 – 79 ). Ma et al ( 77 , 78 ) identified that cancer vaccination induces metabolic changes in CAR-T cells, leading to an increase in the production of interferon gamma (IFN-γ), which may potentially contribute to overcoming the immunosuppressive tumor microenvironment.…”

“…Furthermore, the enhanced efficacy of CAR-T cells induced by tumor vaccination may be associated with DCs, including factors such as DCs recruitment, uptake of tumor antigens, and activation ( 77 , 78 ). In another study, researchers discovered that the combination of tumor vaccines with TCR-T cell therapy significantly enhanced the anti-tumor response of TCR-T cells and induced epitope spreading among the endogenous T cell population, leading to durable eradication of established solid tumors in syngeneic tumor models ( 79 ). The improved anti-tumor efficacy was associated with pro-inflammatory transcriptional reprogramming in lymph nodes and enhanced maturation of antigen presenting cells.…”

“…The improved anti-tumor efficacy was associated with pro-inflammatory transcriptional reprogramming in lymph nodes and enhanced maturation of antigen presenting cells. This led to the expansion and functional enhancement of TCR-T cells in both lymph nodes and the solid tumor tissue, without the need for lymphodepletion ( 79 ). It is important to note that the aforementioned conclusions are based on experimental results obtained from mouse models, further research and validation are required to determine the feasibility and effectiveness of these findings in clinical applications.…”