Background
In recent years, adoptive T cell therapy (ACT) has demonstrated significant effectiveness in treating hematological malignancies. Yet, the clinical benefit in solid tumors is limited and only short-lasting. Although ACT supplies a pool of T cells for initial tumor reduction, challenges like insufficient tumor penetration, limited functionality, and durability as well as the immunosuppressive tumor microenvironment limit its efficacy in solid tumors. To overcome these challenges, vaccination is already being explored in clinical trials as a modality to improve ACT efficacy. mRNA-based vaccines can activate both transferred and endogenous T cells and provide additional immunostimulatory signals. Early phase 1/2 clinical trials combining chimeric antigen receptor T cells (CAR-T) with CAR-T cell amplifying mRNA vaccine therapy showed an overall response rate of 44,7% (18/37) in multiple solid tumors. Another key approach in ACT is the use of transgenic TCRtg T cells. The impact of mRNA-based vaccinations on TCRtg T cells was however unclear. Our preclinical proof-of-concept study investigated the impact of vaccination on transferred TCRtg and endogenous T cells as well as the effect on tumor growth and mouse survival. The obtained data highlight the significant improvement of adoptive TCRtg T cell therapy when combined with mRNA-based vaccination.
Materials and Methods
Prior to conducting the proof-of-concept study, we confirmed the presentation of mRNA encoded epitopes after transfection of murine bone marrow-derived DCs (BMDCs) using a TCR-like antibody recognizing peptide/MHC complexes. To examine the impact of mRNA vaccinations on TCRtg T cells in our proof-of-concept study, we utilized the MC38-OVA colon cancer model in C57BL/6 mice.
Results mRNA-based vaccination after transfer of antigen-specific TCRtg T cells in tumor-bearing mice lead to 10/10 complete responders while vaccination and ACT monotherapies resulted in 5/10 and 6/10 complete responders, respectively. Moreover, during the 6-week observation period, late escaping tumors were observed only in the monotherapy groups, while combination therapy resulted in significantly improved survival. To analyze the underlying mechanism, we took advantage of adoptively transferred OT-1 CD45.2+ T cells in tumor-bearing CD45.1+ mice that enabled the differentiation between host vs donor T cells. Notably, the transferred T cells proliferated following vaccination and were boostable over time. In addition, vaccination positively influenced the differentiation status of these T cells, leading to the development of persistent T cells that could limit tumor regrowth.
Conclusions
Together, our findings highlight the potential of combining adoptive TCRtg T cell therapy with mRNA vaccinations. Such a strategy not only improves therapy efficacy but also ensures sustained immunosurveillance, paving the way for improved treatment outcomes in solid tumors.
J. Krueger: A. Employment (full or part-time); Significant; CureVac Se. J. Lutz: A. Employment (full or part-time); Significant; CureVac SE. J. Ruotsalainen: A. Employment (full or part-time); Significant; CureVac SE. R. Mülfarth: A. Employment (full or part-time); Significant; CureVac SE. R. Heidenreich: A. Employment (full or part-time); Significant; CureVac SE.