Dendritic Cells (DCs) account for the best adaptive immune stimulators promoting their usage as advanced therapy medicinal products (ATMP). Despite the well tolerated profile and the ability to induce anti-tumor immunity, DC vaccine has nowadays failed to translate into prolonged long-term clinical benefit, requiring an update of its therapeutic application.
We conducted a retrospective study correlating clinical and multiple biologic data with the aim to define biomarkers of DC vaccine clinical activity and to exploit its capacity to expand peripheral autologous tumor-specific effector cells. Immunohistochemistry on pre and post FFPE samples, proteomic analysis on plasma and tumor homogenate, multiparametric flow cytometry on the starting apheresis and on DCs, RNAseq and scRNAseq on peripheral monocytes and manufactured DCs respectively, were applied.
Analysis of post-vaccine biopsies highlighted the vaccine ability to induce intratumoral CD8 up-regulation (p=0.0195). The presence of multiple checkpoint molecules was a common denominator of our ATMP (PD-L1 90,1%-98,9%; PD-L2 94,9%-%99,5; VISTA 21,9%-%39,3; TIM-3 17%-59,4%; B7-H3 86,3%-98,8%). Intriguingly, high dimensional analysis of the DC final product revealed the coexistence of B cell clusters (CD19, MS4A1), higher (p=0.0286) in patients displaying clinical response. Of note, GMPc DCs induced a sustained expression of CD137 in co-cultured CD8+ T cells, and anti-PD1 addition enhanced the fraction of CD137+ T cells.
In vivo mechanisms of adaptive immune resistance (e.g. tumoral PDL1 upregulation p=0.0353) as well as the observed expression of checkpoint molecules by our ATMP support the clinical investigation of DC/ICI combination. The association of B cells with tumor response has to be deepened and the B cell frequency assessed also in pretreatment blood samples. Of note, the expansion of bona fide antigen-reactive CD137+ T cells resulting from the designed autologous DC ex vivo platform could translate into the manufacturing of a novel GMPc T cell product.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.