Fifteen-year follow-up of relapsed indolent non-Hodgkin lymphoma patients vaccinated with tumor-loaded dendritic cells

Abstract

We previously published the results of a pilot study showing that vaccination with tumor-loaded dendritic cells (DCs) induced both T and B cell response and produced clinical benefit in the absence of toxicity in patients with relapsed, indolent non-Hodgkin lymphoma (iNHL). The purpose of the present short report is to provide a 15-year follow-up of our study and to expand the biomarker analysis previously performed. The long-term follow-up highlighted the absence of particular or delayed toxicity and the benefit of active immunization with DCs loaded with autologous, heat-shocked and UV-C treated tumor cells in relapsed iNHL (5-year and 10-year progression-free survival (PFS) rates: 55.6% and 33.3%, respectively; 10-year overall survival (OS) rate: 83.3%). Female patients experienced a better PFS (p=0.016) and a trend towards a better OS (p=0.185) compared with male patients. Of note, we observed a non-negligible fraction of patients (22%) who experienced a long-lasting complete response. In a targeted gene expression profiling of pre-treatment tumor biopsies in 11 patients with available formalin-fixed, paraffin-embedded tissue, we observed that KIT, ATG12, TNFRSF10C, PBK, ITGA2, GATA3, CLU, NCAM1, SYT17 and LTK were differentially expressed in patients with responder versus non-responder tumors. The characterization of peripheral monocytic cells in a subgroup of 14 patients with available baseline blood samples showed a higher frequency of the subset of CD14⁺⁺CD16⁺ cells (intermediate monocytes) in patients with responding tumors. Since in patients with relapsed iNHL the available therapeutic options are often incapable of inducing a long-lasting complete remission and can be sometimes characterized by intolerable toxicity, we think that the encouraging results of our long-term follow-up analysis represent a stimulus to further investigate the role of active vaccination in this specific setting and in earlier lines of therapy and to explore novel combinatorial strategies encompassing other innovative immunotherapy agents, such as immune-checkpoint inhibitors.

Keywords: dendritic cells; hematologic neoplasms; immunotherapy; vaccination.

Figure 1

Long-term clinical outcomes of patients with relapsed indolent non-Hodgkin lymphoma vaccinated with tumor-loaded dendritic cells. Panel A shows the swimmer plot illustrating the pattern and the duration of response. The red square indicates a PD, the blue triangle indicates an SD, the light green square indicates a PR, the dark green triangle indicates a CR and the black arrow indicates an ongoing response at the time of data cut-off date. Panel B shows the Kaplan-Meier estimates for progression-free survival (PFS) and overall survival (OS). Blue line indicates PFS, whereas red line indicates OS. The 5-year and 10-year PFS rates were 55.6% (95% CI 36.8 to 84) and 33.3% (95% CI 17.3 to 64.1), respectively, whereas the 10-year OS rate was 83.3% (95% CI 67.8 to 100). CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; UPN, unique progressive number.

Figure 2

Expanded biomarker analysis in patients with relapsed indolent non-Hodgkin lymphoma vaccinated with tumor-loaded dendritic cells. Panel A shows the heatmap of the 10 differentially expressed genes between responder and non-responder tumors (p value <0.05) in a subgroup of 11 patients with available FFPE pretreatment tissue. The color scale represents the relative gene expression changes normalized by the SD. Panel B shows the frequency of peripheral monocytic cell subsets at baseline in patients with responder compared with non-responder tumors in a subgroup of 14 patients with available frozen PBMCs. FFPE, formalin-fixed and paraffin-embedded; PBMCs, peripheral mononuclear cells.