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T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18–80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency., A phase I open-label trial evaluating the immunogencity, reactogenicity and safety of a peptide-based SARS-CoV-2 vaccine candidate to induce SARS-CoV-2-specific T cell responses.

Simple Summary Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Despite the emergence of new therapeutic agents in recent years, curation remains challenging, and new and better treatment options are needed. In the present study, we investigated the expression, prognostic significance, and functional role of the Receptor Activator of Nuclear Factor-κB (RANK) in AML. We found that RANK is expressed on leukemic cells in a substantial proportion of AML patients and is associated with a dismal disease course. We further demonstrated that signaling via RANK induces release of factors that favor AML cell survival and confers resistance to chemotherapeutics in AML treatment. Together, our findings identify RANK as novel prognostic marker and putative candidate for therapeutic intervention in AML to enhance response to treatment. Abstract Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as “functional” prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.

While several genetic and morphological markers are established and serve to guide therapy of acute myeloid leukaemia (AML), there is still profound need to identify additional markers to better stratify patients. CD105 (Endoglin) is a type I transmembrane protein reported to induce activation and proliferation of endothelial cells. In addition, CD105 is expressed in haematological malignancies and the vessels of solid tumours. Here, CD105 associates with unfavourable disease course, but so far no data are available on the prognostic relevance of CD105 in haematological malignancies. We here generated a novel CD105 antibody for analysis of expression and prognostic relevance of CD105 in a cohort of 62 AML patients. Flow cytometric analysis revealed substantial expression in the various AML FAB types, with FAB M3 type displaying significantly lower surface levels. Next we established a cut-off specific fluorescence level of 5.22 using receiver-operating characteristics, which allowed to group patients in cases with CD105lo and CD105hi surface expression and revealed that high CD105 expression correlated significantly with poor overall and progression free survival. In conclusion, we here identify CD105 expression as a novel prognostic marker in AML, which may serve to optimize follow up and treatment decisions for AML patients.

Simple Summary Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries. Despite the substantial progress achieved by the recent introduction of the novel small molecule inhibitors idelalisib, ibrutinib and venetoclax in CLL treatment, therapy resistance occurs frequently and the disease so far remains incurable. In the present study we report that BAFF, a member of the TNF protein family, protects CLL cells from treatment-induced cell death. In turn, the therapeutic effects of idelalisib, ibrutinib and venetoclax can be reinforced by neutralizing BAFF with belimumab, an antibody which presently is clinically approved for treatment of systemic lupus erythematosus. Based on the data presented in this study, a clinical study to evaluate whether drug repurposing of belimumab for BAFF neutralization can serve to improve response to small molecule inhibitor treatment in CLL is in preparation. Abstract The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.