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Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.

Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8 + /CD4 + T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications., Competing Interests: ADG has received speaker/lecture remuneration or consultancy fees from Boehringer Ingelheim, Miltenyi Biotec or Isoplexis. AC is a contracted researcher for Oncoinvent AS and Novocure and a consultant for Sotio a.s., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. Therefore, it has gained attention as a target site. mRNA emerged as a versatile drug class for cancer therapy. We reported that intratumoral administration of mRNA encoding the fusokine Fβ 2 supports tumor-specific T-cell immunity. This study provides proof of concept of the use of mRNA to modulate the TME.

About 25 years ago, mRNA became a tool of interest in anticancer vaccination approaches. However, due to its rapid degradation in situ, direct application of mRNA was confronted with considerable skepticism during its early use. Consequently, mRNA was for a long time mainly used for the ex vivo transfection of dendritic cells, professional antigen-presenting cells known to stimulate immunity. The interest in direct application of mRNA experienced a revival, as researchers became aware of the many advantages mRNA offers. Today, mRNA is considered to be an ideal vehicle for the induction of strong immune responses against cancer. The growing numbers of preclinical trials and as a consequence the increasing clinical application of mRNA as an off-the-shelf anticancer vaccine signifies a renaissance for transcript-based antitumor therapy. In this review, we highlight this renaissance using a timeline providing all milestones in the application of mRNA for anticancer vaccination.

Cancer immunotherapy has been proposed as a powerful treatment modality. Active immunotherapy aspires to stimulate the patient's immune system, particularly T cells. These cells can recognize and kill cancer cells and can form an immunological memory. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system. They take up and process antigens to present them to T cells. Consequently, DCs have been investigated as a means to stimulate cancer-specific T-cell responses. An efficient strategy to program DCs is the use of mRNA, a well-defined and safe molecule that can be easily generated at high purity. Importantly, vaccines consisting of mRNA-modified DCs showed promising results in clinical trials. Therefore, we will introduce cancer immunotherapy and DCs and give a detailed overview on the application of mRNA to generate cancer-fighting DC vaccines.

Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3 + CD8 + T cells and CD11b + cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b + Ly6C high Ly6G - ). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSCs) in the suppression of antitumor immune responses. Although the main site of action for MDSCs is most likely the tumor microenvironment, the study of these cells has been largely restricted to MDSCs derived from peripheral lymphoid organs. Only in a minority of studies MDSCs isolated from the tumor microenvironment have been characterized. This review will give an overview of the data available on the phenotypical and functional differences between tumor-derived MDSCs and MDSCs isolated from the spleen of tumor-bearing mice or from the peripheral blood of cancer patients.

Two decades ago, mRNA became the focus of research in molecular medicine and was proposed as an active pharmaceutical ingredient for the therapy of cancer. In this regard, mRNA has been mainly used for ex vivo modification of antigen-presenting cells (APCs), such as dendritic cells (DCs). This vaccination strategy has proven to be safe, well tolerated and capable of inducing tumor antigen-specific immune responses. Recently, the direct application of mRNA for in situ modification of APCs, hence immunization was shown to be feasible and at least as effective as DC-based immunization in pre-clinical models. It is believed that application of mRNA as an off-the-shelf vaccine represents an important step in the development of future cancer immunotherapeutic strategies. Here, we will discuss the use of ex vivo mRNA-modified DCs and "naked mRNA" for cancer immunotherapy focusing on parameters such as the employed DC subtype, DC activation stimulus and route of immunization. In addition, we will provide an overview on the clinical trials published so far, trying to link their outcome to the aforementioned parameters.

A decade of collective work by tumor immunologists has led to improved large scale generation, maturation, antigen loading and administration of dendritic cells (DCs) to cancer patients, promoting enhanced antitumor activity. We alleviated the HLA-restriction in DC therapy and demonstrated that it is meaningful to treat patients with DCs irrespective of their HLA type.

Mimetics of second mitochondria-derived activator of caspases (SMAC) enhance tumor cell death in a variety of cancers. Several molecular mechanisms of action have been identified. However, it was only recently that the modus of action was linked to stimulation of anti-tumor immunity. Here we comment on these findings, highlighting several remaining questions.

Evaluation of: Fotin-Mleczek M, Duchardt KM, Lorenz C et al.: Messenger RNA-based vaccines with dual activity induce balanced TLR7-dependent adaptive immune responses and provide antitumor activity. J. Immunother. 34(1), 1-15 (2011). Two decades ago, mRNA was proposed as an active pharmaceutical ingredient for the therapy of cancer. Although direct delivery of mRNA to mice was shown to be feasible, mRNA has been mainly used for ex vivo modification of antigen-presenting cells, such as dendritic cells. Fotin-Mleczek et al. introduces a two-component mRNA vaccine, consisting of antigen mRNA (firefly luciferase, ovalbumin or prostate carcinoma-specific antigen) and mRNA that is formulated in protamine as a source of not only antigen but also Toll-like receptor 7 ligands. Direct administration of the mRNA vaccine in mice results in sustained humoral and cellular immune responses, comprising, among others, antigen-specific cytotoxic T cells that mediate strong antitumor responses, in both prophylactic and therapeutic settings. In conclusion, this study highlights the potential of mRNA vaccines to induce immune responses and mediate sustained antitumor activity.

Autoimmune Lymphoproliferative Syndrome (ALPS) is a childhood disorder characterized by chronic nonmalignant lymphoproliferation and autoimmunity. Although the pathogenesis is not fully understood, deficient Fas mediated apoptosis appears to be an important factor. This deficiency can be caused by a mutation of the APTI gene (ALPS type Ia), of the FasL gene (ALPS type Ib), or of the Caspase-10 gene (ALPS type II). In one sub population of patients, no mutations have been identified as yet (ALPS type III). According to published data, the latter group is much smaller than the group of patients with ALPS type Ia. However, because of the variability of the clinical presentation and the absence of a known genetic defect, this disease is difficult to diagnose, the more so as few data have been reported on these patients. Thus, ALPS type III could be more common than believed until now. In this review we provide evidence for this hypothesis.

Autoimmune Lymphoproliferative Syndrome (ALPS) is a childhood disorder characterized by chronic nonmalignant lymphoproliferation and autoimmunity. Although the pathogenesis is not fully understood, deficient Fas mediated apoptosis appears to be an important factor. This deficiency can be caused by a mutation of the APT1 gene (ALPS type Ia), of the FasL gene (ALPS type Ib), or of the Caspase-10 gene (ALPS type II). In one sub population of patients, no mutations have been identified as yet (ALPS type III). According to published data, the latter group is much smaller than the group of patients with ALPS type Ia. However, because of the variability of the clinical presentation and the absence of a known genetic defect, this disease is difficult to diagnose, the more so as few data have been reported on these patients. Thus, ALPS type III could be more common than believed until now. In this review we provide evidence for this hypothesis.

Multiple myeloma is characterized by the monoclonal expansion of plasma cells in the bone marrow. Although the predominant cell type is the plasma cell, the initial oncogenic transformation is considered to take place in a more immature B cell. There is still much controversy about this precursor cell type. Phenotypic analysis of bone marrow and peripheral blood revealed that in multiple myeloma a great diversity exists in the phenotype of the cells considered to be involved. Because of the lack of a myeloma specific genetic lesion it is very difficult to trace back the cell in which the transforming event, leading to multiple myeloma, took place. The only real clonal marker is the idiotype of the immunoglobulin molecule expressed by the myeloma cells. With recombinant DNA technology it is now possible to produce clonal markers for each individual myeloma patient which recognize only the immunoglobulin genes expressed by the myeloma cell and its precursors. The sequences of these myeloma immunoglobulin genes do reveal a lot of information about the stage in the B-cell differentiation pathway in which the oncogenic event might have taken place. The presence of somatic mutations in a non-random fashion without intraclonal variation leads to the conclusion that the precursor myeloma cell could not possibly be a pre-B cell or stem cell but has to be a mature B cell that has been in contact with antigen and has past through the phase of somatic mutation, like a memory B cell or plasmablast.(ABSTRACT TRUNCATED AT 250 WORDS)