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Simple Summary: The melanoma-conditioned microenvironment promotes immune escape and tumor progression, contributing to resistance to anti-melanoma immunotherapy in a large group of treated patients. While two-dimensional cultures lack tissue-context, animals poorly predict human immune responses. Thus, a clear need exists for more physiological human models. We previously described an in vitro human melanoma-in-skin (Mel-RhS) model with the SK-MEL-28 cell line mirroring features of invasive melanoma. Here, we further investigated the tumor-induced microenvironment of this model, generated five additional Mel-RhS models (A375, COLO829, G361, MeWo, and RPMI-7951), and performed in-depth analysis of invasion, immune modulation, angiogenesis, and their respective mediators. We present three-dimensional models allowing for the study of diverse tumor-intrinsic properties that could be used to investigate efficacy of therapeutic interventions. By mimicking different stages of melanoma and related features, each Mel-RhS can be further individually tailored to obtain a physiologically evermore relevant model to study specific mechanisms underlying melanomagenesis and progression. Invasion, immune modulation, and angiogenesis are crucial in melanoma progression. Studies based on animals or two-dimensional cultures poorly recapitulate the tumor-microenvironmental cross-talk found in humans. This highlights a need for more physiological human models to better study melanoma features. Here, six melanoma cell lines (A375, COLO829, G361, MeWo, RPMI-7951, and SK-MEL-28) were used to generate an in vitro three-dimensional human melanoma-in-skin (Mel-RhS) model and were compared in terms of dermal invasion and immune modulatory and pro-angiogenic capabilities. A375 displayed the most invasive phenotype by clearly expanding into the dermal compartment, whereas COLO829, G361, MeWo, and SK-MEL-28 recapitulated to different extent the initial stages of melanoma invasion. No nest formation was observed for RPMI-7951. Notably, the integration of A375 and SK-MEL-28 cells into the model resulted in an increased secretion of immune modulatory factors (e.g., M-CSF, IL-10, and TGFβ) and pro-angiogenic factors (e.g., Flt-1 and VEGF). Mel-RhS-derived supernatants induced endothelial cell sprouting in vitro. In addition, observed A375-RhS tissue contraction was correlated to increased TGFβ release and α-SMA expression, all indicative of differentiation of fibroblasts into cancer-associated fibroblast-like cells and reminiscent of epithelial-to-mesenchymal transition, consistent with A375′s most prominent invasive behavior. In conclusion, we successfully generated several Mel-RhS models mimicking different stages of melanoma progression, which can be further tailored for future studies to investigate individual aspects of the disease and serve as three-dimensional models to assess efficacy of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with HER2-positive metastatic breast cancer develop brain metastases in up to 30% of cases. The aim of this systematic review and meta-analysis was to determine the effect of different systemic therapies in patients with HER2-positive metastatic breast cancer and brain metastases, acknowledging the heterogeneity and sometimes low quality of 51 included studies. Tucatinib (combined with trastuzumab and capecitabine) and trastuzumab-deruxtecan appear to constitute the most effective systemic therapy, while pyrotinib might be an option in Asian patients. Preferably, future research will comprise of randomized controlled trials, including patients with active and/or inactive brain metastases. Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM. Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool. Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43–85%, I2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96). Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Strategies to enhance the preferential accumulation and activation of Natural Killer (NK) cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based cancer immunotherapy. In this study, we report that a bispecific single domain antibody (VHH) that targets CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells can be used to target and enhance cytolysis of cancer cells. The bispecific VHH enhanced NK cell activation and cytotoxicity in an EGFR- and CD16-dependent and KRAS-independent manner. Moreover, the bispecific VHH induced stronger activity of cancer patient-derived NK cells and resulted in tumor control in a co-culture of metastatic colorectal cancer cells and either autologous peripheral blood mononuclear cells or allogeneic CD16+ NK cells. We believe that this novel approach could represent a valid therapeutic strategy either alone or in combination with other NK cell-based therapies. The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of metastatic melanoma has been increasing over the past years with current therapies showing limited efficacy to cure the disease. Therefore, other options are being investigated, such as adoptive cell therapy (ACT) where activated immune cells are infused into a patient to attack melanoma. Natural killer (NK) cells are part of the innate immune system and extremely suitable for this kind of therapy since they show minimal toxicities in the clinical setting. In this review, we focus on current strategies for NK cell therapy and the development of new approaches that hold great promise for the treatment of advanced melanoma. Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited by immune escape of the tumor, cytokine release syndrome, and manufacturing challenges of autologous therapies. Conversely, the clinical use of Natural Killer (NK) cells has demonstrated a favorable clinical safety profile with minimal toxicities, providing an encouraging treatment alternative. Unlike T cells, NK cells are activated, amongst other mechanisms, by the downregulation of HLA class I molecules, thereby overcoming the hurdle of tumor immune escape. However, impairment of NK cell function has been observed in melanoma patients, resulting in deteriorated natural defense. To overcome this limitation, "activated" autologous or allogeneic NK cells have been infused into melanoma patients in early clinical trials, showing encouraging clinical benefit. Furthermore, as several NK cell-based therapeutics are being developed for different cancers, an emerging variety of approaches to increase migration and infiltration of adoptively transferred NK cells towards solid tumors is under preclinical investigation. These developments point to adoptive NK cell therapy as a highly promising treatment for metastatic melanoma in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. While immunotherapy has been deemed a breakthrough treatment for various subtypes of cancer, its efficacy in PDAC is limited. This review discusses a wide range of immunotherapies, providing a general introduction to their working mechanism as well as current evidence on their clinical efficacy and immune eliciting abilities in PDAC. Utilizing combination (immuno)therapies to generate synergistic anti-tumor effects may provide the key to successful PDAC treatment. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic pancreatic ductal adenocarcinoma has a dismal prognosis, and to date no curative treatment options exist. The image guided tumor ablation technique irreversible electroporation (IRE) employs high-voltage electrical pulses through the application of several needle electrodes in and around the tumor in order to induce cell death. IRE ablation of the primary tumor has the ability to reduce pancreatic tumor induced immune suppression while allowing the expansion of tumor specific effector T cells, hereby possibly shifting the pancreatic tumor microenvironment into a more immune permissive state. The addition of immune enhancing therapies to IRE might work synergistically and could potentially induce a clinically significant treatment effect. This study protocol describes the rationale and design of the PANFIRE-III trial that aims to assess the safety of the combination of IRE with IMO-2125 (toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma. Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor's immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC's dismal prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural Killer (NK) cells are innate lymphocytes that play an important role in the immune response against cancer. Their activity is controlled by a balance of inhibitory and activating receptors, which in cancer can be skewed to favor their suppression in support of immune escape. It is therefore imperative to find ways to optimize their antitumor functionality. In this review, we explore and discuss how their activity influences, or even mediates, the efficacy of various anti-cancer therapies and, vice versa, how their activity can be affected by these therapies. Knowledge of the mechanisms underlying these observations could provide rationales for combining anti-cancer treatments with strategies enhancing NK cell function in order to improve their therapeutic efficacy. Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function. [ABSTRACT FROM AUTHOR]

Tumors that lack T cell infiltration are less likely to respond to immune checkpoint inhibition and could benefit from cancer vaccination for the initiation of anti-tumor T cell responses. An attractive vaccine strategy is in vivo targeting of dendritic cells (DCs), key initiators of antigen-specific T cell responses. In this study we generated apoptotic tumor cell-derived extracellular vesicles (ApoEVs), which are potentially an abundant source of tumor-specific neo-antigens and other tumor-associated antigens (TAAs), and which can be manipulated to express DC-targeting ligands for efficient antigen delivery. Our data demonstrates that by specifically modifying the glycocalyx of tumor cells, high-mannose glycans can be expressed on their cell surface and on extracellular vesicles derived after the induction of apoptosis. High-mannose glycans are the natural ligands of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), a dendritic cell associated C-type lectin receptor (CLR), which has the ability to efficiently internalize its cargo and direct it to both major histocompatibility complex (MHC)-I and MHC-II pathways for the induction of CD8+ and CD4+ T cell responses, respectively. Compared to unmodified ApoEVs, ApoEVs carrying DC-SIGN ligands are internalized to a higher extent, resulting in enhanced priming of tumor-specific CD8+ T cells. This approach thus presents a promising vaccination strategy in support of T cell-based immunotherapy of cancer. [ABSTRACT FROM AUTHOR]