Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• Keywords
• B cells, cytokine storm, intratumoral immunotherapy, melanoma, pheochromocytoma,
• MeSH
• B-Lymphocytes * immunology   physiology   MeSH
• Pheochromocytoma * immunology   therapy   pathology   MeSH
• Immunotherapy * methods   MeSH
• Interleukin-6 MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Adrenal Gland Neoplasms * immunology   therapy   pathology   MeSH
• Tumor Necrosis Factor-alpha immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Interleukin-6 MeSH
• Tumor Necrosis Factor-alpha MeSH

Cancer immunotherapy has shown remarkable clinical progress in recent years. Although age is one of the biggest leading risk factors for cancer development and older adults represent a majority of cancer patients, only a few new cancer immunotherapeutic interventions have been preclinically tested in aged animals. Thus, the lack of preclinical studies focused on age-dependent effect during cancer immunotherapy could lead to different therapeutic outcomes in young and aged animals and future modifications of human clinical trials. Here, we compare the efficacy of previously developed and tested intratumoral immunotherapy, based on the combination of polysaccharide mannan, toll-like receptor ligands, and anti-CD40 antibody (MBTA immunotherapy), in young (6 weeks) and aged (71 weeks) mice bearing experimental pheochromocytoma (PHEO). The presented results point out that despite faster growth of PHEO in aged mice MBTA intratumoral immunotherapy is effective approach without age dependence and could be one of the possible therapeutic interventions to enhance immune response to pheochromocytoma and perhaps other tumor types in aged and young hosts.

• Keywords
• TLR ligands, age, anti-CD40 antibody, intratumoral immunotherapy, pancreatic adenocarcinoma, pheochromocytoma,
• MeSH
• CD40 Antigens MeSH
• Pheochromocytoma * therapy   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Mice MeSH
• Adrenal Gland Neoplasms * therapy   MeSH
• Aged MeSH
• Toll-Like Receptors MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Aged MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• CD40 Antigens MeSH
• Toll-Like Receptors MeSH

Despite constant advances in cancer research, the treatment of pancreatic adenocarcinoma remains extremely challenging. The intratumoral immunotherapy approach that was developed by our research group and was based on a combination of mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) showed promising therapeutic effects in various murine tumor models, including a pancreatic adenocarcinoma model (Panc02). However, the efficacy of MBTA therapy in the Panc02 model was negatively correlated with tumor size at the time of therapy initiation. Here, we aimed to further improve the outcome of MBTA therapy in the Panc02 model using the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). The combination of intratumoral MBTA therapy and intraperitoneal administration of DON resulted in the complete elimination of advanced Panc02 subcutaneous tumors (140.8 ± 46.8 mm3) in 50% of treated animals and was followed by development of long-term immune memory. In the bilateral Panc02 subcutaneous tumor model, we observed a significant reduction in tumor growth in both tumors as well as prolonged survival of treated animals. The appropriate timing and method of administration of DON were also addressed to maximize its therapeutic effects and minimize its side effects. In summary, our findings demonstrate that the intraperitoneal application of DON significantly improves the efficacy of intratumoral MBTA therapy in both advanced and bilateral Panc02 subcutaneous tumor murine models.

• Keywords
• Cancer, Glutamine antagonist, Immunotherapy, Intratumoral, Pancreatic adenocarcinoma,
• MeSH
• Adenocarcinoma * drug therapy   MeSH
• Glutamine therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Pancreatic Neoplasms * drug therapy   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Glutamine MeSH

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths, and its therapy remains a challenge. Our proposed therapeutic approach is based on the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 antibody (thus termed MBTA therapy), and has shown promising results in the elimination of subcutaneous murine melanoma, pheochromocytoma, colon carcinoma, and smaller pancreatic adenocarcinoma (Panc02). Here, we tested the short- and long-term effects of MBTA therapy in established subcutaneous Panc02 tumors two times larger than in previous study and bilateral Panc02 models as well as the roles of CD4+ and CD8+ T lymphocytes in this therapy. The MBTA therapy resulted in eradication of 67% of Panc02 tumors with the development of long-term memory as evidenced by the rejection of Panc02 cells after subcutaneous and intracranial transplantations. The initial Panc02 tumor elimination is not dependent on the presence of CD4+ T lymphocytes, although these cells seem to be important in long-term survival and resistance against tumor retransplantation. The resistance was revealed to be antigen-specific due to its inability to reject B16-F10 melanoma cells. In the bilateral Panc02 model, MBTA therapy manifested a lower therapeutic response. Despite numerous combinations of MBTA therapy with other therapeutic approaches, our results show that only simultaneous application of MBTA therapy into both tumors has potential for the treatment of the bilateral Panc02 model.

• Keywords
• Cancer immunotherapy, Checkpoint inhibitors, Mannan, Metastases, Pancreatic adenocarcinoma, TLR ligands,
• MeSH
• Adenocarcinoma immunology   pathology   MeSH
• CD40 Antigens antagonists & inhibitors   MeSH
• Imidazoles pharmacology   MeSH
• Immunotherapy MeSH
• Teichoic Acids pharmacology   MeSH
• Ligands MeSH
• Lipopolysaccharides pharmacology   MeSH
• Mannans pharmacology   MeSH
• Mice MeSH
• Pancreatic Neoplasms immunology   pathology   MeSH
• Poly I-C pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• Toll-Like Receptors MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CD40 Antigens MeSH
• Imidazoles MeSH
• Teichoic Acids MeSH
• Ligands MeSH
• Lipopolysaccharides MeSH
• lipoteichoic acid MeSH Browser
• Mannans MeSH
• Poly I-C MeSH
• resiquimod MeSH Browser
• Toll-Like Receptors MeSH

Immunotherapy has become an essential component in cancer treatment. However, the majority of solid metastatic cancers, such as pheochromocytoma, are resistant to this approach. Therefore, understanding immune cell composition in primary and distant metastatic tumors is important for therapeutic intervention and diagnostics. Combined mannan-BAM, TLR ligand, and anti-CD40 antibody-based intratumoral immunotherapy (MBTA therapy) previously resulted in the complete eradication of murine subcutaneous pheochromocytoma and demonstrated a systemic antitumor immune response in a metastatic model. Here, we further evaluated this systemic effect using a bilateral pheochromocytoma model, performing MBTA therapy through injection into the primary tumor and using distant (non-injected) tumors to monitor size changes and detailed immune cell infiltration. MBTA therapy suppressed the growth of not only injected but also distal tumors and prolonged MBTA-treated mice survival. Our flow cytometry analysis showed that MBTA therapy led to increased recruitment of innate and adaptive immune cells in both tumors and the spleen. Moreover, adoptive CD4+ T cell transfer from successfully MBTA-treated mice (i.e., subcutaneous pheochromocytoma) demonstrates the importance of these cells in long-term immunological memory. In summary, this study unravels further details on the systemic effect of MBTA therapy and its use for tumor and metastasis reduction or even elimination.

• Keywords
• bilateral tumor model, immune memory, intratumoral immunotherapy, pheochromocytoma, toll-like receptor,
• Publication type
• Journal Article MeSH

The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms.

• Keywords
• T cell, Toll-like receptor, Toll-like receptor ligands, adaptive immunity, anti-CD40, glioblastoma, immunotherapy, innate immunity, mannan-BAM, metastatic, neutrophil, pathogen-associated molecular patterns,
• MeSH
• Antigen-Presenting Cells chemistry   MeSH
• CD40 Antigens immunology   MeSH
• Epitopes chemistry   MeSH
• Glioblastoma immunology   therapy   MeSH
• Immunophenotyping MeSH
• Immunotherapy methods   MeSH
• Medical Oncology trends   MeSH
• Humans MeSH
• Ligands MeSH
• Neoplasm Metastasis MeSH
• Mice MeSH
• Brain Neoplasms immunology   therapy   MeSH
• Peptides chemistry   MeSH
• Cancer Vaccines MeSH
• Computational Biology MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• CD40 Antigens MeSH
• Epitopes MeSH
• Ligands MeSH
• Peptides MeSH
• Cancer Vaccines MeSH

Emerging evidence is demonstrating the extent of T-cell infiltration within the tumor microenvironment has favorable prognostic and therapeutic implications. Hence, immunotherapeutic strategies that augment the T-cell signature of tumors hold promising therapeutic potential. Recently, immunotherapy based on intratumoral injection of mannan-BAM, toll-like receptor ligands and anti-CD40 antibody (MBTA) demonstrated promising potential to modulate the immune phenotype of injected tumors. The strategy promotes the phagocytosis of tumor cells to facilitate the recognition of tumor antigens and induce a tumor-specific adaptive immune response. Using a syngeneic colon carcinoma model, we demonstrate MBTA's potential to augment CD8+ T-cell tumor infiltrate when administered intratumorally or subcutaneously as part of a whole tumor cell vaccine. Both immunotherapeutic strategies proved effective at controlling tumor growth, prolonged survival and induced immunological memory against the parental cell line. Collectively, our investigation demonstrates MBTA's potential to trigger a potent anti-tumor immune response.

• Keywords
• TLR, adjuvant, immunogenic tumor cell vaccine, irradiation,
• Publication type
• Journal Article MeSH

: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.

• MeSH
• Biomedical Research MeSH
• Pheochromocytoma * diagnosis   genetics   therapy   MeSH
• Hypertension * MeSH
• Consensus MeSH
• Humans MeSH
• Adrenal Gland Neoplasms * diagnosis   genetics   therapy   MeSH
• Paraganglioma * diagnosis   genetics   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Geographicals
• Europe MeSH

There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.

• Keywords
• Adaptive immunity, Cancer, Immune response, Immunotherapy, Innate immunity,
• MeSH
• Adaptive Immunity MeSH
• Phagocytosis drug effects   immunology   MeSH
• Immune System immunology   metabolism   MeSH
• Immunomodulation MeSH
• Immunotherapy * methods   MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Ligands MeSH
• Tumor Microenvironment drug effects   genetics   immunology   MeSH
• Neoplasms etiology   metabolism   pathology   therapy   MeSH
• Immunity, Innate MeSH
• Antineoplastic Agents, Immunological pharmacology   therapeutic use   MeSH
• Toll-Like Receptors metabolism   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Ligands MeSH
• Antineoplastic Agents, Immunological MeSH
• Toll-Like Receptors MeSH