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

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

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