Induction of Immune Response against Metastatic Tumors via Vaccination of Mannan‐BAM, TLR Ligands, and Anti‐CD40 Antibody (MBTA)

Abstract

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, MBTA's potential to augment CD8+ T‐cell tumor infiltrate when administered intratumorally or subcutaneously is demonstrated as part of a whole tumor cell vaccine. Both immunotherapeutic strategies prove effective at controlling tumor growth, prolong survival, and induce immunological memory against the parental cell line. Collectively, the investigation demonstrates MBTA's potential to trigger a potent anti‐tumor immune response.

Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma

“…Several studies have established that constituents of MBTA immunotherapy result in a substantial response in murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma [ 1 , 2 , 4 , 7 , 23 , 33 ]. One of these studies demonstrated the significant reduction in tumor volume and increased overall survival in a mouse model of metastatic pheochromocytoma treated with intratumoral mannan-BAM and TLR ligands (MBT) injection [ 1 , 2 ].…”

“…Further, in our previous MBTA study using a murine colon carcinoma CT26 cell line, we demonstrated that intratumoral injection of MBTA as well as subcutaneous delivery of a vaccine consisting of irradiated autologous, whole tumor cell pulsed with MBTA could induce a robust tumor-specific adaptive immune response [ 23 ]. Primary and metastatic representative tumors were established by CT26 tumor cell inoculation into the right and left flank, respectively [ 23 ]. Intratumoral injection of MBTA versus saline into the primary right flank tumor was administered according to the treatment schedule.…”

“…Following treatment, MBTA-injected mice demonstrated significantly decreased primary right flank as well as metastatic left flank tumor volumes. Furthermore, MBTA-treated mice demonstrated improved overall survival compared to control saline-treated mice [ 23 ].…”

“…This delivery method, directly into the tumor in situ, precluded MBTA treatment in patients with tumors in eloquent areas susceptible to secondary inflammatory damage or mass effect [ 17 , 18 , 19 , 20 , 21 , 22 ]. In our prior MBTA study, we demonstrated in a preclinical mouse model of colon carcinoma that subcutaneous vaccine delivery of irradiated whole tumor pulsed with MBTA resulted in significantly decreased tumor volumes and increased overall survival when compared to saline or irradiated whole tumor cell vaccine alone [ 23 ].…”

“…By pulsing MBTA with resected autologous whole tumor cells that underwent sublethal irradiation, the vaccine constituents are assembled in vitro with intact whole tumor cells that have been inactivated as a result of radiation-induced (1) cell cycle arrest, (2) direct induction of apoptosis, (3) and mitotic catastrophe [ 24 ]. Subsequent subcutaneous injection of inactivated tumor cells and MBTA into a peripheral site allows for tumor-specific neoantigen processing in vivo through endogenous pathways that activate the innate immune system and result in stimulation of a sustained adaptive immune response [ 23 ].…”