A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma

Abstract

A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity. We also engineered a novel immunotoxin, αFAP-PE38, capable of targeting fibroblast activation protein (FAP)-expressing fibroblasts within the tumor stroma. When combined with αFAP-PE38, LV-3Ag exhibited greatly enhanced antitumor effects on tumor growth in an established B16 melanoma model. The mechanism of action underlying this combination treatment likely modulates the immune suppressive tumor microenvironment and, consequently, activates cytotoxic CD8+ T cells capable of specifically recognizing and destroying tumor cells. Taken together, these results provide a strong rationale for combining an immunotoxin with cancer vaccines for the treatment of patients with advanced cancer.

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

“…Various vaccination modalities have been employed to target FAP + cells in preclinical models, including DNA vaccines( 105 – 108 ), adenoviral vectors( 109 ), peptide immunization( 110 ), and whole-cell vaccines( 111 , 112 ). In addition, various immunotoxins( 113 – 115 ), antibodies( 116 , 117 ), FAP-targeting liposomes( 118 – 121 ), and FAP-directed chimeric antigen receptor T-cells( 122 – 124 ) can also deplete FAP + cells and thus provide therapeutic benefit. From this plethora of treatments, certain patterns emerge.…”

“…Functionally, FAP + cells play important roles in immunosuppression( 111 , 113 , 115 , 123 ), especially of CD8 + T-cells( 109 , 112 ), as well as promoting desmoplasia( 105 , 111 , 124 ). In terms of therapeutic efficacy, FAP-directed treatments often combine effectively with chemotherapy( 108 , 114 ), tumor antigen vaccines( 109 , 115 ), or antibody treatments( 116 , 117 ). This could be an important consideration, since prior single-agent human trials, such as of the anti-FAP antibody sibrotuzumab, have shown limited efficacy( 125 ).…”

Targeting of activated fibroblasts for imaging and therapy

“…FAP-targeting strategies were shown to be more effective when combined with other treatment modalities such as chemotherapy, vaccination or antibodies (Brünker et al 2016, Fang et al 2016a, 2016b, Fang et al 2016a, 2016b, Huang et al 2015, Xia et al 2017, Zhang et al 2016). This may be an approach to address the lack of efficacy observed with sibrotuzumab (Hofheinz et al 2003).…”

Intratumoral immune activation with TLR4 agonist synergizes with effector T cells to eradicate established murine tumors

“…To overcome immune escape due to heterogenous expression of antigens in primary tumors and metastases, immune responses against multiple tumor antigens must be induced. Successful approaches have been reported in both preclinical 23,24 and clinical settings [25][26][27] and are based on direct targeting of multiple tumorassociated antigens 23,25 or the use of tumor cell lysates, which in theory would include all available tumor antigens [28][29][30] . Targeting of tumor antigens requires their identification and characterization and is limited by expression capacity of the vaccine vector and epitope immunodominance phenomena 31,32 .…”