Mesothelin-specific cell-based vaccine generates antigen-specific immunity and potent antitumor effects by combining with IL-12 immunomodulator

Abstract

Ovarian cancer is a gynecologic malignancy with a high mortality rate. In the present study, we developed a novel cell-based vaccine, Meso-VAX, to generate mesothelin antigen-specific immune responses and immunotherapy against ovarian cancer. Mesothelin, a secreted protein anchored at the cell membrane, has recently been identified as a potential new tumor antigen for ovarian cancer. In this study, mice vaccinated with Meso-VAX and adeno-associated virus (AAV)-IL-12 exhibited dramatic increases in the number of mesothelin-specific CD4(+) helper and CD8(+) cytotoxic T-cell precursors, higher titers of anti-mesothelin Abs and in vitro tumor killing activity, and all of these mice were tumor-free after 60 days of tumor challenge. In addition, a significant reduction in peritoneal tumors and longer survival were noted in the mice vaccinated with Meso-VAX combined with AAV-IL-12. CD4(+) helper and CD8(+) cytotoxic T lymphocytes were essential for the antitumor effect generated by Meso-VAX combined with AAV-IL-12. The post-vaccination sera of the mice vaccinated with Meso-VAX and AAV-IL-12 also showed mesothelin-specific complement-dependent cell-mediated cytotoxicity. Our results suggest that a Meso-VAX cell-based vaccine combined with AAV-IL-12 can generate antigen-specific immunological responses and antitumor effects on ovarian cancer.

A new anti-mesothelin antibody targets selectively the membrane-associated form

“…38 Several agents, including immunotoxins, chimeric mAbs, antibody-drug conjugates, anti-mesothelin tumor vaccines and anti-mesothelin chimeric antigen receptors (CARs) are in various stages of development for the treatment of patients with mesothelin-expressing tumors. [39][40][41] A chimeric antibody (MORAb-009) and an immunotoxin (SS1P) constructed from the same murine SS1 scFv targeting mesothelin have already been developed and are currently being evaluated in clinical trials treatments of mesothelioma and pancreatic cancers. The clinical use of SS1P is limited by its propensity to induce neutralizing antibodies.…”

Mesothelin-targeted CAR-T cell therapy for solid tumors

“…JNJ-64,041,757 was used to treat NSCLC patients alone or in combination with nivolumab in two clinical trials (NCT03371381 and NCT02592967) which were, however, terminated due to lack of a favorable clinical effect. Despite the generally disappointing clinical results and small numbers of clinical trials, neoantigen DNA vaccines are being tested and further preclinical efforts are being made with regards to the development of other types of vaccines, such as Meso-VAX in combination with adeno-associated virus (AAV)-IL-12 and CTGF/ MSLN DNA vaccine [66,67].…”

Towards Clinical Implementation of Adeno-Associated Virus (AAV) Vectors for Cancer Gene Therapy: Current Status and Future Perspectives

“…An antigen-specific cancer vaccination approach was published by Chang et al who exploited mesothelin (MSLN) as a frequent tumor antigen for ovarian cancer as a cell-based vaccine. Mesothelin-based vaccination (Meso-Vax) and AAV vector-delivered interleukin (IL)-12 showed potent antitumor immune responses such as increased mesothelin-specific CD4+ and CD8+ T cell precursors and high anti-mesothelin antibodies, which resulted in blockade of tumor formation in 100% of mice for at least 60 days after challenge [ 176 ]. In a subsequent study by the same group [ 177 ], the efficacy of the Meso-Vax and AAV-IL-12 combination for tumor treatment was confirmed.…”