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Cellular vaccination of MLH1-/- mice - an immunotherapeutic proof of concept study.

ABSTRACT: Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1-/- knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers. Therapeutic application of the vaccine prolonged overall survival (median time: 11.5 (lysate) and 12 weeks (lysate + CpG ODN) vs. 3 weeks (control group), respectively) along with reduced tumor burden, as confirmed by PET/CT imaging and immune stimulation (increased CD3+CD8+ T - and NK cell numbers, reduced levels of TIM-3+ cells in both treatment groups). Coding microsatellite analysis of MMR-D-related target genes revealed increased mutational load upon vaccination (total mutation frequency within 28 genes: 28.6% vaccine groups vs. 14.9% control group, respectively). Reactive immune cells recognized autologous tumor cells, but also NK cells target YAC-1 in IFN? ELISpot and, even more importantly, in functional kill assays. Assessment of tumor microenvironment revealed infiltration of CD8+ T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1). The present study is the first reporting in vivo results on a therapeutic cellular MMR-D vaccine. Vaccination-induced prolonged survival was achieved in a clinically-relevant mouse model for MMR-D-related diseases by long-term impairment of tumor growth and this could be attributed to re-activated immune responses.

SUBMITTER: Maletzki C

PROVIDER: S-EPMC5790332 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cellular vaccination of MLH1<sup>-/-</sup> mice - an immunotherapeutic proof of concept study.

Maletzki Claudia C Gladbach Yvonne Saara YS Hamed Mohamed M Fuellen Georg G Semmler Marie-Luise ML Stenzel Jan J Linnebacher Michael M

Oncoimmunology 20171214 3

Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1<sup>-/-</sup> knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompani ...[more]

PMID: 29399413

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Project description:New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs.

Dataset Information

Cellular vaccination of MLH1-/- mice - an immunotherapeutic proof of concept study.

Publications

Cellular vaccination of MLH1<sup>-/-</sup> mice - an immunotherapeutic proof of concept study.

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