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Humanized Mice with Subcutaneous Human Solid Tumors for Immune Response Analysis of Vaccinia Virus-Mediated Oncolysis
Desislava Tsoneva1, Boris Minev2,3, Alexa Frentzen3
1Department of Biochemistry, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany.
Abstract:
Oncolytic vaccinia virus (VACV) therapy is an alternative cancer treatment modality that mediates targeted tumor destruction through a tumor-selective replication and an induction of anti-tumor immunity. We developed a humanized tumor mouse model with subcutaneous human tumors to analyze the interactions of VACV with the developing tumors and human immune system. A successful systemic reconstitution with human immune cells including functional T cells as well as development of tumors infiltrated with human T and natural killer (NK) cells was observed. We also demonstrated successful in vivo colonization of such tumors with systemically administered VACVs. Further, a new recombinant GLV-1h376 VACV encoding for a secreted human CTLA4-blocking single-chain antibody (CTLA4 scAb) was tested. Surprisingly, although proving CTLA4 scAb's in vitro binding ability and functionality in cell culture, beside the significant increase of CD56bright NK cell subset, GLV-1h376 was not able to increase cytotoxic T or overall NK cell levels at the tumor site. Importantly, the virus-encoded β-glucuronidase as a measure of viral titer and CTLA4 scAb amount was demonstrated. Therefore, studies in our "patient-like" humanized tumor mouse model allow the exploration of newly designed therapy strategies considering the complex relationships between the developing tumor, the oncolytic virus, and the human immune system.
Insights
Oncolytic vaccinia virus (VACV) therapy shows promise for cancer treatment. A new VACV encoding a CTLA4-blocking antibody did not enhance anti-tumor immunity in a humanized mouse model.
Area of Science:
- Oncolytic virotherapy
- Immunology
- Cancer research
Background:
- Oncolytic vaccinia virus (VACV) therapy offers targeted tumor destruction and anti-tumor immunity induction.
- Humanized mouse models are crucial for studying complex interactions between tumors, viruses, and the human immune system.
Purpose of the Study:
- To analyze VACV interactions within a humanized subcutaneous tumor mouse model.
- To evaluate a novel recombinant GLV-1h376 VACV encoding a CTLA4-blocking single-chain antibody (scAb).
Main Methods:
- Development of a humanized mouse model with subcutaneous human tumors.
- Systemic administration of VACV and a recombinant GLV-1h376 VACV.
- Analysis of tumor infiltration by human immune cells (T cells, NK cells).
- Assessment of viral colonization and CTLA4 scAb functionality in vivo.
Main Results:
- Successful human immune cell reconstitution and tumor infiltration were observed.
- Systemic VACV administration led to successful in vivo tumor colonization.
- The recombinant GLV-1h376 VACV increased CD56bright NK cells but not cytotoxic T or overall NK cells at the tumor site.
- Virus-encoded β-glucuronidase confirmed viral titer and CTLA4 scAb levels.
Conclusions:
- The humanized tumor mouse model effectively simulates patient-like conditions for evaluating oncolytic virus therapies.
- The novel VACV encoding CTLA4 scAb did not enhance cytotoxic T or NK cell levels despite in vitro efficacy.
- This model facilitates exploration of new therapeutic strategies by considering tumor-virus-immune system dynamics.
