Projects / Programmes
Time-lapse intra-vital imaging of immune response after electrochemotherapy induced in situ vaccination and Interleukin-12 gene therapy boost
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
intra-vital real-time imaging, immune response, electrochemotherapy, in situ vaccination, interleukin 12
Researchers (21)
Organisations (2)
Abstract
Cancer immunotherapy is experiencing a renaissance in the last couple of years. Currently, numerous approaches are being tested in preclinical and clinical trials, and a few have also reached the regulatory approval. One promising idea that has not been thoroughly tested in preclinical trial is to use the therapy killed tumor cell as a live, in situ vaccine, to prime the endogenous immune response to the numerous tumor antigens released from the dying cells. This could be achieved by various standard local ablative treatments that have been lately listed as so called immunogenic cell death inducers. To induce a durable systemic immune response, this therapies need to be optimized and combined with immunotherapies that boost the endogenous immune response.
Recently, we proposed a model how electrochemotherapy could be used as in situ vaccine in combination with interleukin 12 gene electrotransfer to boost the primed immune response against tumor associated antigens released from the therapy killed tumor cells (Sersa et al., Cancer Immunol Immunother, 2015). Electrochemotherapy is an established local ablative therapy for the treatment of cutaneous and subcutaneous tumors, where electroporation is applied to locally increase the concentration of chemotherapeutic. Gene electrotransfer is yet another biomedical application of electroporation which has reached clinical evaluation for the local delivery of a powerful imunostimulatory cytokine interleukin 12. The viability of the combined use of this two approaches was already demonstrated in a clinical trial on client-owned dogs (Cemazar et al., Vet Comp Oncol, 2016), however the exact mechanisms of the clinically observed antitumor effectiveness at the level of immune cells involvement has not been elucidated.
With the emergence of new imaging technologies, like confocal microscopy, combined with new or repurposed in vivo or ex vivo cell labelling techniques, it is now possible to image the dynamic interactions between individual cells of the immune system with each other and with host cells directly within tumor microenvironment and in lymph organs.
In the proposed research we will use this advanced methods to follow the immune response after electrochemotherapy induced vaccination boosted with interleukin 12 gene electrotransfer in a mouse tumor model. First, electrochemotherapy and interleukin 12 gene electrotransfer and their combination, will be evaluated for therapeutic effectiveness using standard phenomenological models for local and systemic inhibition of tumor growth. Next, using intra-vital confocal microscopy and fluorescent markers, cell deaths after electrochemotherapy and expression gene electrotransfer will be mapped in real-time. Finally, immunological events occurring at the tumor site and in the skin surrounding the tumor and also in the draining lymph nodes after electrochemotherapy induced in situ vaccination and interleukin 12 gene electrotransfer boost will be imaged.
The results of our proposed research will provide a better understanding of antitumor mechanisms of both electrochemotherapy and interleukin 12 gene electrotransfer that could lead to better planning of combined approach, specifically with respect to appropriate timing, sequencing and dosing of the therapies. Furthermore, the imaging methodologies developed during this project could be implemented in the future studies to evaluate the immunological response after upcoming combinations before clinical testing.
Significance for science
Combination of local ablative therapies, such as radiotherapy, radiofrequency ablation and electrochemotherapy, in combination with immunotherapies has a great potential for curative treatment of cancer. To ensure that they reach their full potential, much more must be learned about the immune system’s response to therapies and its interactions within the complex tumor microenvironment. Intra-vital imaging is certainly an important tool for monitoring of the immune responses during therapy that can, not only help us understand the underlying mechanisms of the antitumor effectiveness, but also initiate ideas about new cancer treatments. In the proposed project, we hope to develop improved treatment strategies, by identifying the exact mechanisms of the involvement of immune response in the observed antitumor effectiveness, specifically with respect to appropriate timing, sequencing and dosing of the therapies. Furthermore, the imaging methodologies developed in this project based on our therapy model could be implemented in the future studies to evaluate the immunological response after upcoming combinations before clinical testing.
Significance for the country
The project can have a direct impact on the society, specifically cancer patients. Namely, the proposed project is designed as a preclinical project with apotential for clinical impact; therefore our ultimate mission is to help improve lives of cancer patients. The acquired data can contribute to the utilization of therapeutics used in the project (electrochemotherapy, interleukin 12 gene electrotransfer) and can have an impact on the design of new cancer treatment trials. The main advantages of the proposed treatment is its robustness in comparison to many new biological treatments that target only one cancer feature, and the universality of this approach against different cancer types. Further advantage is that there is no need to identify tumor antigens. This means, the combined approach could be suitable for the treatment of different types of cancer, independently of the mutation, and that less costly diagnostic methods would be needed prior to the therapy. For instance, using the proposed therapy approach, problem of recurrence in melanoma patients could be reduced, and the approach implemented also in the treatment of other metastatic cancers.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
