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Oncolytic virus and CAR-T open a new way to overcome the problem of solid tumors

2020-10-13
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Due to the combination of tumor and CAR-T immunotherapy, the amazing results produced are exciting. Medicilon followed closely with international companies in tumor models, especially in the field of immune tumor animal model evaluation systems, and introduced internationally advanced PET-CT imaging systems, radiotherapy radiation systems, IVIS small animal imaging systems, multi-channel flow cytometry analyzers, etc. Precision instruments and equipment, development of key technologies for drug research and development, and systematically established more than 250 tumor models. Pharmaceutical and other customers provide anti-tumor drug research services.

As two currently extremely popular tumor immune methods, oncolytic virus and CAR-T therapy (insert antigen receptor T cell immunotherapy) are favored by many companies and scientific research centers, and the research progress is constantly updated. However, CAR-T therapy under development is unable to break through metastasis to recognize tumor antigens and it is difficult to overcome the impact of tumor microenvironment on CAR-T cells. Therefore, CAR-T research has concerns about safety and cannot Extend the field of treatment to solid tumors.
Professor Saul Priceman, one of the authors of the study, said, “First, on solid tumors, there are limited targets suitable for CAR redirection of T cells. Second, solid tumors are surrounded by the so-called immunosuppressive tumor microenvironment. When CAR-T cells try to enter the tumor, survive and kill the tumor, they cannot function effectively because of this barrier. Oncolytic viruses can break through this barrier.”
On the other hand, oncolytic viruses have become a promising treatment for solid tumors because of their fully decomposed tumors, sufficiently good immunogenicity and the ability to carry foreign genes into tumors. The oncolytic virus drug T-VEC used, research found that it can expose soluble tumor antigens and guide the host’s anti-tumor immune response.
The article’s research takes advantage of this and uses oncolytic viruses as the “driver” of CAR-T cells into solid tumors. They genetically engineered an oncolytic virus, entered tumor cells, and implanted cells that express short CD19 (CD19t) on the surface. The experiments in this article show that this oncolytic virus (called OV19t) can work in triple-negative breast cancer cell lines as well as pancreatic cancer, prostate cancer, ovarian cancer, head and neck cancer, and brain tumor cells.

Oncolytic virus and CAR-T open a new way to overcome the problem of solid tumors

01 Oncolytic virus successfully provided CD19t to solid tumor cells (in vitro)

The researchers used the clip PSE promoter and CD19t osteosarcoma oncolytic virus to infect a wide range of solid tumors. In order to more intuitively express the ability of the oncolytic virus to transfect antigen and the expression of CD19t on the surface, the researchers stained tumor cells. After the oncolytic virus is used to infect the millimeter wave, the antigen expresses abundant CD19 on its surface. Furthermore, the researchers used flow cytometry to quantitatively measure the expression of CD19t on the surface of tumor cells in different time periods, and found that after 72 hours of transfection, 70% of tumor cells could still detect the expression of CD19t, thus giving CAR-T The identification and replacement of cells provides ample time.
After that, the researchers tested the “OV19t + CD19-CAR-T” combination therapy in cells from a variety of solid tumors, including squamous cell carcinoma, prostate cancer and ovarian cancer.

“OV19t + CD19-CAR-T” combination therapy in cells  (Image source: Science Translational Medicine)

02 CD19t expressed by solid tumors can redirect the activity and cytotoxicity of CD19-CAR-T cells (in vitro)

In this step of verification, the researchers co-infected OV19t-infected tumor cells with CD19-CAR T cells, and used the expression of CD25 and 4-1BB on the surface of T cells to indicate T cell activation. The results show that the oncolytic virus can present antigens to T cells multiple times and mediate the immune response of CAR T cells to tumors.

antigens to T cells
present antigens to T cells multiple times and mediate the immune response of CAR T cells to tumors  (Image source: Science Translational Medicine)

03 Anti-cancer efficacy test of animal models in non-clinical studies (in vivo)

Subsequently, the researchers continued to try this strategy in mouse tumor models. They found that the combination of OV19t and CAR-T cells produced a powerful synergistic effect, curing more than half of the mice, ~60% of the mice were in complete remission, while only 22% of the mice independently treated with OV19t completely resolved their tumors.
The researchers also found that in mice receiving the combination therapy, OV19t will continue to spread, and the killed tumor cells will release additional copies of the virus, causing neighboring tumor cells to express CD19, resulting in a significantly stronger Tumor cell killing activity. More importantly, when the cured mice were challenged again with Micron, no new tumors were formed, indicating that this virus-CAR-T combination program helped establish tumor diagnostic immune memory and could prevent cancer recurrence.

04 The tumor killer received by CD19-CAR T therapy can release the oncolytic virus OV19t


In order to check whether this method can overcome the suboptimal or uneven infection of solid tumors by oncolytic viruses, the experimenters tested whether the killed tumor cells can release oncolytic virus fragments in the environment of solid tumors. The results showed that CD19-CAR-T cell-mediated tumor killing promoted the release of virus particles and continued tumor cell infection. In addition to expressing CD19t, research has also confirmed that dating virus reverses the harsh microenvironment of tumors, making it easier to accept CAR-T cell therapy.
Medicilon will also continue to pay attention to the new progress and new ideas of tumor immunotherapy. This discovery provides new ideas and hopes for the treatment of solid tumors, and integrates CAR-T therapy and oncolytic viruses to bring better efficacy . And use the continuously improved tumor immunotherapy evaluation platform to help research and development.
References: Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu J, Jangg B, Chang WC, Chen NG, Thomas SH, Forman SJ, Priceman SJ. Effective combination immunotherapy using oncolytic viruses can deliver CAR targets to solid tumors. Scientific translation of medicine. 2020 Sep 2; 12 (559): eaaz1863. doi: 10.1126/scitranslmed.aaz1863. PMID: 32878978.

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