How do oncolytic viruses work in CAR-T therapy?
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How do oncolytic viruses work in CAR-T therapy?
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Science Translational Medicine: How do oncolytic viruses work in CAR-T therapy?
The rate-limiting steps for CAR-T therapy to intervene in solid tumors lie in the inability of T cells to expand effectively in the body, the difficulty of T cells reaching the lesions accurately, and the obstruction of the tumor microenvironment [1, 2, 3, 4] .
CAR-T cells can recognize tumor surface antigens through the major histocompatibility complex.
Although CAR molecules can effectively mimic T cell receptors and costimulatory signals at the beginning of their design, their sensitivity, ligand-receptor binding and downstream signaling pathways are still variable [5] . Moreover, different antigens correspond to different co-stimulatory signals and cytokines.
For example, tumor antigens are usually present in the inhibitory tumor microenvironment, while viral polypeptides are mostly present in the inflammatory environment induced by viral infection.
Oncolytic viruses can expand in tumor cells and induce a highly inflamed tumor microenvironment and activate innate and adaptive antitumor immune responses, all of which contribute to the immunotherapy of solid tumors [6, 7] .
However, the author’s previous work found that the effect of oncolytic virus has two sides, although infection with oncolytic virus can induce T cell-related chemokines, but type I interferon can also promote CAR-T cell apoptosis [8] .
In 2022, Richard G. Vile ‘s research group from the Mayo Medical Center in the United States published an article entitled Oncolytic virus–mediated expansion of dual-specific CAR T cells efficacy against solid tumors in mice in Science Translational Medicine , which improved the above CAR. T therapy.
First, the authors’ previous work employed a mouse melanoma model with intratumoral injection of oncolytic virus (VSV-mIFN) prior to transfusion of CAR T cells .
The authors found that a large amount of type I interferon was produced in tumor lesions after injection of oncolytic virus, which would deplete a large number of CAR T cells recruited to the lesion .
Therefore, the authors switched their thinking and injected oncolytic virus loaded with mIFNb 5 days after transfusion of CAR T cells, and found that the level of CD8+ CAR T cells targeting VSV increased significantly, and there was no CAR T cell depletion in the tumor, spleen and blood.
Moreover, the effect of subcutaneous injection is better than that of intratumoral injection. CAR T cells peaked 7 days after virus injection, and CAR T cells were still detectable after 100 days.
The authors found that virus-specific CAR T cells could reach 25% of the total CAR T cells, indicating the selectivity of CAR T cell expansion.
Moreover, CAR T cells isolated from mice transfused with CAR T cells and injected with oncolytic virus have strong tumor cell killing effects in vitro.
Next, the authors investigated why virus-specific CAR T cells are more active. The authors found that this type of CAR T cells highly expressed CD107a, IFNr, TNF-a and other cytokines, and also had a stronger degranulation effect.
In addition, the authors’ previous work found that oncolytic virus can be loaded into CAR T cells before transfusion, and the antitumor effect is better than subcutaneous injection alone.
Based on this phenomenon, the authors speculate that the anti-tumor effect of the above-mentioned CAR T cells can be further enhanced in this regard.
The authors found that mice transfused with CAR T cells preloaded with oncolytic virus had higher viral titers and higher levels of CAR T cells at the lesion.
The authors also found that the above phenomenon was not related to virus type and tumor type.
Finally, the authors investigated whether human-derived virus-specific T cells could also efficiently expand and function.
The authors used a mouse-loaded human Mel888-CD19 tumor model and found that the anti-tumor effect of virus-preloaded CAR T cells was significantly better than that of normal CAR T cells.
15 days after transfection of cells, compared with direct virus injection, preloading the virus on CAR T cells can both protect the virus and improve the efficiency of virus transport.
In conclusion, the authors propose a new approach to improve the efficacy of CAR T therapy.
The authors found that virus injection after transfusion of CAR T cells can effectively increase the level of CD8+ CAR T cells and anti-tumor effect.
At the same time, oncolytic virus can also specifically promote the expansion and activation of virus-specific CAR T cells.
In addition, the antitumor effect of CAR T cells preloaded with virus transfection into mice was better.
The author’s work demonstrates the good effect of oncolytic virus and CAR T cells synergistically fighting tumors, and proposes a new idea to promote the expansion of CD8+ CAR T cells.
Refereence:
Original link: www.science.org/doi/10.1126/scitranslmed.abn2231
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7. N. M. Durham, K. Mulgrew, K. McGlinchey, N. R. Monks, H. Ji, R. Herbst, J. Suzich,S. A. Hammond, E. J. Kelly, Oncolytic VSV primes differential responses to immuno-oncology therapy. Mol. Ther. 25, 1917–1932 (2017).
8. L. Evgin, A. L. Huff, P. Wongthida, J. Thompson, T. Kottke, J. Tonne, M. Schuelke,K. Ayasoufi, C. B. Driscoll, K. G. Shim, P. Reynolds, D. D. Monie, A. J. Johnson, M. Coffey, S. L. Young, G. Archer, J. Sampson, J. Pulido, L. S. Perez, R. Vile, Oncolytic virus-derived type I interferon restricts CAR T cell therapy. Nat. Commun. 11, 3187 (2020).
Science Translational Medicine: How do oncolytic viruses work in CAR-T therapy?
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