Virus and antibodies – together against the tumor
Researchers at Memorial Sloan-Kettering Cancer Center have demonstrated that the effectiveness of antitumor immunotherapy can be significantly improved by combining it with therapy with oncolytic viruses.
As part of their work, they injected the Newcastle disease virus – a bird–infecting virus that is not dangerous to humans - directly into one of two melanomas implanted in mice. After that, the animals were injected with antibodies against CTLA-4, a molecule expressed on the surface of T–lymphocytes that suppresses the activity of these immune cells. As a result, the animals developed a powerful systemic antitumor immune response, which ensured the destruction of both tumors. Moreover, this effect was manifested independently of the susceptibility of tumor cells to immunotherapy or the action of an oncolytic virus when they were used separately.
The authors found that the main mechanism ensuring the effectiveness of combination therapy is an inflammatory immune response induced in the tumor by the Newcastle disease virus. To their surprise, they found that at the same time, activated immune cells infiltrated not only the tumor infected with the virus, but also a second tumor located at a certain distance.
Apparently, infection with the Newcastle disease virus gives the T-cells of the immune system a kind of alarm signal, indicating the presence of tumor cells in the body, which in their normal state are able to suppress the immune response directed against them. The subsequent administration of anti-CTLA-4 antibodies activates the nascent immune response so strongly that, as a result, it leads not only to overcoming the immunosuppression caused by the tumor, but also to the destruction of all tumor foci, including those not infected with the oncolytic virus. Moreover, when re-administered to animals undergoing therapy, tumor cells were very quickly destroyed by their immune system, which indicates the stability of the effect achieved.
According to the first author of the work, Dmitry Zamarin, the combination of two therapeutic approaches makes it possible to overcome the disadvantages of their individual application. The effectiveness of therapy with oncolytic viruses is severely limited by the fact that with systemic administration, immune cells neutralize viral particles long before they penetrate the tumor. The researchers managed to avoid this by locally injecting the virus directly into the tumor.
On the other hand, anti-CTLA-4 antibodies are ineffective against tumors that suppress the ability of the immune system to detect and destroy them. Infection with the virus causes the cells of such tumors to give themselves away at the moment of "informing" the immune system about infection with the virus.
The researchers also found that the Newcastle disease virus can be used to enhance the effects of experimental antitumor immunotherapy, known as adaptive T-lymphocyte transfer. This approach involves isolating the patient's own T-cells, "training" them for the antigens of his own tumor and introducing them back into the bloodstream. The effectiveness of adaptive transfer is also not high enough due to the ability of tumors to suppress immune responses.
The authors believe that the preliminary introduction of the Newcastle disease virus into the tumor can similarly increase the effectiveness of other immunotherapeutic approaches. Viral particles can also be modified so that they express immune factors that can further enhance certain components of the antitumor immune response. Currently, researchers are working on methods for obtaining large amounts of viral particles, as well as developing protocols for early stages of clinical trials to evaluate the effectiveness of combination therapy.
Article by Dmitriy Zamarin et al. Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy is published in the journal Science Translational Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Ludwig Cancer Research: Going viral to target tumors.
17.03.2014