Combination of Viral Therapy and T Cell Therapy to Improve The Cure Rate of Cancer

Although the cure rate of several cancers has increased significantly, the prognosis of patients with advanced solid tumors has remained severe in the past few decades. Therefore, there is a need for new therapies that can improve the outcome of patients whose current therapies have failed. Oncolytic (cancer-destroying) vaccinia virus (VV) will be an attractive supplement to current cancer therapy because it can infect, replicate, and lyse tumor cells, and spread to other tumor cells in successive rounds of replication. Although clinical studies have proven their safety, the anti-tumor efficacy of oncolytic VV is not ideal.

Oncolytic VV's main mode of action is to destroy tumor cells, which can then activate components of the immune system called T cells, which can spread to remote sites and target any tumors they find. Currently, the spread of the virus in tumors and the activation of tumor-specific T cells are limited, which explains the poor anti-tumor activity of current oncolytic VVs observed. Therefore, it is hoped that by activating the resident T cells in the tumor, oncolytic VV can become a more powerful immunostimulant, thereby killing tumor cells and preventing the growth of new tumors.

T cell is a type of white blood cell that plays a central role in cell-mediated immunity. T cells express membrane receptors on their surface and recognize their targets by binding to target molecules related to MHC class I molecules expressed on the surface of tumor cells. Reminded by this tumor target molecule, T cells are activated and then produce cytokines and killer molecules, such as perforin, granzyme A, and granzyme B, which cause tumor cell lysis.

More and more evidences show that T cells can effectively control tumor growth and prolong the survival of cancer patients in the early and late stages of the disease. Tumor-specific T cells have been produced in vitro and then reinjected into cancer patients, which is called adoptive T cell therapy.

It can be assumed that oncolytic VV and bispecific T cell cements have a strong synergistic therapeutic effect, because T cells can induce bystanders to kill tumor cells that are not infected with the virus, and the cytokines released when they are activated will produce promotor The inflammatory microenvironment inhibits tumor growth, while killing tumor cells through oncolytic VV overcomes the tumor heterogeneity that limits the participation of bispecific T cells in the therapeutic efficacy.

In order to activate T cells in tumors, a new T cell involved in the strategy of armed vaccinia virus (TEA-VV) expresses secreted bispecific antibodies that bind to CD3 and the tumor cell surface antigen EphA2 (EphA2-TEA-VV).

T cell adapter-armed VV therapy is better than unmodified and other drug-armed VV. As mentioned above, oncolytic VV has been genetically equipped with antibodies, cytokines and chemokines to induce or enhance tumor-specific adaptive immunity. However, in view of the numerous immune escape mechanisms of tumor cells selected by cancer patients during the immunoediting process, it is difficult to induce tumor-specific immune responses. TEA-VV exerts its effective role by directly binding endogenous T cells and tumor cells in a tumor antigen-specific manner, leading to tumor lysis. In addition, T cell participants induce the secretion of pro-inflammatory cytokines, thereby reversing the immunosuppressive environment present in most solid tumors.

Cancer is usually incurable when it is diagnosed in the late metastatic stage. Therefore, there is an urgent need to develop new anti-tumor therapies. Genetically modified oncolytic viruses have been extensively evaluated in clinical research and represent a potentially exciting new treatment paradigm for human cancer. In particular, the T cell adaptor armed oncolytic virus with the unique ability to guide a large number of endogenous T cells to tumor cells not infected by the oncolytic virus can overcome the main limitations of current oncolytic viruses. Therefore, oncolytic viruses armed with T cell adapters represent an effective and unique strategy to improve oncolytic viral therapies by using T cells for cancer treatment.

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