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Replication-Competent Viruses as Cancer Immunotherapeutics: Emerging Clinical Data.

ABSTRACT: Replication-competent (oncolytic) viruses (OV) as cancer immunotherapeutics have gained an increasing level of attention over the last few years while the clinical evidence of virus-mediated antitumor immune responses is still anecdotal. Multiple clinical studies are currently ongoing and more immunomonitoring results are expected within the next five years. All viruses can be recognized by the immune system and are therefore potential candidates for immune therapeutics. However, each virus activates innate immune system by using different combination of recognition receptors/pathways which leads to qualitatively different adaptive immune responses. This review summarizes immunological findings in cancer patients following treatment with replication-competent viruses.

SUBMITTER: Zamarin D

PROVIDER: S-EPMC4968310 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Replication-Competent Viruses as Cancer Immunotherapeutics: Emerging Clinical Data.

Zamarin Dmitriy D Pesonen Sari S

Human gene therapy 20150801 8

Replication-competent (oncolytic) viruses (OV) as cancer immunotherapeutics have gained an increasing level of attention over the last few years while the clinical evidence of virus-mediated antitumor immune responses is still anecdotal. Multiple clinical studies are currently ongoing and more immunomonitoring results are expected within the next five years. All viruses can be recognized by the immune system and are therefore potential candidates for immune therapeutics. However, each virus acti ...[more]

PMID: 26176173

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Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) can subvert early innate immunity, which leads to ineffective antimicrobial responses. Overcoming immune subversion is critical for developing vaccines and other measures to control this devastating swine virus. The overall goal of this work was to enhance innate and adaptive immunity following vaccination through the expression of interferon (IFN) genes by the PRRSV genome. We have constructed a series of recombinant PRRS viruses using an infectious PRRSV cDNA clone (pCMV-P129). Coding regions of exogenous genes, which included Renilla luciferase (Rluc), green and red fluorescent proteins (GFP and DsRed, respectively) and several interferons (IFNs), were constructed and expressed through a unique subgenomic mRNA placed between ORF1b and ORF2 of the PRRSV infectious clone. The constructs, which expressed Rluc, GFP, DsRed, efficiently produced progeny viruses and mimicked the parental virus in both MARC-145 cells and porcine macrophages. In contrast, replication of IFN-expressing viruses was attenuated, similar to the level of replication observed after the addition of exogenous IFN. Furthermore, the IFN expressing viruses inhibited the replication of a second PRRS virus co-transfected or co-infected. Inhibition by the different IFN subtypes corresponded to their anti-PRRSV activity, i.e., IFNω5 ° IFNα1 > IFN-β > IFNδ3. In summary, the indicator-expressing viruses provided an efficient means for real-time monitoring of viral replication thus allowing high‑throughput elucidation of the role of host factors in PRRSV infection. This was shown when they were used to clearly demonstrate the involvement of tumor susceptibility gene 101 (TSG101) in the early stage of PRRSV infection. In addition, replication‑competent IFN-expressing viruses may be good candidates for development of modified live virus (MLV) vaccines, which are capable of reversing subverted innate immune responses and may induce more effective adaptive immunity against PRRSV infection.

Project description:More than 80% of all cancers arise from epithelial cells referred to as carcinomas. Adenocarcinomas are the most common type of carcinomas arising from the specialized epithelial cells that line the ducts of our major organs. Despite many advances in cancer therapies, metastatic and treatment-refractory cancers remain the 2nd leading cause of death. Immunotherapy has offered potential opportunities with specific targeting of tumor cells and inducing remission in many cancer patients. Numerous therapies using antibodies as antagonists or checkpoint inhibitors/immune modulators, peptide or cell vaccines, cytokines, and adoptive T cell therapies have been developed. The most innovative immunotherapy approach so far has been the use of engineered T cell, also referred to as chimeric antigen receptor T cells (CAR-T cells). CAR-T cells are genetically modified naïve T cells that express a chimeric molecule which comprises of the antigen-recognition domains (scFv) of an anti-tumor antibody and one, two, or three intracellular signaling domains of the T cell receptor (TCR). When these engineered T cells recognize and bind to the tumor antigen target via the scFv fragment, a signal is sent to the intracellular TCR domains of the CAR, leading to activation of the T cells to become cytolytic against the tumor cells. CAR-T cell therapy has shown tremendous success for certain hematopoietic malignancies, but this success has not been extrapolated to adenocarcinomas. This is due to multiple factors associated with adenocarcinoma that are different from hematopoietic tumors. Although many advances have been made in targeting multiple cancers by CAR-T cells, clinical trials have shown adverse effects and toxicity related to this treatment. New strategies are yet to be devised to manage side effects associated with CAR-T cell therapies. In this review, we report some of the promising immunotherapeutic strategies being developed for treatment of most common adenocarcinomas with particular emphasis on the future generation of CAR-T cell therapy.

Dataset Information

Replication-Competent Viruses as Cancer Immunotherapeutics: Emerging Clinical Data.

Publications

Replication-Competent Viruses as Cancer Immunotherapeutics: Emerging Clinical Data.

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