Harnessing the Immune System to Potentiate Oncolytics
Authors: Stephen Gottschalk, Cliona M Rooney
Journal: Molecular Therapy (2014)

Oncolytic viruses (OVs) have already been widely studied for the treatment of cancer,1Russell SJ Peng KW Bell JC Oncolytic virotherapy.Nat Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (962) Google Scholar,2Miest TS Cattaneo R New viruses for cancer therapy: meeting clinical needs.Nat Rev Microbiol. 2014; 12: 23-34Crossref PubMed Scopus (192) Google Scholar but the development of multiple approaches that use OVs to recruit antitumor immunity is emphasizing just how powerful this approach may become. In the first half of the twentieth century, clinical case reports documenting dramatic regression of malignancies after viral infections gave rise to the concept of using replicating viruses to treat malignancies. More detailed knowledge of the molecular biology of viruses and malignancies made it possible to adapt viruses so that they could selectively replicate in cancer cells, causing tumor cell death while sparing normal cells. These OVs have been developed from adeno-, herpes simplex, reo, mumps, West Nile, vaccinia, measles, and Newcastle disease viruses, all of which have now been tested clinically. OVs most commonly contain mutations, such as missing transcriptional regulators that are complemented in trans by rapidly dividing malignant cells. For example, the oncolytic adenovirus dl1520 (Onyx-015) has a deletion of the viral E1B gene that limits its replication to (malignant) cells with a defective p53 pathway that complements dl1520-defective viral RNA export. Although clinical trials with “unarmed” OVs have shown modestly encouraging results, they have also highlighted limitations, including low efficiency of initial tumor transduction, the development of neutralizing antibodies limiting systemic delivery, and the elimination of virus-infected cells by virus-specific T cells (VSTs), thereby inhibiting replicative spread. Strategies to shield OVs from neutralizing antibodies include switching of virus serotype, the use of chimeric envelopes, or chemical modification of the viral envelope. Alternatively, T cells and mesenchymal stromal cells have been used to shield OVs and deliver them to tumor sites even in the presence of neutralizing antibodies.3Willmon C Harrington K Kottke T Prestwich R Melcher A Vile R Cell carriers for oncolytic viruses: Fed Ex for cancer therapy.Mol Ther. 2009; 17: 1667-1676Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Despite these and other strategies to enhance transduction, viral spread, and replication, it remains a formidable task to infect all tumor cells. Therefore, in efforts to kill residual, uninfected tumor cells, OVs have been “armed” with transgenes that encode prodrug-metabolizing enzymes that activate “diffusible” cytotoxic compounds or ion transporters to allow for the accumulation and transfer of radioisotopes. Even these, however, may fail to reach distant metastases. Most efforts now focus on redirecting the immune response itself, so that it facilitates rather than inhibits the success of OVs. For example, the innate immune response, so potently activated by virus-associated molecular patterns, may be exploited to target uninfected tumor cells by enhancing the ability of OVs to recruit and activate adaptive T-cell immunity directed to nonviral tumor-associated antigens, to produce the phenomenon of epitope spreading. Both oncolytic vaccinia viruses and adenoviruses encoding granulocyte-macrophage colony–stimulating factor or CD40 ligand have been shown to induce such epitope spreading in clinical trials.4Heo J Reid T Ruo L Breitbach CJ Rose S Bloomston M et al.Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.Nat Med. 2013; 19: 329-336Crossref PubMed Scopus (535) Google Scholar,5Pesonen S Diaconu I Kangasniemi L Ranki T Kanerva A Pesonen SK et al.Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients.Cancer Res. 2012; 72: 1621-1631Crossref PubMed Scopus (106) Google Scholar Alternatively, OVs may be modified with secretable, bispecific T-cell engagers, which consist of two single-chain variable fragments derived from monoclonal antibodies joined by a short linker. One single-chain variable fragment recognizes a tumor-associated antigen; the other recognizes CD3 present on T cells. Any T cell in the tumor environment can thus be rendered tumor-specific, producing potent antitumor activity in preclinical animal models.6Yu F Wang X Guo ZS Bartlett DL Gottschalk SM Song XT T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy.Mol Ther. 2014; 22: 102-111Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Because these tumor-directed T cells have the ability to actively patrol the body, traverse tissue planes, and seek out metastases, and because they are self-perpetuating, they have the potential to provide lifelong protection. The ability of OVs to recruit, reactivate, and expand VSTs at the tumor site may also be exploited to enhance the killing of uninfected tumor cells by genetically modifying VSTs to express a tumor-directed chimeric antigen receptor. Such VSTs will be activated by OV-infected tumor cells via their virus-specific T-cell receptor, allowing antitumor activity even against uninfected tumor cells via their coexpressed tumor-specific chimeric antigen receptor. Moreover, repeat OV injection may be able to sustain this antitumor activity even without direct infection or lysis of residual tumor. Thus, after decades of research, preclinical and emerging clinical data suggest that the manipulation of the interactions of OVs with the immune system will further increase the potential of these agents to have a major impact on cancer therapy. The projected launch of a journal dedicated to the field—Molecular Therapy: Oncolytics—should accelerate this scientific and clinical progress.