More than a hundred years ago, a woman with cervical cancer in Italy was bitten by a dog. After being given the rabies vaccine for her dog bite, her large cervical tumor disappeared, and she lived for 8 more years. The medical community took note and began giving rabies vaccine to other patients with cervical cancer. In these patients, the cancer eventually relapsed and they all died. However, the idea that viruses could kill malignant cells remained interesting but problematic. For example, how could viral infection of healthy tissue be avoided? And how could the body's natural immune system be prevented from attacking the virotherapy?
Since the 1990s, advances in genetic engineering have permitted researchers to design solutions to these problems. In 2005, an oncolytic virus was approved in China for treatment of head and neck cancer. Nearly a dozen other oncolytic viruses are now in human testing in a wide variety of cancers.
Amgen has recently reported promising results from a Phase 3 randomized open-label clinical study investigating the use of talimogene laherparepvec (T-Vec), a genetically modified form of herpes simplex virus 1 (HSV-1), in the treatment of patients with Stage IIIB, IIIC, and IV melanoma1. To make T-Vec, 2 viral genes were deleted from HSV-1 so that the virus would selectively replicate only within the tumor, and the human gene for granulocyte-macrophage colony stimulating factor (GM-CSF) was encoded to enhance systemic antitumor immune responses. Patients with injectable melanoma that was not surgically resectable (N=436) were randomly assigned (2:1) to receive intralesional T-VEC or subcutaneous GM-CSF. Results showed that the primary endpoint, durable response rate (DRR; defined as objective response of ≥50% decrease in tumor size lasting continuously ≥6 months) was significantly higher with T-VEC than with GM CSF (16.3% and 2.1%, respectively; P<.001). Overall response rate was also higher with T-VEC (26.4% vs. 5.7%, respectively). Median overall survival (OS) was longer in the V-TEC group (23.3 months compared with 18.9 months in the GM-CSF group; hazard ratio 0.79, P=.051). In the V-TEC group, the most common adverse events (AEs) were fatigue, chills, and pyrexia; cellulitis (2.1%) was the only Grade 3 or 4 AE that occurred in more than 2% of patients; and no fatal treatment-related AEs were reported.
Mahoney and colleagues describe how viruses work in a tumor cell, including hijacking the cell's gene-copying and protein-making machinery to make new copies of itself2. Then as the viral particles leave the tumor cell, they lyse the cell or program it to self-destruct. These departing clones can then infect neighboring or distant tumor cells. When used in combination with drug therapy, viruses may help reduce the likelihood of drug resistance developing. Some strains of oncolytic viruses can infect tumor blood vessels, which stimulates an immune response. Immune stimulation is now considered a net positive effect in virotherapy. Interesting areas of viral engineering include creating viral particles with specificities for tumor cells such as for cell wall receptors, for raw materials required for replication within tumor cells, or for defects in protective antimicrobial and antiviral elements in tumor cells. Genes can be added to the virus that encode tumor antigens, which will elicit an immune response.
Virotherapy has been remarkably nontoxic thus far, especially in comparison with chemotherapy. As Mahoney and colleagues point out, it will be important to continue monitoring safety as these viral therapies are combined with complementary immunotherapies or increased in dosage.
1 Andtbacka RHI, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015 May 26.
2 Mahoney DJ, Stojdl DF, Laird G. Can viruses treat cancer? Sci Am 2014; 311(5):54-9.
Image credit: CDC
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