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Oncolytic birotherapy and the dermatologist


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By Warren R. Heymann, MD
March 8, 2018

My late British cousin Tim, a brilliant, kind, benevolent husband, father, gastroenterologist, and MBA, lost his battle with glioblastoma in 2016 at age 55.* I was hoping that he might be able to get into a trial using an oncolytic virus (OV), but that was not possible.

Although more than a century has transpired since viruses were considered as therapy for cancer, in 2015, talimogene laherparepvec became the first approved OV for patients with locally advanced or non-resectable melanoma. Other OVs as potential anti-neoplastic therapy include DNA viruses (vaccinia, adenovirus, and parvovirus) and RNA viruses (reovirus, coxsackie, measles, ECHO, and others). (1)

Conry et al state: “Oncolytic viruses mediate tumor regression through two distinct mechanisms. First, many viruses possess an innate ability to selectively replicate within and lyse tumor cells where antiviral pathways have been inactivated as part of the malignant phenotype. The release of new viral particles allows continued infection which amplifies the locoregional lytic effect. Secondly, locoregional activation of the innate immune system by the virus coupled with antigen release by dying tumor cells creates a favorable microenvironment for priming of adaptive systemic antitumor immunity capable of regressing tumor at distant, uninjected sites.” Talimogene laherparepvec (TVEC) is a type I herpes simplex virus (HSV) genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase tumor-antigen presentation by dendritic cells. TVEC has been engineered by deleting a gene that blocks antigen presentation and the neurovirulence genes to prevent development of fever blisters. TVEC uses surface nectins to enter tumor cells and propagates by exploiting disrupted oncogenic and anti-viral pathways, primarily the protein kinase R (PKR) and type I interferon (IFN) pathways. (2)
 
The past several years has witnessed a revolution in melanoma treatments including targeted agents (vemurafenib, dabrafenib, cobimetinib and trametinib), immune checkpoint blockers (ipilmumab, pembrolizumab and nivolumab), and TVEC. In a phase 3 trial with patients with stage IIIB-IV melanoma, intratumoral injections of TVEC produced an improved durable response rate compared to intratumoral GM-CSF alone (16.3% vs. 2.1%; p<0.001), leading to its approval by regulatory agencies. Phase 1b studies tested combinations of TVEC with systemic immunotherapies, revealing a safe profile and interesting results. TVEC in association with ipilimumab produced an objective response rate (ORR) of 50%, with 44% of the patients having durable responses of at least 6 months; the 18-month overall survival was 67%. The combination of TVEC with pembrolizumab achieved an ORR of 57.1%, with 23.8% having confirmed complete responses. (3)
 
The dosing and administration of TVEC is described by Khalsa et al with the recommendation of using dermoscopy in recognizing metastatic melanoma lesions requiring injection. The features of a blue-gray color and shiny white lines was most valuable in recognizing melanoma and avoiding injection of benign mimickers. (4)

Assessing the response to TVEC to determine if there is residual melanoma or not may be difficult. Blackmon et al detailed the case of a 79-year-old man with melanoma and in-transit metastases who received 8 doses of TVEC. Two months after the last TVEC dose, biopsies of residual, raised erythematous lesions from four sites demonstrated granulomatous inflammation with no detectable melanoma. (5) Everett et al reported 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient had 4 dermal metastases; one site had persistent melanoma following TVEC injections. The patient was rendered melanoma-free by resection of the nodule. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Factors in granuloma formation may include GM-CSF production or the herpes virus itself (although granulomas are more frequently observed in response to the varicella-zoster virus). The authors recommended that biopsies be performed in lesions that have not regressed after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation, thereby enabling the clinician to determine if further TVEC therapy is warranted. (6)

We are on the threshold of expanding use of OVs for a spate of malignancies; aside from melanoma, clinical trials are underway for their use in glioblastoma, myeloma, mesothelioma, and carcinomas of the breast, lung, colon, prostate, kidney, liver, pancreas, bladder, ovary, and head and neck. (2) As in all forms of anti-neoplastic therapy, dermatologists must remain cognizant of cutaneous adverse reactions to these agents.

Point to remember: The oncolytic virus talimogine laherparepvec may cause granulomas that must be differentiated from residual melanoma.

1. Fountzilas C, et al. Review: Oncolytic virotherapy, updates and future directions. Oncotarget 2017; 8: 102617-39.
2. Conry RM, et al. Talimogene laherparepvec: First in class oncolytic virotherapy. Hum Vaccin Immunother 2018; Feb 8:1-8. doi: 10.1080/21645515.2017.1412896. [Epub ahead of print].
3. Hepner A, et al. Treatment of advanced melanoma – A changing landscape. Rev Assoc Med Bras 2017; 63: 814-23.
4. Khalsa A, et al. Dermoscopic guidance of talimogen laherparepvec injection for metastatic melanoma. Dermatol Surg 2017; Nov 6 [Epub ahead of print].
5. Blackmon JT, et al. Inflammatory melanoma in transit metastases with complete response to talimogene laherparepvec. JAAD Case Reports 2017; 3: 280-3.
6. Everett AS, et al. Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases. J Cutan Pathol 2018; 45: 48-53.

*This spring, Tim’s daughter JoJo, a freshman at Oxford, will be rowing solo from London to Oxford (165 km) in Tim’s memory, to support cancer research (details here). I am incredibly proud of this remarkable young woman.

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