Intralesional immunotherapy for melanoma

Abstract

Intralesional immunotherapy of melanoma has two complementary aims. One is to cause regression of the injected metastasis. The other is to incite or modulate systemic immune responses in such a way that non-injected metastases will also undergo regression. A number of phase 1 and phase II studies with cytokines, viral, or bacterial agents have been conducted but their use has remained sporadic and has not progressed to become established treatments. Two treatments have progressed to randomized phase III studies. The most promising of these is based on intralesional injection of a genetically modified herpes simplex virus (HSV) (T-Vec). Initial results have shown a significant effect on durable response rates (DRR) but effects on overall survival remain under study. The second involved injection of plasmids coding for the HLA B7 antigen (Allovectin). Despite encouraging early results the treatment did not reach its endpoints and its use has been discontinued. A phase II study involving intralesional injection of oncolytic A21 coxsackie virus (Cavatak) is also under way and is showing promise.

ΔPK oncolytic activity includes modulation of the tumour cell milieu

“…We focused on the immunosuppressive cytokine IL-10 that inhibits antigen presentation (Buelens et al, 1997), and expression of MHC class II and co-stimulatory molecules (de Waal Malefyt et al, 1991), and promotes myeloid-derived suppressor cells and regulatory T-cell recruitment to the tumour microenvironment (Marvel & Gabrilovich, 2015). We also studied the inflammatory cytokines TNF-a and GM-CSF, which were individually associated with improved efficacy of virotherapy (Hersey & Gallagher, 2014;Hirvinen et al, 2015), and IL-1b, which induces robust and durable primary and secondary CD4 + T-cell responses (Ben-Sasson et al, 2009). Despite their known heterogeneity, the studied melanoma cells constitutively secreted IL-10, but not TNF-a, IL-1b and GM-CSF, and this pattern was reversed by D PK infection.…”

“…Some are also deleted in ICP47, which functions in virus immune evasion, but the role of this deletion in oncolytic potential is still unclear (Chiocca & Rabkin, 2014). T-Vec, an oHSV armed with granulocyte macrophage colony-stimulating factor (GM-CSF), has recently passed phase III clinical trials in stage III and IV melanoma (Hersey & Gallagher, 2014).…”

Intratumoral immunotherapy for melanoma

“…ICAM-1 is also recognized as a viral attachment receptor for many enteroviruses including CVA13, CVA15 and CVA18 [22]. Phase I/II trials using oncolytic A21 coxsackievirus (Cavatak) have been conducted and found effective and safe [37].…”

Armed antibodies for cancer treatment: a promising tool in a changing era

“…Intralesional immunotherapies (IITs) have attracted the interest of many investigators because of distinctive advantages over systemic approaches [31,32]. Clinical responses during IIT in melanoma metastases with several agents have been reported since 1960 in up to 90 % of injected lesions [40].…”

“…Moreover, combination therapies with ipilimumab and new anti-programmed cell death protein 1 (PD1) blocking monoclonal antibodies induced durable responses in more than half of the patients treated [49,50]. A recent debate has postulated that the future of IITs may be seen more as ancillary therapies to checkpoint inhibitors rather than primary treatments [32].…”