Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives

Abstract

The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

“…T-VEC is an engineered virus, that only replicates in tumor cells and induces secretion of the cytokine GM-CSF from its transgene. Oncolytic viruses can induce local and systemic anti-tumor immune responses through immunogenic cell death induction ( 75 ). The local release of GM-CSF results in recruitment and activation of DCs, but likely will also drains to nearby TDLN to activate lymph node resident (LNR)-DCs and promote T cell priming and activation.…”

Advances in Targeting Cutaneous Melanoma

“…Even though the anti-tumor efficacy of intratumoral IL-2 appears to be durable, it is limited to the injected lesions suggesting that intratumoral IL-2 does not have strong systemic effects. Unlike systemic IL-2, however, intratumoral IL-2 is generally well tolerated [ 79 , 80 ]. In a phase 2 study, tavokinogene telseplasmid—a synthetic plasmid encoding the cytokine IL-12—demonstrated the induction of an anti-tumor immune response and a high control rate in patients with CM.…”

“…Moreover, it has been detected that cyclic dinucleotides may represent immune adjuvants by activating STING, in turn stimulating a pro-inflammatory immune response. Hence, phase 1 studies on 2 intratumoral STING agonists have been initiated [ 79 , 83 ]. A synergy between intratumoral agents and ICI may be expected.…”

“…A synergy between intratumoral agents and ICI may be expected. In fact, treatment regimens combining therapies that have different modes of action without enhancing toxicity are probable to feature in future investigations [ 79 ]. There is increasing data indicating that the combination of intratumoral agents and systemic regimens can even achieve responses in anti-PD1-refractory cancers, thereby overcoming resistance.…”

“…There is increasing data indicating that the combination of intratumoral agents and systemic regimens can even achieve responses in anti-PD1-refractory cancers, thereby overcoming resistance. Importantly, intratumoral strategies may be considered for use in any cancer that is injectable [ 79 ].…”