Abstract
Simple SummaryTalimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations.Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.
Highlights
Melanoma is an aggressive cutaneous malignancy that is growing in incidence worldwide [1]
In the final analysis of this study, Andtbacka and colleagues reported significantly higher durable response rate (DRR) with Talimogene laherperepvec (T-VEC) (19.3%) than granulocyte-macrophage colony-stimulating factor (GM-CSF) (1.4%) as per investigator assessment
In a Phase II, single-arm, biomarker study of T-VEC monotherapy (ClinicalTrials.gov: NCT02366195), performed on biopsy samples obtained from uninjected lesions, Gogas and colleagues reported that T-VEC treatment is able to increase CD8+ tumor-infiltrating lymphocytes, granzyme B+ effector CD8+ T cells, memory CD8+ T cells, and CD8+ T cells expressing checkpoint markers, but not macrophages [48,49]
Summary
Melanoma is an aggressive cutaneous malignancy that is growing in incidence worldwide [1]. PV-10 and BCG were able to induce mainly a regression of most of the injected melanoma lesions, while the others demonstrated activity in non-injected ones, showing a sort of “bystander effect” in up to half of the treated patients [16,17] All these agents may be mostly useful in highly selected cases for local disease control, since their cutaneous toxicity and the lack of a durable benefit have limited their clinical utility. Other intratumoral immunotherapies with more elaborated mechanisms of action and rationale of use, demonstrated promising antitumor activity with tolerable toxicities on both local and systemic disease They include non-oncolytic viral therapies (toll-like receptor agonists) and oncolytic viral therapies (CAVATAK, HF10) [18,19,20]. Results obtained in recently published clinical trials, showed an effective efficacy of this intralesional treatment on both injected and not-injected lesions, low collateral effects and a significant systemic disease control especially through the combination with immune checkpoint inhibitors
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