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Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.

ABSTRACT: Melanoma often spreads to cutaneous or subcutaneous sites that are amenable to direct, intralesional injection. As such, developing effective injectable agents has been of considerable interest. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has now been assessed in Phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival compared to granulocyte-macrophage colony-stimulating factor. Despite these promising results, responses have been uncommon in patients with visceral metastases. T-VEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity. In this review, we discuss the preclinical rationale, the clinical experience, and future directions for T-VEC in advanced melanoma.

SUBMITTER: Johnson DB

PROVIDER: S-EPMC4519012 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.

Johnson Douglas B DB Puzanov Igor I Kelley Mark C MC

Immunotherapy 20150622 6

Melanoma often spreads to cutaneous or subcutaneous sites that are amenable to direct, intralesional injection. As such, developing effective injectable agents has been of considerable interest. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting ...[more]

PMID: 26098919

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Project description:Simple Summary Talimogene 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. Abstract 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.

Project description:Background: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates. The oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) has recently been approved for treatment of locally advanced or unresectable melanoma. T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response. Our rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade. Objective: To report the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of Talimogene laherparepvec. Case Report: A 78-years old female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and obtained a stable disease lasting for 30 weeks. However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intravaginal metastases, while nodal metastases remained stable. We stopped treatment with pembrolizumab and administered T-VEC directly into the intravaginal mucosal metastases. After five injections T-VEC yielded a partial response with clinical regression of the injected mucosal metastases. Disease remained stable for 16 weeks under biweekly T-VEC treatment. Thereafter the patient showed disease progression in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but failed to achieve a response. Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing. Conclusion: T-VEC represents an effective and well-tolerated treatment option for patients with loco-regionally advanced mucosal melanoma. In combination with immunotherapy, T-VEC bears the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade.

Dataset Information

Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.

Publications

Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma.

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