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Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors.

ABSTRACT: Talimogene laherparepvec is a first-in-class intralesional oncolytic immunotherapy. In a recent Phase III trial (OPTiM), talimogene laherparepvec significantly improved durable response rate compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall response rate was also higher in the talimogene laherparepvec arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma. Talimogene laherparepvec was well tolerated, with the majority (89%) of adverse events being grade 1 or 2. Preclinical studies have shown that talimogene laherparepvec exerts antitumor activity by selectively replicating within and destroying cancer cells, and through the release of tumor-associated antigens and expression of GM-CSF, which facilitates a wider antitumor immune response. It is hypothesized that combining talimogene laherparepvec with a systemic immunotherapy may, by bringing together complementary mechanisms of action, further enhance the efficacy of both agents. Indeed, talimogene laherparepvec is currently being assessed in combination with immune checkpoint inhibitors, including ipilimumab and pembrolizumab, in trials for melanoma and other solid tumors. Early results in melanoma indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy than either therapy alone, without additional safety concerns above those expected for each monotherapy. In this review, we discuss the latest results from trials assessing talimogene laherparepvec in combination with other immunotherapies, provide an overview of ongoing and upcoming combination trials, and suggest future directions for talimogene laherparepvec in combination therapy for solid tumors.

SUBMITTER: Dummer R

PROVIDER: S-EPMC5445176 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors.

Dummer Reinhard R Hoeller Christoph C Gruter Isabella Pezzani IP Michielin Olivier O

Cancer immunology, immunotherapy : CII 20170225 6

Talimogene laherparepvec is a first-in-class intralesional oncolytic immunotherapy. In a recent Phase III trial (OPTiM), talimogene laherparepvec significantly improved durable response rate compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall response rate was also higher in the talimogene laherparepvec arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma. Talimogene laherparepvec was well tolerat ...[more]

PMID: 28238174

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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:Talimogene laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma. METHODS:In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 106 plaque-forming units (PFU)/mL, 108 PFU/mL 21?days later, and 108 PFU/mL every 14 (±3) days thereafter. Injected lesions were covered with occlusive dressings for ?1?week. Blood, urine, and swabs from exterior of occlusive dressings, surface of injected lesions, oral mucosa, anogenital area, and suspected herpetic lesions were collected throughout the study. Detectable T-VEC DNA was determined for each sample type; infectivity was determined for all swabs with detectable T-VEC DNA. FINDINGS:Sixty patients received ?1 dose of T-VEC. During cycles 1-4, T-VEC DNA was detected in blood (98·3% of patients, 36·7% of samples), urine (31·7% of patients, 3·0% of samples) and swabs from injected lesions (100% of patients, 57·6% of samples), exterior of dressings (80% of patients,19·5% of samples), oral mucosa (8·3% of patients, 2·5% of samples), and anogenital area (8·0% of patients, 1·1% of samples). During the safety follow-up period, T-VEC DNA was only detected on swabs from injected lesions (14% of patients, 5.8% of samples). T-VEC DNA was detected in 4/37 swabs (3/19 patients) of suspected herpetic lesions. Among all samples, only those from the surface of injected lesions tested positive for infectivity (8/740 [1·1%]). Three close contacts reported signs and symptoms of suspected herpetic origin; however, no lesions had detectable T-VEC DNA. INTERPRETATION:Using current guidelines, T-VEC can be administered safely to patients with advanced melanoma and is unlikely to be transmitted to close contacts with appropriate use of occlusive dressings. FUND: This study was funded by Amgen Inc.: ClinicalTrials.gov, NCT02014441.

Dataset Information

Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors.

Publications

Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors.

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