Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors

Dummer, Reinhard; Höeller, Christoph; Gruter, Isabella Pezzani; Michielin, Olivier

doi:10.1007/s00262-017-1967-1

Cited by 56 publications

(41 citation statements)

References 53 publications

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“…Several mouse experiments, with different types of cancer cells, reported that both CTLA-4 and PD-L1 checkpoints blockade enhanced the OV therapy [ 29 – 33 ]. There are also several clinical trials with OV and checkpoint inhibitors [ 34 – 37 ].…”

Section: Introductionmentioning

confidence: 99%

Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model

Friedman¹,

Lai

2018

PLoS ONE

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Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment. Since T cells kill not only virus-free cancer cells but also virus-infected cancer cells, the following question arises: Does increasing the amount of the checkpoint inhibitor always improve the efficacy? We address this question, by a mathematical model consisting of a system of partial differential equations. We use the model to construct, by simulations, an efficacy map in terms of the doses of the checkpoint inhibitor and the OV injection. We show that there are regions in the map where an increase in the checkpoint inhibitor actually decreases the efficacy of the treatment. We also construct efficacy maps with checkpoint inhibitor vs. the replication potential of the virus that show the same antagonism, namely, an increase in the checkpoint inhibitor may actually decrease the efficacy. These results have implications for clinical trials.

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Section: Introductionmentioning

confidence: 99%

Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model

Friedman¹,

Lai

2018

PLoS ONE

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“…Furthermore, the understanding of irAEs related to T‐VEC treatment is of growing importance. T‐VEC may be expanded to new indications, and investigation into combined therapy with ICIs is underway . The potential to encounter histopathologic panniculitis in either T‐VEC or ICI monotherapy means that combined therapies could produce a new spectrum of irAEs and/or unusual histopathologic findings that could occur with combined therapy.…”

Section: Discussionmentioning

confidence: 99%

“…T-VEC may be expanded to new indications, and investigation into combined therapy with ICIs is underway. 36 The potential to encounter histopathologic panniculitis in either T-VEC or ICI monotherapy means that combined therapies could produce a new spectrum of irAEs and/or unusual histopathologic findings that could occur with combined therapy. Thus, increased awareness of the various presentations of panniculitis in immunomodulatory cancer treatments such as T-VEC is essential to providing a diagnosis that is as accurate and etiologically specific as possible.…”

Section: Granulomatous Dermatitis Has Been Reported In Association Withmentioning

confidence: 99%

Panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent, in‐transit melanoma

et al. 2018

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Talimogene laherparepvec (T-VEC) is a novel intralesional oncolytic genetically modified herpes simplex virus type 1 vector for the treatment of unresectable cutaneous, subcutaneous, and nodal melanoma. Although immunological therapies such as T-VEC offer therapeutic promise, they carry a risk of immune-related adverse events (irAEs), the full spectrum of which is incompletely understood. We report a 63-year-old previously healthy man with cutaneous melanoma of the right ankle and progressive right lower extremity in-transit metastases despite systemic therapy with immunomodulatory and molecularly targeted treatments. T-VEC treatment resulted in a complete pathologic response on scouting biopsies. Biopsy of the right lateral calf showed lobular and septal panniculitis with lymphoplasmacytic infiltrate and lipophages. Gomori methenamine silver (GMS) stain and acid-fast bacilli (AFB) stains were negative, and no polarizable foreign material was noted. T-VEC was discontinued due to complete pathologic response and, in part, concern for development of irAEs including this panniculitis and an early concomitant autoimmune colitis. This case highlights a previously unreported irAE with this novel treatment for advanced cases of melanoma.

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“…The combination of pembrolizumab and T‐VEC was postulated to enhance the systemic antitumor response by enhancing the recognition and killing of tumor cells by T cells that have been primed as a result of T‐VEC injection . This combination was first evaluated in the phase 1b portion of the Phase 1b/III clinical trial (MASTERKEY‐265) launched in 2014 .…”

Section: Systemic Therapiesmentioning

confidence: 99%

Management of local or regional non‐nodal disease

Racz

Block

Baum

et al. 2018

Journal of Surgical Oncology

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Some melanomas develop a striking avidity for lymphatic spread. In spite of multiple recurrences, patients can remain years without visceral metastasis. There is clearly a biologic reason for this lymphotrophic pattern of growth and dissemination, which we have yet to uncover. In-transit metastases have widely diverse clinical presentations and can be a stubborn disease to cure. As a result, a host of treatments exist that should be tailored to the individual patient. K E Y W O R D S diphenylcyclopropenone, in transit, intralesional therapy, limb perfusion, melanoma, stage III, talimogene laherparepvec 1 | INTRODUCTION Non-nodal locoregional metastasis in the setting of melanoma includes microsatellites, satellites, and in-transit metastasis (ITM). This pattern of spread is primarily the result of dermal and subcutaneous intralymphatic contamination. The presence of melanoma cells within this rich lymphatic plexus can result in recurrent disease anywhere from the primary site to the regional nodal basin and rarely retrograde, distal to the primary lesion. Historically, microsatellites were defined as microscopic foci identified on pathologic analysis, adjacent or deep to the primary. Clinically detected cutaneous and/or subcutaneous locoregional metastases were arbitrarily categorized based on their proximity to the primary melanoma; satellite lesions occurring within 2 cm of the primary and ITM lesions >2 cm from the melanoma. All these disease patterns have similar prognoses and the 8th edition of The American Joint Committee on Cancer Staging System has added clarity to this issue. 1The updated edition categorizes all regional nodal and intralymphatic disease as N1-N3 disease. Additionally, number of lesions differentiates N1-N3 and the subcategories a-c are distinguished based on clinically occult, clinically detected, matted and/or intralymphatic disease. One should make a distinction, when possible, between a true local recurrence, which represents subclinical persistent primary tumor after initial management; often in the setting of inadequate management such as incomplete resection, as opposed to intralymphatic disease. A true local recurrence portends a better prognosis than cutaneous metastases. 2 The distinction between distant skin, subcutaneous or lymph node metastasis is even more important as these are categorized as M1a, stage IV disease.In-transit metastases occur in 5% to 10% of patients with intermediate thickness melanoma [3][4][5][6][7] and have a propensity for the lower extremities. 8,9 In-transit metastasis often appear indolent and easily treatable, particularly when few in number. However, due to the aforementioned concept of lymphatic contamination, recurrence remains the rule and not the exception especially when management consists of targeted treatment of individual lesions rather than a more holistic approach that addresses the involved lymphatic network and nodal basin. Before embarking on treatment of new ITM, we obtain systemic imaging, PET scan preferred, to rule out clinically ...

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Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors

Cited by 56 publications

References 53 publications

Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model

Combination therapy for cancer with oncolytic virus and checkpoint inhibitor: A mathematical model

Panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent, in‐transit melanoma

Management of local or regional non‐nodal disease

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