Talimogene laherparepvec (T-VEC) treatment increases intratumoral effector T-cell and natural killer (NK) cell density in noninjected tumors in patients (pts) with stage IIIB–IVM1c melanoma: Evidence for systemic effects in a phase II, single-arm study

Gogas, Helen; Samoylenko, Igor; Schadendorf, Dirk; Gutzmer, Ralf; Grob, Jean Jacques; Sacco, Joseph J.; Gorski, Kevin; Anderson, Abraham; Liu, C.; Malvehy, Josep

doi:10.1093/annonc/mdy289.002

Cited by 16 publications

(17 citation statements)

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“…In a phase II, single‐arm, biomarker study of T‐VEC monotherapy (EudraCT number: 2013‐005552‐15), analysis using biopsy samples from uninjected lesions showed that T‐VEC treatment resulted in increases in CD8+ tumor‐infiltrating lymphocytes, granzyme B+ effector CD8+ T cells, memory CD8+ T cells, and CD8+ T cells expressing checkpoint markers PD‐1 and CTLA‐4 but not macrophages . Additionally, in patients with melanoma treated with T‐VEC and pembrolizumab combination, CD8+ T cell increases after T‐VEC treatment correlated with clinical response, and the level of PD‐L1 expression was also shown to be increased after T‐VEC treatment.…”

Section: Systemic Antitumor Immunity Induced By T‐vecmentioning

confidence: 99%

Intratumoral Immunotherapy—Update 2019

2019

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Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications. Implications for Practice This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

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Section: Systemic Antitumor Immunity Induced By T‐vecmentioning

confidence: 99%

Intratumoral Immunotherapy—Update 2019

2019

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“… 18 , 22 This implication is also supported by a prospective Phase 2 trial in which T-VEC led to a significant increase in the number of CD8 + T cells, effector and memory cytotoxic lymphocytes (CTLs), natural killer cells, and CTLs expressing PD-1 and CTLA-4 (indicative of immune activation) in uninjected lesions. 50 …”

Section: Currently Available Hit-its For Unresectable and Metastatic mentioning

confidence: 99%

“…HIT-ITs that elicit a local immune response have been shown to promote immune cell infiltration into the tumour in both injected and uninjected lesions. 26 , 37 , 50 Consequently, by altering the tumour microenvironment and converting a non-responsive ‘cold’ tumour into a responsive ‘hot’ tumour, HIT-IT might enhance response to systemic immunotherapies. 26 , 37 , 38 …”

Section: Combining Intratumoural and Systemic Immunotherapiesmentioning

confidence: 99%

“… 89 , 90 Indeed, a 2018 Phase 2 trial of T-VEC showed that this therapy leads to an increase in the number of CTLs expressing PD-1 and CTLA-4. 50 Blocking PD-1 or CTLA-4 might restore suppressed antitumour immune responses and enhance the ability of T cells (which have been primed by intratumoural injection) to recognise and kill tumour cells. 35 , 91 CPIs might also enhance the systemic effects of some HIT-ITs.…”

Section: Combining Intratumoural and Systemic Immunotherapiesmentioning

confidence: 99%

“… 35 , 91 CPIs might also enhance the systemic effects of some HIT-ITs. 35 , 37 , 38 , 50 Therefore, combination therapy might result in improved clinical activity beyond what would be expected with either agent alone. Additionally, owing to the low toxicity of HIT-IT, combination therapy has the potential to be tolerated at effective doses.…”

Section: Combining Intratumoural and Systemic Immunotherapiesmentioning

confidence: 99%

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

et al. 2020

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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.

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A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB–IVM1a Melanoma in Four European Countries

et al. 2020

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Introduction Talimogene laherparepvec (T-VEC; IMLYGIC ® , Amgen Inc.) is an oncolytic immunotherapy approved in Europe for the treatment of unresectable metastatic melanoma (stage IIIB–IVM1a). This study characterised real-world use of T-VEC in four European countries. Methods Data on demographics, treatment pattern, safety, and clinical effectiveness were examined in a retrospective chart review of patients with stage IIIB–IVM1a unresectable melanoma treated with T-VEC in surgical (the Netherlands) and medical (Austria, Germany, UK) oncology settings. Results Overall, 66 patients were included (the Netherlands: n = 31; Austria, Germany, UK: n = 35). The median age was 69 years and 59.1% were female. At the time of T-VEC initiation, 47 patients (71.2%) had stage IIIB/C disease; of these, 30 were from the Netherlands. Although 72.7% patients overall received T-VEC as first-line therapy, this was higher in the Netherlands than the other countries (93.5% vs 54.3%). Of the 47 patients who discontinued T-VEC, 26 (55.3%) had no remaining injectable lesions (potentially indicating complete response); 20/26 of these patients were from the Netherlands. One patient discontinued T-VEC due to toxicity. Conclusion This study is the first comprehensive multinational evaluation of the use of T-VEC to treat unresectable stage IIIB/C–IVM1a melanoma in real-world clinical practice in Europe. The differences between European countries were apparent, with physicians in the Netherlands using T-VEC in patients with earlier advanced disease stage and in the first-line setting compared with other countries. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01590-w.

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Talimogene laherparepvec (T-VEC) treatment increases intratumoral effector T-cell and natural killer (NK) cell density in noninjected tumors in patients (pts) with stage IIIB–IVM1c melanoma: Evidence for systemic effects in a phase II, single-arm study

Cited by 16 publications

References 0 publications

Intratumoral Immunotherapy—Update 2019

Intratumoral Immunotherapy—Update 2019

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

A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB–IVM1a Melanoma in Four European Countries

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