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Talimogene Laherparepvec Upregulates Immune-Cell Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001621 on 30 March 2021. Downloaded from Talimogene laherparepvec upregulates immune- cell populations in non-injected lesions: findings from a phase II, multicenter, open- label study in patients with stage IIIB–IVM1c melanoma 1 2 3,4 5 Josep Malvehy , Igor Samoylenko, Dirk Schadendorf, Ralf Gutzmer, Jean- Jacques Grob,6 Joseph J Sacco,7,8 Kevin S Gorski,9 Abraham Anderson,10 Cheryl A Pickett,10 Kate Liu,10 Helen Gogas11 To cite: Malvehy J, ABSTRACT virus-1 (HSV-1)- derived oncolytic immuno- Samoylenko I, Schadendorf D, Background Talimogene laherparepvec (T- VEC), an therapy.1 2 Based on data from the phase III et al. Talimogene laherparepvec oncolytic virus, was designed to selectively replicate in upregulates immune- cell OPTiM (Oncovex (GM- CSF) Pivotal Trial and lyse tumor cells, releasing tumor- derived antigen to 3–5 populations in non- injected in Melanoma) study, T- VEC was the first stimulate a tumor- specific immune response. lesions: findings from a phase oncolytic virus to be approved in the United Methods In this phase II study in patients with II, multicenter, open- label States6 and Europe.7 T- VEC selectively repli- unresectable stage IIIB–IV melanoma, we evaluated non- study in patients with stage cates within tumor cells, resulting in cell lysis; IIIB–IVM1c melanoma. Journal injected lesions to establish whether baseline or change + for ImmunoTherapy of Cancer in intratumoral CD8 T- cell density (determined using this leads to release of tumor- specific antigens 2021;9:e001621. doi:10.1136/ immunohistochemistry) correlated with T- VEC clinical as well as new viral particles, which can infect 1 8 jitc-2020-001621 response. other nearby tumor cells. Local expression Results Of 112 enrolled patients, 111 received ≥1 dose of of virally encoded granulocyte- macrophage Accepted 10 January 2021 T- VEC. After a median follow- up of 108.0 weeks, objective/ colony- stimulating factor (GM- CSF)1 8 is complete response rates were 28%/14% in the overall postulated to enhance the recruitment of population and 32%/18% in patients with stage IIIB–IVM1a antigen- presenting cells, including dendritic disease. No unexpected toxicity occurred. Baseline and + cells. These antigen-presenting cells take up week 6 change from baseline CD8 T- cell density results http://jitc.bmj.com/ released tumor- specific antigens and mature were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8+ T- cell density correlated as a result of contact with innate immune with objective response rate, changes in tumor burden, danger signals. Maturing dendritic cells with duration of response or durable response rate. However, endocytosed tumor- derived antigens migrate a 2.4- fold median increase in CD8+ T- cell density in non- to draining lymph nodes and present these injected lesions from baseline to week 6 was observed. In antigens to T- cells, including to cytotoxic exploratory analyses, multiparameter immunofluorescence CD8+ T- cells. After expansion of relevant T- cell on September 24, 2021 by guest. Protected copyright. showed that after treatment there was an increase in clones in draining lymph nodes, they enter + the proportion of infiltrating CD8 T- cells expressing the circulation to act regionally and system- granzyme B and checkpoint markers (programmed ically to destroy cells expressing the same death-1, programmed death- ligand 1 (PD- L1) and tumor antigens.1 8–13 Thus, T- VEC is believed cytotoxic T- lymphocyte antigen-4) in non- injected lesions, together with an increase in helper T-cells. Consistent with to act through a mechanism comprising T- cell infiltrate, we observed an increase in the adaptive direct oncolytic activity and stimulation of resistance marker PD- L1 in non- injected lesions. local innate and systemic adaptive immune © Author(s) (or their Conclusions This study indicates that T- VEC induces responses, which then confers distant anti- employer(s)) 2021. Re- use systemic immune activity and alters the tumor tumor effects.1 8–13 permitted under CC BY-NC. No microenvironment in a way that will likely enhance the commercial re- use. See rights This mechanism of action (MOA) has and permissions. Published by effects of other immunotherapy agents in combination been explored in preclinical tumor models. BMJ. therapy. In preclinical studies with a syngeneic B- cell Trial registration number NCT02366195. For numbered affiliations see lymphoma tumor model (A20), administra- end of article. tion of OncoVEXmGM- CSF, an HSV-1 modi- Correspondence to BACKGROUND fied similarly to T- VEC (but with murine Dr Josep Malvehy; Talimogene laherparepvec (T- VEC) is an GM- CSF), led to complete regression of all JMALVEHY@ clinic. cat intratumorally injected herpes simplex injected tumors and ~50% of contralateral, Malvehy J, et al. J Immunother Cancer 2021;9:e001621. doi:10.1136/jitc-2020-001621 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001621 on 30 March 2021. Downloaded from non- injected tumors, supporting the hypothesis that non- injected lesions (6 weeks after treatment); and the therapy induces a systemic antitumor immune change in PD- L1 expression (6 weeks after treatment). response.8 Furthermore, a significant increase in tumor- specific T- cells was observed in injected and contralateral 8 tumors. In a D4M3A melanoma murine model (a low- METHODS STING- expressing melanoma model that is resistant to Study design and patients anti- programmed death-1 (PD-1) treatment), therapeutic This phase II, open- label, single- arm study (T- VEC-325) responses were observed with T- VEC in injected and non- was conducted at 36 sites in 12 European countries. 11 injected tumors. Additionally, T-VEC was able to recruit Eligible patients were aged ≥18 years with histologi- + viral and tumor antigen- specific CD8 T-cells and induce cally confirmed unresectable stage IIIB–IV melanoma; 11 a proinflammatory gene signature. Eastern Cooperative Oncology Group (ECOG) perfor- However, to date, the MOA has not been fully demon- mance status ≤1; serum lactate dehydrogenase (LDH) strated in patients, and human tumoral adaptations ≤1.5× upper limit of normal and with adequate organ remain unclear. Data reported by Ribas et al (n=21) function. Patients were required to have melanoma suggested that T- VEC can increase immune infiltration in lesions (cutaneous, subcutaneous or nodal) appro- tumors; however, the biomarker results were derived from priate for intralesional injection, defined as ≥1 lesion both injected and non- injected lesions, with only a small with a diameter of ≥10 mm or multiple lesions with subset of the patients from whom non- injected lesions a combined diameter of ≥10 mm and ≥1 melanoma 9 were examined (n=6). In the current study, we sought to lesion that could be accurately and serially measured by clinically confirm the systemic immune effects of T-VEC by clinical (caliper) assessment or by contrast- enhanced characterizing changes in the tumor microenvironment or spiral CT scan, MRI or ultrasound for nodal/soft- during T- VEC treatment in a sizeable number of patients tissue disease (including lymph nodes). Patients with with melanoma (stage IIIB–IVM1c). Exploratory analyses >3 visceral lesions (excluding lung or nodal metastases included measurement of changes in various immune associated with visceral organs), primary ocular or + cells from non-injected lesions, including CD8 T- cells, mucosal melanoma, bone metastases, or active cere- + + helper T- cells (CD4 ) and macrophages, as well as CD8 bral metastases were excluded. Full inclusion/exclu- T- cells expressing granzyme B and checkpoint markers sion criteria are listed in online supplemental table 1. (eg, PD-1, programmed death-ligand 1 (PD-L1) and cyto- Study procedures were approved by the institutional toxic T- lymphocyte antigen-4 (CTLA-4)). This is thus review boards or ethics committees for each partic- the first clinical study to evaluate the systemic immune ipating site. All patients provided written informed response with T- VEC monotherapy. This is important as consent. it has been established that the concentration and type of immune cells infiltrating the tumor microenvironment Study drug administration alter the course of melanoma, regardless of treatment.14 T- VEC was administered by intralesional injection, with http://jitc.bmj.com/ Furthermore, an understanding of treatment- related or without image ultrasound guidance, using the dosing tumor microenvironment adaptations may support a regimen described in the registrational phase III OPTiM rational approach to combinatorial strategies. study.4 If there were ≥2 lesions at baseline, one (the lowest Additionally, the study investigated potential predic- priority lesion for injection) was left non- injected. tors of response to T- VEC, which could ultimately be Treatment continued until one of the following used to stratify patients. For other immunotherapies, occurred: complete response (CR); all injectable tumors on September 24, 2021 by guest. Protected copyright. such as anti- PD-1 agents, several predictive biomarkers disappeared; clinically significant (resulting in clinical have been identified and continue to be investigated, deterioration or requiring change of therapy) disease including immune cell infiltration in the tumors progression (as per modified WHO response criteria25); + (including CD8 T- cells), PD- L1 expression and muta- or intolerance of
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