Talimogene Laherparepvec Research Articles

28414 Recurrent melanoma treated with talimogene laherparepvec in combination with radiation therapy: A case report

An 88-year-old female presented with an erythematous, rapidly enlarging 5 cm mass involving her right eyelid. Biopsy revealed this to be a recurrence of her melanoma initially biopsied a year prior. The original lesion was a 1.5 cm ulcerated desmoplastic melanoma with a Breslow thickness of 7.06 mm. Final pathology was stage pT4b pN0. Wide local excision was performed with clear margins and the sentinel lymph node biopsy was negative. No evidence of metastasis was found on repeat imaging. Given the high propensity for aggressive local disease seen in pure desmoplastic melanomas and the difficult anatomic location, treatment with Talimogene laherparepvec (T-VEC) and radiation was pursued given surgical intervention would have required enucleation.

Efficacy and safety of oncolytic viruses in advanced or metastatic cancer: a network meta-analysis

BackgroundOncolytic viruses (OVs) have shown prospects in advanced and metastatic cancer, and many clinical trials have been carried out. To compare OV therapies comprehensively and provide a categorized profile and ranking of efficacy and safety, a network meta-analysis was conducted.MethodsA total of 5948 studies were screened and 13 randomized controlled trials with 1939 patients, of whom 1106 patients received OV therapies, comparing four OVs (NTX-010, pexastimogene devacirepvec (Pexa-Vec), talimogene laherparepvec (T-VEC), and pelareorep) were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: objective response rate (ORR) and grade ≥ 3 adverse events.ResultsCompared to systemic treatments alone, talimogene laherparepvec (T-VEC) (OR 7.00, 95% CI 1.90–26.00) and T-VEC plus systemic treatment (2.90, 0.80–11.00) showed better objective response rates (ORRs), whereas Pexa-Vec 1 * 109 pfu plus systemic treatment (0.91, 0.26–3.00) and pelareorep plus systemic treatment (1.10, 0.61–2.00) were found to be comparable. The grade ≥ 3 adverse event ranking of the treatments from worst to best was as follows: T-VEC (ranking probability 24%), Pexa-Vec 1 * 109 pfu plus systemic treatment (21%), Pexa-Vec 1 * 109 pfu (17%), T-VEC plus systemic treatment (13%), pelareorep plus systemic treatment (13%), systemic treatments (18%), Pexa-Vec 1 * 108 pfu (12%), and NTX-010 (20%).ConclusionsCompared with other oncolytic virus therapies for patients with advanced or metastatic cancer, T-VEC and T-VEC plus systemic treatment appear to provide the best ORR therapy in terms of monotherapy and combination respectively, but should be given with caution to grade ≥ 3 adverse events. Conversely, combining OVs with chemotherapy or target agents was demonstrated not to improve efficacy compared with chemotherapy or target agents alone. Combining OV therapies with immune-checkpoint inhibitors, instead of chemotherapy or target agents, tended to provide better ORRs without causing severe adverse events. This study will guide treatment choice and optimize future trial designs for investigations of advanced or metastatic cancer.

Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells.

Oncolytic viruses (OVs) are an emerging class of anti-cancer agents that replicate selectively within malignant cells and generate potent immune responses. Their potential efficacy has been shown in clinical trials, with talimogene laherparepvec (T-VEC or IMLYGIC®) now approved both in the United States and Europe. In healthy individuals, NK cells provide effective surveillance against cancer and viral infections. In oncolytic viral therapy, NK cells may render OV ineffective by rapid elimination of the propagating virus but could also improve therapeutic efficacy by preferential killing of OV-infected malignant cells. Existing evidence suggests that the overall effect of NK cells against OV is context dependent. In the past decade, the understanding of cancer and OV biology has improved significantly, which helped refine this class of treatments in early-phase clinical trials. In this review, we summarised different strategies that have been evaluated to modulate NK activities for improving OV therapeutic benefits. Further development of OVs will require a systematic approach to overcome the challenges of the production and delivery of complex gene and cell-based therapies in clinical settings.

False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).

Talimogene laherparepvec (T‐VEC) is a genetically modified herpes simplex virus‐1‐based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T‐VEC treatment, tumor response is often evaluated using [18F]2‐fluoro‐2‐deoxy‐ d‐glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one‐third of patients developed new‐onset FDG uptake in uninjected locoregional lymph nodes during T‐VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as “suspected metastases” without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new‐onset FDG uptake in locoregional lymph nodes during T‐VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T‐VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T‐VEC.

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial

BackgroundSoft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical...

Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study.

PurposeRising melanoma incidences lead to an increasing need for individual therapy strategies in old patients. Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, approved for the local treatment of unresectable metastatic melanoma. Since data on the efficacy and safety of geriatric patients are sparse, this study was conducted to gain further real-world experience in the treatment of old and oldest-old patients with T-VEC and to obtain data on therapy costs in this population in Germany.Patients and MethodsWe performed a retrospective analysis, including all patients with a minimum age of 75 years who were treated with T-VEC from August 2016 to September 2020 in the Skin Cancer Center of the University Hospital Frankfurt, Germany. Patient clinicopathological data, treatment responses, toxicities, treatment-specific data and therapy costs were assessed.ResultsTwelve patients with a median age of 83 years (75–89 years) at the start of treatment were identified. By the end of the study, three (25%) patients experienced complete remission (CR), four (33%) experienced partial response (PR), two patients (17%) remained at stable disease (SD) and three (25%) patients suffered from progressive disease (PD). Overall response rate was 58.3%, and durable response rate was 41.7%. There were no treatment-related adverse events grade 3 or higher. The median duration of treatment was seventeen weeks (3–57 weeks). Median medication costs in the patients who had completed treatment (n=10) were calculated to be 27,325 Euros in Germany.ConclusionThis study provides further evidence for an effective use of T-VEC in old and oldest-old patients. The low rate of adverse events seems to be favorable compared to other systemic melanoma therapies. Furthermore, duration of treatment was short and therapy costs were lower than would have been expected from clinical trial data. Altogether, these data encourage the use of T-VEC in this special patient cohort.

Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo.

Simple SummaryTalimogene laherparepvec (T-VEC), a first-in-class oncolytic herpes simplex virus, improves the outcome of patients suffering from unresectable melanoma, in particular in combination with checkpoint inhibitors. However, a certain percentage of patients does not profit from this treatment, which raises the question of potential biomarkers to predict success or failure of oncolytic herpes viruses. For these purposes, we studied the oncolytic activity of T-VEC in a panel of 20 melanoma cell lines and evaluated the clinical response of 35 melanoma metastases to intralesional T-VEC application. Through these studies, we characterized Nectin-1 as a suitable biomarker predicting 86% and 78% of melanoma regression in vitro and in vivo, respectively. In contrast, other molecules involved in the entry (HVEM) and signal transduction (cGAS, STING) of herpes simplex viruses were not predictive. Altogether, our data support the role of Nectin-1 in pretreatment biopsies to guide clinical decision-making in malignant melanoma and supposedly other tumor entities.Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.

Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases

IntroductionCutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. MethodsIn total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately. ResultsMedian follow-up time was 30.5 (range 0.8–154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40–0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45–1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. ConclusionPatients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.

Surgical Resection After Talimogene Laherparepvec for Melanoma: Persistent Fuorodeoxyglucose Avidity on Positron Emission Tomography Despite No Viable Disease

Talimogene laherparepvec (TVEC) is an injectable attenuated oncolytic herpes simplex virus (HSV-1) used in the treatment of loco regionally metastatic melanoma. Lesions managed by TVEC are generally considered unresectable at time of initiation of intralesional therapy; however, a subset of patients go on to have surgical resection of loco regionally controlled disease. We sought to review our experience with surgical excision of treated lesions to offer an insight into the radiologic correlate, treatment effect, and pathological findings of intralesional TVEC therapy. This is a retrospective descriptive case series of patients who underwent TVEC injection at Mayo Clinic, Rochester, MN, between October 2016 and July 2020. Institutional Institutional Review Board approval was obtained. Twenty-one patients underwent intralesional TVEC, met inclusion criteria, and were included in this series. Seven went on to surgical excision of the injected lesions after an initial course of TVEC. Of those 7 patients, 4 had residual melanoma in the specimen on final pathology, while 3 had a complete pathologic response. All 3 patients who had no residual disease on pathology continued to have fluorodeoxyglucose (FDG) avidity on preoperative positron emission tomography scan of the excised lesions. Despite ongoing FDG avidity on PET scan, patients who have well-controlled disease and stability over time of the injected lesions may benefit from surgical excision following a course of TVEC. This may render the patient clinically disease free and/or allow them a reprieve from TVEC treatment.

Current status of intralesional agents in treatment of malignant melanoma.

Prognosis of metastatic melanoma has undergone substantial improvement with the discovery of checkpoint inhibitors. Immunotherapies and targeted therapies have improved the median overall survival (OS) of metastatic melanoma from 6 months to more than 3 years. However, still about half of the patients die due to uncontrolled disease. Therefore, multiple strategies are currently being investigated to improve outcomes. One such strategy is intralesional/intratumoral (IT) therapies which can either directly kill the tumor cells or make the tumor more immunogenic to be recognized by the immune system. Talimogene laherparepvec (T-VEC), an oncolytic virus, is the first FDA approved IT therapy. This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

Talimogene laherparepvec with systemic immunotherapy in melanoma: A real-world experience.

e21549 Background: Talimogene laherparepvec (TVEC) is an FDA approved oncolytic herpes virus for intralesional therapy in unresectable metastatic melanoma. Real world data is sparse regarding the efficacy of TVEC in combination with other systemic therapies used in melanoma. We present outcomes of the largest single institution observational study of the off-label use of TVEC in combination with systemic immunotherapy. Methods: Patients with metastatic melanoma receiving TVEC simultaneously with ipilimumab-nivolumab (Ipi/Nivo) or single agent immunotherapy (either nivolumab or pembrolizumab) were evaluated. The demographics, clinicopathological characteristics, responses to injected lesions and remote metastatic lesions were evaluated. Clinical documentation was used to assess improvement in injected lesion size; time points for initial response and best response were identified. Review of imaging by a radiologist was evaluated to assess responses in remote metastatic lesions. Results: A total of 67 patients receiving TVEC from 2016 to 2020 were evaluated, of which 50 remained evaluable after excluding Merkel cell carcinoma, patients on clinical trial, TVEC monotherapy or those on BRAF-MEK inhibitors, and patients lost to follow up. In total, 29 received systemic immunotherapy simultaneously with TVEC and had been followed for at least a year, with a median follow-up time of 34 months (range, 12-56). At the time of analysis, 14 of 29 patients were alive. 6 of the 29 patients had received prior lines of therapy. Four patients received Ipi/Nivo, while 25 patients received monotherapy including 9 on nivolumab and 16 on pembrolizumab. The median number of TVEC doses received was 6 (range, 2-55) with median average TVEC dose being 3.47 ml (0.5-4 ml). Median time to initial local response was 6 weeks, whereas time to best local response was 14 weeks. Overall response rate in the injected target lesions was in 19 (66%), with complete local response (CR) in 12 (41%), partial response (PR) in 7 (24%), and progressive disease (PD) in 8 (28%). The response rate in distant non-injected lesions was 4 out of 16 (25%), 2 of which had previously progressed on prior systemic therapy. Stable disease was observed in 8 (50%) patients, and progression of disease in 4 (25%). The 1-year overall survival rate in patients receiving TVEC with systemic monotherapy was 80%, 95% CI 0.651-0.9730. Progression free survival at 1-year in the monotherapy group was 71.6%, 95% CI 0.557-0.918. Conclusions: This is the largest single institution, real world experience to our knowledge, which assesses the efficacy of TVEC in combination with systemic immunotherapy. Our cohort suggests that TVEC is an effective treatment in combination with systemic immunotherapy, with a better overall survival observed with combination TVEC and anti-PD1 than seen with historical data from clinical trials of anti-PD-1 monotherapy.

A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer.

578 Background: TVEC is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of unresectable cutaneous and nodal melanoma. TVEC is designed to preferentially lyse tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report results of a phase 2 trial combining NAC with TVEC in stage 2-3 TNBC. Methods: Stage II-III TNBC pts (N = 37) were to be enrolled into a single arm, optimal Simon 2 stage phase 2 trial with TVEC (10^6 PFU 1st dose then 10^8 PFU x 4 doses) weeks 1,4,6,8,10 + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone given preoperatively. Primary endpoint was residual cancer burden 0 rate (RCB0). Trial meets primary endpoint with ≥15 RCB0 responses out of 37 evaluable pts, assuming p1 = 45% vs. p0 = 30% with one sided type I error rate at 0.10 and power at 70%. Results: Forty pts were enrolled at Moffitt (5/2018 – 4/2020) and evaluable for safety with 3 pts non-evaluable for efficacy due to incomplete treatment. Study demographics: median age 49 (27-66), 67.5% White, 10% Black, 15% Hispanic, clinical stage II 83% and III 17%, node + 42%. The RCB0 rate = 16/37 (43%, 95% CI 27-61%) and additional 9 pts with RCB-1 (RCB0/1 rate 68%, 95% CI 50-82%). Toxicities did not differ significantly from expected NAC toxicities except for increased brief G1-2 fevers, chills, injection site pains. Four pts had G2-3 thromboembolic events (10%) slightly greater than expected 6% rate on NAC. Conclusions: Addition of TVEC to NAC increased RCB0 rates with manageable toxicities and warrants additional investigation in TNBC. Immune correlates and updated survival data will be presented at the meeting. Clinical trial information: NCT02779855.

A phase 2 study of talimogene laherparepvec, nivolumab, and trabectedin (TNT) in advanced sarcoma.

11567 Background: Combination trabectidin (T) and nivolumab (N) has been shown to be a safe and effective therapy in soft tissue sarcoma (STS). Intratumoral injection of talimogene laherparepvec (TVEC) has a local oncolytic effect, and increases immune response via enhanced recruitment of antigen presenting cells, and thereby cytotoxic immune response. This study aims to determine if the addition of TVEC to combination trabectedin and nivolumab is effective and safe in advanced sarcoma. Methods: Eligible patients include patients ≥ 18 years of age with locally advanced unresectable or metastatic STS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg i.v. q 2 weeks), T (1.2 mg/m2 i.v. q 3 weeks) and TVEC (1x10e8 PFU/ml q 2 weeks depending on tumor size) were administered. A test dose of TVEC (1x10e6 PFU/ml) was initially given, followed three weeks later by full dose TVEC. Primary endpoint: Progression-free survival (PFS); Secondary endpoints: (1) Best overall response during treatment period, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to resectable tumor, and (5) Incidence of treatment-related adverse events. Interim. Results: There were 36 evaluable subjects under the Modified Intention-to-Treat (MITT) population, having completed the first cycle of TNT and a CT or MRI scan at the 6-week follow-up period. The most common histological subtypes include leiomyosarcoma (9), liposarcoma (5), spindle cell sarcoma (3), pleomorphic sarcoma (2), Ewing’s sarcoma (2), and other (5). Median number of prior lines of therapy was 4 (range 1-8). Best Overall Response by RECIST v1.1 = 3 PR, 27 SD, 5 PD. One patient, with previously unresectable disease was taken for resection and was found to have 100% necrosis on surgical pathology. Disease control rate (CR+PR+SD) was 86.1%. The median PFS was 5.5 (range: 1-18) months; 6-month PFS rate: 62.1%. Median PFS on therapy immediately preceding this trial was 2.0 months (range = 1-14 months). There were 47 evaluable subjects for OS analysis under the Intention-to-Treat (ITT) population having received at least one dose of T and N. The median OS was 9.0 (range 0-20) months; 6-month OS rate: 73%. Safety analysis: There were 47 evaluable subjects under the ITT population. 28% of these patients experienced ³1 SAE. The most common grade 3/4 TRAEs include anemia (12), increased ALT (8), fatigue (4), thrombocytopenia (4), neutropenia (4). There were no grade 3/4 TVEC injection site reactions. 22% of patients in the MITT cohort remain on study. Conclusions: These results suggest that combination therapy with TNT appears to be as effective as standard therapy, with no new safety signals seen. Furthermore, median PFS exceeded that of the immediately preceding lines of therapy in this heavily pre-treated cohort. As data matures, further data will be reported. Clinical trial information: NCT03886311.

Final analysis of a phase 1b, randomized, multicenter study of talimogene laherparepvec (T-VEC) plus pembrolizumab (pembro) combination for the treatment (Tx) of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC): MASTERKEY-232.

6036 Background: T-VEC, a genetically modified herpes simplex virus-1, is the first FDA- and EMA-approved oncolytic viral immunotherapy designed to enhance systemic antitumor immune responses. R/M HNSCC is a disease with considerable clinical complexity and poor prognosis. Pembro is a PD-1-specific humanized monoclonal antibody currently approved as first-line Tx for this disease, but there is an unmet need among many patients (pts). To meet this gap, the safety and preliminary efficacy of T-VEC plus pembro in pts with R/M HNSCC was evaluated in a phase 1b study (Harrington et al. Clin Cancer Res. 2020). Here, we present results of the final analysis of this study (NCT02626000). Methods: Eligible pts (≥18 yrs) had ECOG-PS of 0 or 1; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx unsuitable for curative surgical resection or radiotherapy; platinum-refractory and with injectable tumors. Pts with known active CNS metastases and any systemic or local therapy 28 days before enrollment were excluded. T-VEC was injected intralesionally up to 8.0 mL of 106 PFU/mL according to lesion sizes on day 1; after 3 weeks, subsequent doses of ≤8.0 mL of 108 PFU/mL were given Q3W. Pembro was given intravenously at 200 mg Q3W. Pts were followed-up for 36 mos after the last patient was enrolled in the study. Key endpoints (irRECIST per investigator assessment) were objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 36 pts (80.6% male) were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor (CPS ≥1), 5 (13.9%) were HPV-positive, 13 (36.1%) had metastatic disease, and 19 (52.8%) had prior lines of therapy in the R/M setting. At the final analysis, 7 pts (19.4%) completed the study, and 29 (80.6%) discontinued the study due to death. Safety profile was consistent with that at 1-yr analysis (Harrington et al. Clin Cancer Res. 2020). Confirmed ORR was seen in 16.7% (95% CI, 6.4–32.8). No patient had a complete response as their BOR, 6 (16.7%) had a partial response, 8 (22.2%) had stable disease, 6 (16.7%) had progressive disease, 6 (16.7%) were unevaluable, and 10 (27.8%) died before the first response assessment. The DCR was 38.9% (95% CI, 23.1–56.5). The median DOR was 45.9 mos (95% CI, 8.5–NE). The median PFS was 3.0 mos (95% CI, 2.0–5.8), and the median OS was 5.8 mos (95% CI, 2.9–11.4). Conclusions: The safety results at 3 yrs for T-VEC plus pembro in pts with R/M HNSCC were consistent with those of the 1-yr analysis. Although the response rate was consistent with that observed with pembro alone in historical HNSCC studies, the extended DOR in responding patients warrants further investigation. Clinical trial information: NCT02626000.

External validation of a Dutch predictive nomogram for complete response to T-VEC in an independent American patient cohort.

9563 Background: Talimogene Laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous, and nodal melanoma lesions in stage IIIB-IVM1a patients. Recently, Stahlie et al. published (Cancer Immunol Immunother '21) a model for predicting a complete response (CR) to T-VEC based on 3 easily accessible tumor characteristics identified using univariable and multivariable logistic regression analysis. The aim of this study was to externally validate this model in an independent, American patient cohort. Methods: A total of 76 patients with stage IIIB-IVM1a melanoma treated with T-VEC at Moffitt Cancer Center were included. A second nomogram was built incorporating the same predictive factors: tumor size (diameter of largest metastasis in mm), type of metastases (cutaneous, subcutaneous and nodal) and number of metastases (cut-off: &lt;20 and &gt;20). Predictive accuracy was assessed through calculation of overall performance, discriminative ability, and calibration. Outcomes and previously published outcomes were compared. Statistical analyses were done using R software. Results: Overall performance of the validation dataset nomogram was calculated with the Brier score and found to be 0.195, demonstrating good overall performance and similar to the original model Brier score of 0.182. Discriminative power, assessed by calculating the area under the receiver operating characteristic (ROC) curve was similar for both models, 0.767 and 0.755 for the NKI and Moffitt, respectively, resulting in a fair discriminative ability. The calibration curve showed mostly slight underestimation for predicated probabilities &gt;0.37 and slight overestimation &lt;0.37. Conclusions: An independent dataset externally validated a recently published predictive nomogram for CR to T-VEC in stage IIIB-IVM1a melanoma, with both models resulting in overall performances that were comparable and good. The second model reinforces the conclusion that for the best response to T-VEC, it should be used early on in the course of the disease, when the patient’s tumor burden is cutaneous with smaller diameter and fewer of metastases.[Table: see text]

First-in-human CAN-3110 (ICP-34.5 expressing HSV-1 oncolytic virus) in patients with recurrent high-grade glioma.

2009 Background: Recurrent glioma patients have few therapeutic options and an expected survival of only 7 to 10 months. New treatments to improve the prognosis of this patient population are a dire medical need. Oncolytic viruses (OVs) are emerging as important new agents for cancer treatment. The first FDA approved OV was talimogene laherparepvec (Imlygic, T-Vec) for treatment of melanoma. T-Vec, as most other clinical HSV-1 based OVs, is deleted in the ICP34.5 gene, which is responsible for HSV-1 neurovirulence. However, deletion of ICP34.5 also impedes efficient viral replication. CAN-3110 (rQNestin34.5v2) maintains a copy of the HSV1 ICP34.5 gene under transcriptional control of the tumor-specific promoter for nestin to drive robust tumor-selective replication. CAN-3110 replicates in malignant glioma cells far above levels seen with ICP34.5 deleted viruses. This potency also created the hypothetical risk for increased neurovirulence, thus the regulatory advice to conduct a cautious nine-dose-level Phase-1 dose escalation study in patients with recurrent high-grade glioma (HGG). Methods: From September 2017 to February 2020, thirty patients with biopsy-confirmed recurrent high-grade glioma were treated in an open label clinical trial. Patients with multifocal, multicentric, tumors larger than 5 cm, and tumors that had recurred multiple times were eligible. All patients received best standard of care treatments as indicated by their physician. CAN-3110 was injected intratumorally starting at 1x106 plaque forming units (pfu) and dose-escalating (3+3 design) by half log increments up to 1x1010 pfu. Tissue (when possible) and blood samples were obtained before and during treatment for experimental medicine analyses. Results: CAN-3110 was well tolerated with no dose limiting toxicity observed. The initial tissue diagnosis of the recurrent tumor for the 30 subjects was 26 glioblastoma, 3 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. The median overall survival (mOS) of the entire study group is 13.25 months. Post-treatment tissue is available for 18/30 subjects and revealed persistence of HSV antigen and CD8+ T cell infiltrates. Additional response, immunologic (including T cell receptor repertoire), transcriptomic and single cell RNA sequencing analyses are ongoing. Conclusions: Administration of CAN-3110 into recurrent glioma was well tolerated without evidence of ICP34.5-induced encephalitis/meningitis. Histological and molecular analyses showed evidence of biological activity and that CAN-3110 injection was associated with immune activation and viral antigen persistence. Although definitive clinical efficacy cannot be determined in this small phase 1 study, OS of CAN-3110 treated subjects compares favorably to historical reports and warrants further clinical studies. Clinical trial information: NCT03152318.

Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines.

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

Systemic Therapy of Metastatic Melanoma: On the Road to Cure

Simple SummaryMalignant melanoma is more dangerous than most other skin cancers due to its ability to spread early and aggressively. Until the development of new therapeutic strategies, the median survival of patients with metastatic melanoma was just a few months. Immunotherapy, the first regimen, leading to significant improvement, blocks immune checkpoints, which normally dampen immune responses, enabling our defense cells to recognize and destroy cancer cells again. Immunotherapy achieves long-term survival in about 50% of metastatic melanoma patients. Besides, targeted therapy has also significantly improved the survival of melanoma patients, blocking cell-signaling proteins, which are altered in about 50% of melanomas and lead to uncontrolled tumor cell growth. In addition to the approved regimens, there are numerous new treatment strategies, ranging from modified viruses to personalized immune cells that attack and destroy tumor cells. This review shall give an insight into both already approved regimens and upcoming developments.This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.

Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma.

Simple SummaryTalimogene 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.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.

Advancing oncolytic virus therapy by understanding the biology.

Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of patients with recurrent melanoma. Now, a recent study in patients with primary cutaneous B cell lymphoma confirms prior results in melanoma and reveals new mechanisms of action. Herein, we discuss these findings and their implications for expanding the role of oncolytic viruses.