Imlygic (talimogene laherparepvec)

P2, N=28, Recruiting, University of Louisville | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2024 --> Jun 2026

In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

P1, N=3, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Due to Covid and poor enrollment

Our findings illustrate that G47Δ-mIL2 is efficacious, stimulates antitumor immunity against orthotopic GBM, and may also target GSC. OHSV expressing IL-2 may represent an agent that merits further exploration in patients with GBM.

P2, N=19, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Feb 2024 | Trial primary completion date: Jun 2024 --> Feb 2024

P2, N=72, Completed, Amgen | Active, not recruiting --> Completed

T-VEC was oncolytic for an extended period of time as viral replication continued, which could be partially blocked by the antiviral drug aciclovir. When markers of immunogenic cell death were assessed, ATP was released more efficiently in the context of T-VEC than HSV-1 d106S infection, whereas HMGB1 was induced comparatively well. Overall, the early oncolytic effect on three different tumour entities was stronger with the non-replicative strain, while the replication-competent virus elicited a stronger innate immune response and more pronounced immunogenic cell death.

P1, N=36, Completed, Amgen | Phase classification: P1b --> P1

P1/2, N=217, Completed, Amgen | Phase classification: P1b/2 --> P1/2

P1, N=5, Completed, Rutgers, The State University of New Jersey | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Feb 2023 | Trial primary completion date: Sep 2024 --> Feb 2023

P2, N=41, Active, not recruiting, Memorial Sloan Kettering Cancer Center

P2, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Since the approval of talimogene laherparepvec (T-VEC) in 2015, HSV has been thoroughly researched to discover novel mechanisms to combat cancer and treat other diseases. Another HSV-based drug, beremagene geperpavec (B-VEC), received approval in 2023 to treat the rare genetic disease dystrophic epidermolysis bullosa, and was also the first clinically approved HSV vector carrying an extracellular matrix (ECM)-modifying transgene...The viral replication, transgene expression and cytotoxic effect of the novel vector was studied in glioma cells. Our results show that an attenuated, replication-competent HSV vector expressing a foreign ECM-modifying transgene, namely HAS2, provides an effective tool to study and combat cancer in humans.

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Nov 2024

Given the relative safety and tolerability of oncolytic viruses, and the lack of reports of dose-limiting-dependent toxicities, more patients treated with T-VEC with or without ICIs should be added to future assessment analyses. There is still a long way to go before it can be used as a first-line therapy for patients with advanced or unresectable melanoma.

PRV-LAV can infect cancer cells via NRP1/EGFR signaling and induce cancer cells apoptosis via ER stress. PRV-LAV treatment also restores CD8 T cell function against cancer. The combination of PRV-LAV and immune checkpoint inhibitors has a significant synergistic effect. Overall, these findings point to PRV-LAV as a serious potential candidate for the treatment of NRP1/EGFR pathway-associated tumors.

P2, N=24, Active, not recruiting, The Netherlands Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2023 --> Jan 2025 | Trial primary completion date: Jan 2023 --> Apr 2023

Comparing pts who had TVEC and RT to different regions of the body, there was an association with improvements in PFS and DM when both modalities were delivered to the same region of the body. However, we did not find a significant difference in locoregional recurrence or OS. Given some promise with the combined approach and potential immune enhancement from RT, larger trials are needed to better understand the potential positive signal from our study.

P1/2, N=50, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Aug 2023 --> Aug 2024

The Food and Drug Administration in the United States has approved one oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene Laherparepvec) for the treatment of metastatic melanoma, and others could soon follow for this and other cancers...The results demonstrated that TPV/Δ66R/mIL-2 treatment IV or IM had significantly greater rates of tumor regression than RC-treated mice but failed to exert this effect when both routes were used simultaneously. Data obtained through these experiments support the continued development of Tanapoxvirus for the treatment of human melanoma and using immune reconstitution to create intact adaptive immunity in a xenograft context, which can allow other tropism-limited OVs to be studied against human cancers.

Eligibility for this pilot phase I trial included patients with localized HER2-negative breast cancer who received systemic nivolumab and ipilimumab and intratumor talimogene laherparepvec (T-VEC; NCT04185311). This triple immunotherapy regimen provided responses in patients with advanced or relapsed HER2-negative breast cancer, at the expense of long-term toxicities. Systemic immune checkpoint blockade with a programmed death receptor 1 and a CTL antigen-4 blocking antibody, combined with intralesional oncolytic virotherapy, is a chemotherapy-free combination aimed at inducing an antitumor immune response locally and systemic immunity.

As immunotherapy-related toxicities have been extensively reviewed, herein, we discuss injectable talimogene laherparepvec and touch on recent breakthroughs in the immunotherapy space. Dermatologic adverse events may severely impact quality of life and are associated with response and survival. It is therefore essential that clinicians are aware of their diverse presentations and management strategies.

Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic virus for CM treatment, and other oncolytic viruses, such as coxsackieviruses and HF-10, are being investigated. Furthermore, combining oncolytic viruses with immunotherapies, such as CAR-T cell therapy, holds great potential. Understanding the intrinsic molecular features of melanoma and their role in shaping novel therapeutic approaches provides insights into targeted interventions and paves the way for more effective treatments for CM and UM.

In two preclinical mouse models of MPNST, we combined the oncolytic virus T-VEC with myeloid-cell targeting therapeutics, Pexidartinib or Trabectedin, to assess the combination therapy's antitumor efficacy and survival benefits. Our findings provide compelling evidence that myelomodulatory therapies can augment the antitumor T-cell response and improve the therapeutic benefits of oncolytic virotherapy in murine models of MPNST. These results provide valuable insights for designing and implementing future immunotherapeutic strategies in the management of MPNST.

Neoadjuvant intratumoral TVEC at 8 mL of 108 PFU/mL dosing with concurrent EBRT increased pathological necrosis rate relative to EBRT alone for locally advanced STS. Intratumoral TVEC treatment in addition to EBRT increases cytotoxic CD8+ T cells in STS compared with EBRT alone treated and pre-treatment biopsy sarcoma tissue. Overall, no new safety signals were observed.

P1, N=6, Terminated, Jonsson Comprehensive Cancer Center | Trial completion date: Jul 2024 --> May 2023 | Active, not recruiting --> Terminated; enrollment

Localized intralesional therapies such as Talimogene laherparepvec (T-VEC) and Tavokinogene Telseplasmid (TAVO) electro-gene-transfer combined with anti-PD1 have demonstrated favorable pathologic responses and increased immune activation...Current evidence supports neoadjuvant therapy as a standard of care for locoregionally advanced melanoma. Ongoing research will define the optimal regimens and the biomarkers of therapeutic predictive and prognostic value.

Regimen was switched to oral Binimetinib 45 mg daily for advanced NRAS mutant melanoma...Immune checkpoint inhibitors Pembrolizumab, Ipilimumab and Nivolumab are the most common immunotherapeutic agents used for mucosal melanomas. More recently Talimogene Laherparepvec (T-VEC) intra-lesional therapy is used to invoke local immune response which has promising results. Rapid progression of mucosal melanomas require early detection and intervention to prevent metastasis and recurrence however overall survival rate is not affected.

P1b/2, N=127, Completed, Amgen | Active, not recruiting --> Completed

P2, N=68, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.

However, since the U.S. Food and Drug Administration (FDA) approved the first OV therapy drug, T-VEC, in 2015, interest in OV has grown significantly. In recent years, oncolytic virus therapy has shown increasingly promising application prospects and has become a major research focus in the field of cancer treatment. This article reviews the development, classification, and research progress of oncolytic viruses, as well as their mechanisms of action, therapeutic methods, and routes of administration.

No abstract available

Studies mainly focused on multi-metastatic patients, with some positive trials such as T-VEC in melanoma, but evidence of clinical benefit is still lacking...The clinical benefit might be improved in patients with a low tumor burden. Future clinical trials should focus on adequate timing of treatment delivery during the course of the disease, particularly in the neoadjuvant setting.

Our results show comparable efficacy and side-effects to published clinical trials and demonstrate that T-VEC is a well-tolerated and safe treatment option, delaying or potentially avoiding need for more toxic systemic agents. We highlight that dermatologists and nurse specialists are well placed to deliver T-VEC in patients with melanoma.

No abstract available

P1/2, N=8, Active, not recruiting, Mohammed Milhem | Recruiting --> Active, not recruiting | N=46 --> 8 | Trial completion date: Jun 2024 --> Nov 2024

P1/2, N=30, Completed, University of Iowa | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Mar 2023

These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of unresectable melanoma...Moreover, human monocytic leukemia cells selectively delivered oHSV-1 to human head-and-neck xenograft tumors grown on the chorioallantoic membrane (CAM) of fertilized chicken eggs after intravascular injection. Thus, our work shows that monocytes are promising carriers for the delivery of oHSV-1s in vivo, deserving further investigation in animal models.

ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.