Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

Canton, David A.; Shirley, Shawna A.; Wright, Jocelyn H.; Connolly, Richard J.; Burkart, Christoph; Mukhopadhyay, Anandaroop; Twitty, Christopher G.; Qattan, Kristen E; Campbell, Jean S.; Le, Mai H.; Pierce, Robert H.; Gargosky, Sharron; Daud, Adil; Algazi, Alain P.

doi:10.2217/imt-2017-0096

Cited by 46 publications

(34 citation statements)

References 59 publications

(62 reference statements)

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“… 5 Subsequently, cytokine fusion proteins and plasmids expressing cytokines have been developed with the aim of increasing efficacy. 75 , 76 For example, the immunocytokine fusion protein L19–IL-2 (Darleukin) is a targeted form of IL-2 that recognises the extra domain B of fibronectin, which is expressed in cancer-associated blood vessels and extracellular matrix but absent from almost all healthy tissue. 75 In a single-arm Phase 2 trial, L19–IL-2 resulted in local responses, including local complete responses.…”

Section: Novel Agents In Development For Unresectable and Metastatic mentioning

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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Section: Novel Agents In Development For Unresectable and Metastatic mentioning

confidence: 99%

“…78 Tavokinogene telseplasmid was given orphan drug status by the US Food and Drug Administration (FDA) in 2017 for the treatment of unresectable metastatic melanoma. 76 …”

Section: Novel Agents In Development For Unresectable and Metastatic mentioning

confidence: 99%

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

et al. 2020

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“…Therefore, combination therapy of IL-2 and rituximab could benefit patients with refractory NHL. In patients with melanoma given a combination of IL-12 and PD-1-targeted therapy in a 24-week treatment cycle, the disease control rate reached 59%, and 41% (9/22) of patients had a CR [ 19 ]. IL-12 greatly reduced the incidence of adverse reactions caused by the administration of the anti-PD-1 antibody alone, and it potentiated the activity of PD-1 antibodies without increasing significant toxicity [ 19 ].…”

Section: Progress In Therapeutic Strategies Of Il-12 Treatment For Camentioning

confidence: 99%

A Review of Clinical and Preclinical Studies on Therapeutic Strategies Using Interleukin-12 in Cancer Therapy and the Protective Role of Interleukin-12 in Hematological Recovery in Chemoradiotherapy

Zhang

et al. 2020

Med Sci Monit

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Interleukin-12 (IL-12), a heterodimeric glycoprotein with α and β subunits covalently bonded with a disulfide bond, is a potent anticancer agent. Its action is accomplished through a linkage of the adaptive and innate immune responses. IL-12 can promote the recovery of the hematopoietic system after cancer chemoradiotherapy by stimulating the physiological processes of stem cells, including cell proliferation and differentiation, reconstitution of hematopoietic function, and peripheral blood count recovery. We review therapeutic strategies using IL-12 in clinical studies, including single-agent and combination strategies in hematological tumors and solid tumors, and studies on the protective effects of IL-12 in chemoradiotherapy. This review highlights promising therapeutic strategies based on the anticancer role of IL-12 and the potential protective effects of IL-12 for cancer patients receiving chemoradiotherapy.

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“… 9 10 In preclinical models, IL-12 has consistently been shown to reduce tumor burden and increase survival though early clinical trials revealed IL-12-driven systemic toxicities. 11 Recent clinical studies; however, demonstrate that locally-delivered IL-12 is well-tolerated in high-grade glioma 12 and metastatic melanoma, 13 14 suggesting that methods to deliver IL-12 to the TME could harness the preclinical successes for use in humans.…”

Section: Introductionmentioning

confidence: 99%

Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses

Brempelis

Cowan

Kreuser

et al. 2020

J Immunother Cancer

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BackgroundThough currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.MethodsUsing lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.ResultsHere, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.ConclusionsOur data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.

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Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

Cited by 46 publications

References 59 publications

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

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

A Review of Clinical and Preclinical Studies on Therapeutic Strategies Using Interleukin-12 in Cancer Therapy and the Protective Role of Interleukin-12 in Hematological Recovery in Chemoradiotherapy

Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses

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