Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical coxsackievirus A21

Pandha, Hardev; Annels, Nicola; Arif, Mehreen; Mostafid, Hugh; Sandhu, Sarbjinder; Harrington, Kevin J.; Melcher, Alan; Mansfield, David; Au, Gough G.; Grose, Mark; Karpathy, Roberta; Shafren, Darren R.

doi:10.1093/annonc/mdw378.09

Cited by 6 publications

(5 citation statements)

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“…At 24 h, each well was transfected with 1 mg in vitro-derived RNA transcripts or infected at an MOI of 3. Distinct samples were collected at specific times postinfection (2,4,6,8,12,24, and 48 h) or transfection (6,12,24, and 48 h) and stored at À80 C. Following the completion of all time points, samples were frozen and thawed three times, and cellular debris was cleared from the lysates by centrifugation. The cleared lysates were then titrated as described above.…”

Section: Virus and Rna Growth Curvesmentioning

confidence: 99%

“…The tolerability and efficacy of CVA21 has been demonstrated in phase I and II clinical trials. [1][2][3][4][5] However, these studies are limited to immune-competent patients R18 years of age, leaving the safety of CVA21, which has the potential to cause myositis in immunocompromised hosts, in pediatric/adolescent or severely immunocompromised patients largely unknown. 6,7 Additionally, clinical protocols can include up to 19 treatments, a significant financial burden that will continually increase with combination therapies.…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic Activity of Targeted Picornaviruses Formulated as Synthetic Infectious RNA

Elsedawy

Nace

Russell

et al. 2020

Molecular Therapy - Oncolytics

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Infectious nucleic acid has been proposed as a superior formulation for oncolytic virus therapy. Oncolytic picornaviruses can be formulated as infectious RNA (iRNA), and their unwanted tropisms eliminated by microRNA (miRNA) detargeting. However, genomic insertion of miRNA target sequences into coxsackievirus A21 (CVA21) iRNA compromised its specific infectivity, negating further development as a novel oncolytic virus formulation. To address this limitation, we substituted a muscle-specific miRNA response element for the spacer region downstream of the internal ribosomal entry site in the 5 0 non-coding region of CVA21 iRNA, thereby preserving genome length while avoiding the disruption of known surrounding RNA structural elements. This new iRNA (R-CVA21) retained high specific infectivity, rapidly generating replicating miRNA-detargeted viruses following transfection in H1-HeLa cells. Further, in contrast with alternatively configured iRNAs that were tested in parallel, intratumoral administration of R-CVA21 generated a spreading oncolytic infection that was curative in treated animals without associated myotoxicity. Moreover, R-CVA21 also exhibited superior miRNA response element stability in vivo. This novel formulation is a promising agent for clinical translation.

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Section: Virus and Rna Growth Curvesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oncolytic Activity of Targeted Picornaviruses Formulated as Synthetic Infectious RNA

Elsedawy

Nace

Russell

et al. 2020

Molecular Therapy - Oncolytics

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“…(1) CAVATAK (Viralytics, Sydney, Australia), a proprietary formulation of the common cold coxsackievirus type A21 (CVA21), is being investigated against advanced malignancies in several clinical studies. [330][331][332][333][334] The completed Phase II CALM trial (NCT01227551) demonstrated the tolerability and efficacy of intralesional CVA21 monotherapy in 57 patients affected by late-stage melanoma. 334,335 The ORR assessed by irRECIST was 28.1% with a ≥ 6 months durable response rate (DRR) of 21.1%.…”

Section: Completed and Advanced Clinical Studiesmentioning

confidence: 99%

“…[330][331][332] The latter observation is encouraging for a synergistic effect with pembrolizumab considering the ability of CVA21 tumor infection to restore immune cell infiltration and upregulate the expression of immune checkpoint molecules. 334 Finally, the Phase I/II CANON trial (NCT02316171) is investigating the safety and efficacy of escalating doses of neoadjuvant CVA21, delivered i. v. in 16 first-line patients with bladder cancer, either alone or in combination with low-dose mitomycin C. 333 Observations indicate general tolerance of i.v. CVA21.…”

Section: Completed and Advanced Clinical Studiesmentioning

confidence: 99%

“…Evidences of complete tumor response, viral replication and signs of virusinduced tumor inflammation demonstrated clinical activity of CVA21, likely associated with the induction of local and systemic anti-tumor immunity. 333 (2) Two case reports suggested that oncolytic virotherapy with Rigvir, a wild-type enterovirus ECHO-7 (Riga Eastern Clinical University Hospital, Riga, Latvia), could be applied for long-term treatment of patients with melanoma stage IV M1c (n = 2), small cell lung cancer stage IIIA (n = 1), and histiocytic sarcoma stage IV (n = 1). Prospective clinical studies are encouraged.…”

Section: Completed and Advanced Clinical Studiesmentioning

confidence: 99%

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Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

et al. 2018

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Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.

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Oncolytic virotherapy for urological cancers

et al. 2016

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Oncolytic virotherapy is a cancer treatment in which replication-competent viruses are used that specifically infect, replicate in and lyse malignant tumour cells, while minimizing harm to normal cells. Anecdotal evidence of the effectiveness of this strategy has existed since the late nineteenth century, but advances and innovations in biotechnological methods in the 1980s and 1990s led to a renewed interest in this type of therapy. Multiple clinical trials investigating the use of agents constructed from a wide range of viruses have since been performed, and several of these enrolled patients with urological malignancies. Data from these clinical trials and from preclinical studies revealed a number of challenges to the effectiveness of oncolytic virotherapy that have prompted the development of further sophisticated strategies. Urological cancers have a range of distinctive features, such as specific genetic mutations and cell surface markers, which enable improving both effectiveness and safety of oncolytic virus treatments. The strategies employed in creating advanced oncolytic agents include alteration of the virus tropism, regulating transcription and translation of viral genes, combination with chemotherapy, radiotherapy or gene therapy, arming viruses with factors that stimulate the immune response against tumour cells and delivery technologies to ensure that the viral agent reaches its target tissue.

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Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical coxsackievirus A21

Cited by 6 publications

References 0 publications

Oncolytic Activity of Targeted Picornaviruses Formulated as Synthetic Infectious RNA

Oncolytic Activity of Targeted Picornaviruses Formulated as Synthetic Infectious RNA

Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Oncolytic virotherapy for urological cancers

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