Measles to the Rescue: A Review of Oncolytic Measles Virus

Our plain-English summary of Measles to the Rescue: A Review of Oncolytic Measles Virus, by S. Aref, K. Bailey, A. Fielding (Viruses, 2016).

The study

• Authors: S. Aref, K. Bailey, A. Fielding
• Journal: Viruses
• Published: 2016;8(10)
• Type of article: Review
• Cited by: 100 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and "blinding" the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

In plain English

This was a narrative review of measles virus (MV) as an oncolytic (cancer-killing) agent, written by authors at UCL Cancer Institute. It summarised laboratory work, animal studies and early-phase clinical trials of the attenuated vaccine strain of measles virus. The authors described the three cell-entry receptors used by MV (CD150/SLAM, CD46 and nectin-4), defects in the interferon response that make tumour cells permissive to infection, and ways the virus has been genetically engineered: retargeting to antigens such as CEA, CD20 and CD38, adding reporter genes such as carcinoembryonic antigen and the sodium iodide symporter (NIS), prodrug-converting "suicide" genes, and immune-stimulating genes including antibodies against CTLA-4 and PD-L1. Clinical trial results reported included a Swiss study that enrolled five patients with cutaneous T-cell lymphoma, in which five of six treated lesions had regressed by day 28, a 21-patient intraperitoneal MV-CEA trial in recurrent ovarian or primary peritoneal cancer with median overall survival of 12.15 months, and a 16-patient MV-NIS ovarian trial with median overall survival of 26.6 months. Mesothelioma appeared only as an open trial (NCT01503177) and in interferon-beta-armed MV xenograft work. The authors concluded MV shows promise but that the exact oncolytic mechanisms remain elusive.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of pre-clinical and early clinical studies of oncolytic measles virus
• Who was studied: No new patients or animals were studied; the review covered published laboratory, xenograft and early-phase clinical trial work, including seven then-active early phase trials
• Exposure: Vaccine (attenuated Edmonston-lineage) strains of measles virus, unmodified and genetically engineered (retargeted H protein, reporter genes CEA and NIS, prodrug convertases, immune-stimulating transgenes), given intratumourally, intraperitoneally or intravenously
• Main results:
  • The first clinical trial of oncolytic MV enrolled five patients with cutaneous T-cell lymphoma stage IIb or higher
  • In that Swiss study, five of a total six lesions had regressed at day 28 and one disappeared completely; one patient had progressive disease and adverse effects were limited to grade 1
  • In the 21-patient intraperitoneal MV-CEA trial in recurrent or progressive ovarian or primary peritoneal cancer, doses from TCID50 10^3 to 10^9 caused no dose limiting toxicity and median overall survival was 12.15 months
  • In the 16-patient ovarian cancer trial using MV-NIS, SPECT/CT uptake was seen in only three of the 13 patients given the highest dose, and median overall survival was 26.6 months
  • In multiple myeloma, intravenous MV at 10^11 TCID50 was reported as supporting the safety of systemic administration, with improvement in two heavily pre-treated patients attributed partly to their low anti-measles antibody titres
  • Mesothelioma featured as an open recruiting trial and in xenograft work with interferon-beta-armed MV, which slowed tumour growth and angiogenesis
  • Reported mechanisms of tumour selectivity included CD46 overexpression on tumour cells, SLAM-dependent oncolysis in mantle cell lymphoma, and nectin-4 expression in adenocarcinomas
• The authors' conclusion: The authors concluded that measles virus has been extensively investigated pre-clinically and is showing promise in on-going and completed clinical trials
• Limitations the authors state:
  • The authors stated that the exact mechanisms of MV-mediated oncolysis remain elusive
  • The authors noted the role of the immune system has been hard to study because of a lack of mouse models both susceptible to MV and immunocompetent
  • The authors noted pre-existing anti-measles immunity in most of the population may diminish or prevent oncolysis, especially with intravenous therapy
  • The authors noted that reporter genes cannot distinguish infection of cancer cells from normal cells
  • The authors noted nanoparticle shielding of virus remains, to their knowledge, restricted to in vitro studies

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Carcinoembryonic Antigen (CEA), checkpoint inhibitors, Ovarian Cancer, Myeloma, Mesothelioma, Squamous Cell Carcinoma.

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• Personalized Oncolytic Therapy: The Next Step Toward the Successful Clinical Application of Vaccine-Strain Measles Viruses for Cancer Therapy? — T. Peikert (2020)
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