by ecancer reporter Janet Fricker

A modified measles virus produced complete remission at all tumour sites in a heavily pre treated patient with multiple myeloma (MM), reported a phase 1 clinical trial in the journal Mayo Clinic Proceedings.

“It’s a landmark [study]. We’ve known for a long time that we can give a virus intravenously and destroy metastatic cancer in mice. Nobody’s shown that you can do that in people before,” said Stephen Russell, the principal investigator of the study from the Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.

MM, the second most common haematological malignancy in North America, although treatable essentially represents an incurable disease with five-year survival rates of less than 40%.

MV-NIS is an engineered measles virus that targets CD46, a complement regulatory protein highly expressed on human myeloma cells, making them abnormally susceptible to MV-NIS infection.

The virus was further modified to contain the mammalian NIS gene encoding the sodium iodide symporter – the pump protein responsible for concentrating iodine in the thyroid.

An additional consequence of infection is that tumour cells become endowed with the ability to concentrate radioactive iodine, providing the ability to assess the extent and duration of infection.

In the current report the investigators provide preliminary data on two patients from the phase 1 trial.

The two patients had received the highest possible virus dose, and additionally had limited previous exposure to measles and therefore possessed fewer antibodies to the virus.

Both had not responded to multiple rounds of conventional therapy for MM and were at risk of imminent death.

In the proof of concept study the modified measles virus (MV-NIS) was infused into a superficial vein on the left forearm of the patient over the course of an hour.

The women were then monitored with modalities including pharmacokinetic studies, eight colour plasma cell flow cytometry and SPECT-CT imaging studies.

Patient 1 was a 49-year-old woman with heavily pre treated light chain MM who experienced relapse while receiving no therapy nine months after her second autologous stem cell transplant (ASCT).

MM had been diagnosed nine years earlier and treated with thalidomide and dexamethasone followed by consolidative ASCT, lenalidomide and dexamethasone; cyclophosphamide, bortezomib, and dexamethasone.

Following MV-NI infusion she experienced durable complete remission at all disease sites and M protein reduction and resolution of bone marrow plasmacytosis.

Patient 2 was a 65-year-old woman with relapsing IgA κ MM refractory to all approved antimyeloma drugs who experienced disease progression while receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Following MV-NI infusion she showed M protein reduction and resolution of bone marrow plasmacytosis.

“Despite the long history of the field of oncolytic virotherapy (OV), complete remission of a disseminated malignancy mediated by a systemically administered virus has not previously been documented in a human subject, nor has the specific targeting of OV infection to sites of tumour growth,” write the authors.

One key factor that may have contributed to successful outcomes for the two patients in the current study was their low pre treatment serum titres of anti measles antibodies.

In an accompanying commentary John Bell, from the Centre for Innovative Cancer Research, Ottawa, Ontario, wrote, “Russell et al now provide compelling evidence that a single infusion of an OV can lead to complete systemic antitumor responses, even in patients with advanced cancer. For the rest of the OV field, these are exciting results that finally validate the clinical potential of this class of therapeutics. However, there is much research to be done. We still know remarkably little about the best way to deliver OVs intravenously to patients. The speed and duration of infusion, the quantity of virus, and the number of doses to be administered are all poorly understood at this time, but the study by Russell et al now provides a benchmark to strive for and improve.”

To support a planned phase 2 expansion of the clinical trial in measles-seronegative patients additional MV-NIS is now undergoing manufacture.

References

S Russell, M Federspiel, K Peng et al. Remission of Disseminated Cancer After Systemic Oncolytic Virotherapy. Mayo Clinic Proceedings. Available here. 

J C Bell. Taming Measles Virus to Create an Effective Cancer Therapeutic. Available here.