This week I had a chance to talk to Dr. Stephen Russell of the Mayo Clinic about the new measles virotherapy findings and the future of virotherapy for myeloma patients, including a virus that may be an even more potent destroyer of myeloma than the measles virus!
While the news about Stacy Erholtz, a 50-year-old myeloma patient at the Mayo Clinic, may have caught the myeloma community by surprise last week, Dr. Russell, along with Dr. Angela Dispenzieri, have been conducting a trial with engineered measles virus since 2006. In fact, he presented preliminary results at the IMF's International Working Myeloma Group (IMWG) Summit in London in 2011. At that point however, the patients were being treated with lower doses of the measles virus. About three patients per year were entering the study and no responses were seen.
Then, in May 2013, Stacy was treated with the massive 100 billion dose - equivalent to enough measles virus to vaccinate 10 million people! - and everything changed.
A first patient at the 100-billion-dose level had the intravenous infusion stopped after five minutes because of severe headache. Stacy, the second patient at this dose level, also developed a bad headache, but was able to complete the one-hour infusion. There was a lot of anxiety about possible side reactions. Her temperature spiked to 105Â°F and she developed shaking chills, which continued over the next two to three days. She also developed surface inflammation at the site of infusion in her left arm. Her blood platelets and white blood cells (lymphocytes) dropped significantly. But dramatically, after 36 hours, the plasmacytoma (myeloma lesion) on Stacy's forehead started to shrink!
A Very Special Patient
Within the first week, her Freelite level dropped. By six weeks, her forehead plasmacytoma had disappeared and the Freelite level plus bone marrow had returned to normal: her marrow was MRD negative according to a flow test. A PET/CT continued to show active myeloma at several sites (in the clavicle, sternum, and T11) but at a much reduced level. By seven months, Stacy's PET/CT was fully negative. As can be imagined, everyone was thrilled.
However, by nine months, her forehead lesion started to grow back. But, there were no other lesions anywhere. This lesion has been treated with local radiation and Stacy is again without evidence of active disease. There will be follow-up testing in June 2014. Thus, a fantastic response, but certainly not a "one-shot cure" yet.
Stacy is a special patient who had myeloma confined to her bones and did not have antibodies against measles in her blood stream.
How Measles Virotherapy Works Against Myeloma
Of the 31 patients who are part of this measles virotherapy program, about 50% have zero or very low antibody levels. This means that when the engineered measles virus is injected intravenously, it is not immediately destroyed -- as it would be in a patient who had high antibody levels -- and travels to "infect" the myeloma cells. Once in the myeloma cells, the virus "takes over": it divides and divides and divides!! This destroys the myeloma cells (which basically explode), and virus spills into the marrow microenvironment infecting surrounding myeloma cells.
The virus also activates the local immune system to help "mop up" residual disease in that area. So, this process seems to have worked very well for Stacy and is a tremendous "proof of principle" outcome for her. This type of systemic (whole body) virotherapy can work.
Six patients have now been treated at the massive 100-billion-dose level in two "cohorts" of three each. The second patient in the second cohort also had some response, but to a much lesser degree. This patient also had low measles antibody levels but was rather different in that myeloma was located in muscle tissue outside of the bone marrow.
The toxicities were similar in this second patient, and there was definite uptake of the measles virus into the plasmacytoma tissue documented by nuclear scan. There was also pain at the sites of the plasmacytomas, which seemed promising. But although there was some reduction in Freelite level, by day 45, the level had bounced back up, and the myeloma was clearly progressing again. So quite disappointing compared to Stacy. Of note, this patient has since had an unexpectedly good response therapy using Velcade/Revlimid/dexamethasone.
Treating more patients is the obvious next step. But this is more easily said than done. To produce (manufacture) enough engineered measles virus to treat a patient with the massive dose requires a culture of Hela cells (written about in Rebecca Skloot's bestselling book, "The Immortal Life of Henrietta Lacks") in a 75-liter vat. It takes time to grow up enough virus, then purify, safety check and prepare for intravenous injection. It is estimated that a new larger trial can start by September this year. To treat 100 patients in a trial will require 1,000 to 2,000 liters of cultured cells! For this huge operation a commercial company with a dedicated facility will be used. This is a very expensive project which will cost approximately $50,000 per patient for the massive measles dose. With bulk processing the price will no doubt decrease, and the goal is to achieve a price point of $5,000 per dose.
Dr. Russell openly discusses the magnitude of the project and the commitments which are needed to move this project rapidly forward. The stunning result with Stacy opens many possibilities for further trials.
Other viruses have been discussed with potential advantages over the engineered measles virus. The measles virus is safe and has been used for many years and thus is very attractive from that standpoint. Another virus, vesicular stomatitis virus (VSV), however, has some attractive features. Since it causes blistering around the mouth, there is no systemic (whole body) antibody response. All patients can be expected to have zero antibodies. In addition, in a model where it is possible to compare, the VSV works faster and is definitely a more potent (in destroying myeloma) versus measles virus. For these reasons, a new protocol with VSV is planned by Dr. Russell and has been submitted to the FDA for review. Feedback is awaited. The clinical lead for this new protocol is Dr. Martha Lacy. Dr. Dispenzieri will continue as the clinical lead for the measles protocol.
Thus, despite many challenges, there is considerable optimism that virotherapy is a dramatic new way forward to treat myeloma using a completely different approach. It may or may not ever be a "one-shot cure" but maybe a "one-two punch" in which follow-up radiation or other therapy can provide a "knock-out" blow. Ideas for further research include ways to increase the number of myeloma cells taking up virus (to 100%, if feasible) and to enhance the local immune "mop-up" process. In addition, as for all novel approaches, combining with/or integrating into other treatments/protocols can undoubtedly improve outcomes.
Dr. Russell will discuss his results at the upcoming IMWG Summit in Milan, Italy. A very lively discussion is expected as the gathered myeloma experts will consider the ramifications of this successful systemic virotherapy breakthrough. Stay tuned!
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