TWiV 395: The cancer thief

Vincent, Rich and Kathy speak with Stephen Russell about his career and his work on oncolytic virotherapy – using viruses to treat cancers. Recorded before an audience at ASV 2016 at Virginia Tech in Blacksburg, Virginia.

You can find TWiV #395 at microbe.tv/twiv, or listen/view below.

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TWiV 359: A Blossom by any other name

On episode #359 of the science show This Week in Virology, Vincent speaks with Blossom about her laboratory’s research on Kaposi’s sarcoma-associated herpesvirus, including how it transforms cells, the switch between lytic and latent replication, and its interaction with the innate immune system of the host.

You can find TWiV #359 at www.microbe.tv/twiv.

TWiV 337: Steamer

On episode #337 of the science show This Week in Virology, Vincent meets up with Michael and Steve to discuss their finding of a transmissible tumor in soft-shell clams associated with a retrovirus-like element in the clam genome.

You can find TWiV #337 at www.microbe.tv/twiv.

Therapeutic teamwork: Coupling oncolytic viruses with immunotherapy to destroy tumor cells

NDV infected glioma cellsThis article was written for extra credit by a student in my recently concluded virology course.

by Nayan Lamba

A recent study by scientists at the Ludwig Center for Cancer Immunotherapy offers a new, multifaceted therapy for destroying tumors. A team of researchers led by Dmitriy Zamarin combined checkpoint blockade, a technique aimed at enhancing antitumor immune responses, with oncolytic viral therapy, a technique that uses viruses to kill tumor cells. By employing the two immunotherapies together, the researchers had more success in destroying tumor cells than they have had while investigating each therapy independently.

While checkpoint blockade has been effective as a therapy against some tumors, its major drawback seems to be an inability to destroy strongly immunosuppressing tumors that evade immune system detection. While many oncolytic viruses have also had success as antitumor agents, their impact thus far has been limited to locally restricted tumors. Scientists major concern about oncolytic viruses has thus been whether they must be injected at all possible tumor sites in order to combat metastatic tumors. In an innovative approach aimed at overcoming the weaknesses of the two independent therapies, Zamarin and his team were able to destroy previously resistant tumor cells.

The researchers initially injected mice with melanoma tumor cells, followed by injection of Newcastle disease virus (NDV) directly into these tumor sites. Newcastle disease virus is an avian virus that is non-pathogenic in humans and capable of inducing a robust immune response. Initial injection of NDV resulted in a pronounced inflammatory response in the mice, with increased activation of both innate and adaptive players of immunity. What is perhaps most striking about the data is that despite direct injection of NDV at a local tumor site, increased inflammation was also observed in sites distal and contralateral to tumor injection. The researchers noted tumor growth delay at sites both local and distant to sites of injection, indicating a potential for use of NDV in targeting metastatic tumors. While this observation was certainly promising, the researchers noted that complete, long-term destruction of distant tumor cells was seen in only 10% of animals. The researchers attributed this low level to the increased immunosuppression performed by the distant tumors. This suggestion was based on their observation that the distant tumor sites exhibited increased activity of CTLA-4 cells, which down-regulate the immune system.

While a more traditional, unilateral approach employing oncolytic viruses would have stopped here, the researchers instead proceeded to couple NDV injection with antibodies to CTLA-4 cells. They hypothesized that because NDV caused an increased level of inflammation at distant tumor sites, the anti-CTLA-4 antibodies might have more of an effect if they had been administered without NDV. Indeed, the researchers found that NDV coupled with anti-CTLA-4 resulted in long-term tumor suppression at sites both local and distant to NDV injection. By increasing the inflammatory response via NDV injection, they made the immune cells more receptive to the anti-CTLA-4 antibodies. Through a combination of oncolytic virus therapy and checkpoint blockade, the researchers overcame the limitations faced when each one is employed independently.

What is perhaps most promising about this therapy is that it has also proved effective against tumors that have previously shown resistance to oncolytic viral therapies. For example, TRAMP C2 prostrate adenocarcinoma cells previously showed resistance to lysis by NDV in vitro, unlike the melanoma cells discussed above. Yet, despite this resistance, when both therapies were employed on the adenocarcinoma cells in vivo, researchers noted distant tumor regression and long-term survival, just as they did with the melanoma cells. When they examined these adenocarcinoma cells in vitro, they noted an increased inflammatory response. They noted an up-regulation of MHC I molecules in all cells, even cells that were not infected with NDV. MHC I cells are important players of the immune system, responsible for presenting fragments of virus at the surface of infected cells so that the body can recognize when a cell is infected and subsequently destroy that cell. By demonstrating that a tumor cell does not need to be permissive to a virus in order to be a target for therapy, Zamarin’s approach greatly expands the potential applicability of NDVs and other oncolytic viruses. It seems that what is most important to tumor suppression is the virus-generated inflammatory response and the increased tumor immogenicity that this approach facilitates.

The clinical potential of this double-therapy in humans is particularly exciting to me, especially in light of the fact that both oncolytic therapies and checkpoint blockade have independently been successful in combating tumors in humans. This observation certainly suggests that the two therapies may prove even more effective when combined in humans. Indeed, such a clinical trial is already underway in humans; a current study is studying the effects of ipilimumab, a CTLA-4 target, administered with a herpes simplex oncolytic virus, in the treatment of melanoma. It will be interesting to see how the double-therapy plays out in a human population, and how these results affect the future use of oncolytic viruses.

TWiV 218: Monkeys turning valves and pushing buttons

On episode #218 of the science show This Week in Virology, Vincent, Alan, and Welkin discuss how endogenous retroviruses in mice are held in check by the immune response.

You can find TWiV #218 at www.microbe.tv/twiv.

TWiV 214: This is your brain on polyomavirus

On episode #214 of the science show This Week in Virology, Vincent, Alan, and Kathy discuss how coagulation factor X binding to adenovirus activates the innate immune system, and a novel polyomavirus associated with brain tumors in raccoons.

You can find TWiV #214 at www.microbe.tv/twiv.

TWiV 142: Viral oinkotherapy

seneca valley virusHosts: Vincent Racaniello, Rich Condit, and Alan Dove

Vincent, Rich, and Alan discuss a method for identifying viruses of individual environmental bacteria, and the using a picornavirus for oncotherapy.

Click the arrow above to play, or right-click to download TWiV 142 (69 MB .mp3, 95 minutes).

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Weekly Science Picks

Alan – Germlines podcast
Rich – science360
Vincent – Google+

 

Listener Pick of the Week

AngusScience Weekly with Alok Jha

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

TWiV 124: Viruses that make you better

Rabbits Myxomatosis Trial WardangIsland 1938Hosts: Vincent Racaniello, Dickson DespommierAlan DoveRich Condit, and Grant McFadden

On episode #124 of the podcast This Week in Virology, Vincent, Dickson, Alan, Rich, and Grant discuss a tanapoxvirus protein that inhibits tumor necrosis factor, purging tumors with myxoma virus, and destruction of the last known stocks of smallpox virus.

Click the arrow above to play, or right-click to download TWiV #124 (74 MB .mp3, 103 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

Weekly Science Picks

Grant – A Short History of Nearly Everything by Bill Bryson
Dickson – An Inquiry into the Causes and Effects of the Variolae Vaccinae by Edward Jenner
Rich –
Selinah (Topsy Foundation) thanks Meghan!
Alan – Draft report (pdf) on WHO’s H1N1 response and NY Times summary
Vincent – 10 stunning science visualizations

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

Poliovirus vaccine, SV40, and human cancer

SV40Deep sequencing – which identified a viral contaminant of the rotavirus vaccine Rotarix – could have revealed the presence of simian virus 40 (SV40) in the poliovirus vaccine, had the technique been available in the 1950s. Exposure of over 100 million Americans to SV40, and many more worldwide, could have been avoided, as well as the debate about the role of this monkey virus in human cancer.

SV40 was discovered by Maurice Hilleman in 1960 as a contaminant of poliovirus vaccine. It was present in batches of both the Salk and Sabin poliovirus vaccines produced and distributed from 1954 to 1963. The source was the rhesus and cynomolgous monkey kidney cells used to produce the vaccine. Even more troubling was the observation that SV40 could cause tumors in hamsters. By 1963 screening procedures were instituted to ensure the absence of SV40 in poliovirus vaccines. Ironically, monkey cells were used for poliovirus vaccine production because it was feared that human cells might contain unknown human cancer viruses.

SV40 does not cause tumors in its natural host – monkeys – because it kills infected cells. However, in the wrong host- such as a hamster – the viral replication cycle is incomplete and virions are not produced. At a very low frequency, pieces of the viral DNA become integrated into the host chromosomal DNA. Problems arise if these viral DNA fragments encode the viral T (tumor) antigen. This protein is essential for lytic replication (which takes place in monkey cells) because it kick-starts cellular DNA synthesis. The cellular DNA synthetic machinery is then co-opted for replication of the viral DNA. When only T antigen is present, the cells divide without stopping – they are transformed, and on the way to becoming a tumor. SV40 does not need to cause tumors as part of its life cycle; they are an aberrant result of having T antigen push the cells to divide. SV40 T antigen can transform human cells, and therefore in theory the virus could cause human tumors.

The results of epidemiological studies initiated in the 1960s through the 1970s, in which thousands of poliovirus vaccine recipients were studied, indicated that this population did not have an increased risk of developing cancer. More recent reports that SV40 viral DNA is present in human tumors have led to a debate on the contribution of this virus to human cancer. Some of the arguments for and against presence of SV40 in human cancers are presented below.

Evidence that SV40 is present in human tumors

  • SV40 DNA has been detected in several human tumors, including osteosarcoma, mesothelioma, and non-Hodgkin’s lymphoma. Similar tumors are induced by the virus in hamsters.
  • Poliovirus vaccine produced in 1954 contained a variant of SV40 that can be distinguished from common laboratory strains. This viral variant has been found in three non-Hodgkin’s lymphoma patients

Evidence that SV40 is not present in human tumors

  • SV40 DNA is not present in all samples of a cancer, and in some studies of mesotheliomas, it has not been detected in any.
  • SV40 viral DNA has been detected in tumors of those who could not have received contaminated poliovirus vaccine.
  • In a comparison of mesotheliomas and normal tissues, SV40 DNA has been detected as frequently in both.
  • Analysis of the SV40 sequences in mesotheliomas showed that the viral DNA was derived from a laboratory strain which contains a gap that is not present in the wild type viral genome.

Even if SV40 DNA were definitively shown to be present in human tumors, this would not answer the question of whether the virus caused the cancer. The debate on the role of SV40 in human malignancy illustrates the difficulty in establishing cause and effect, and provides ample impetus for using genomic technologies to ensure that vaccines and other biological products are free of adventitious agents.

Garcea, R., & Imperiale, M. (2003). Simian Virus 40 Infection of Humans Journal of Virology, 77 (9), 5039-5045 DOI: 10.1128/JVI.77.9.5039-5045.2003

López-Ríos F, Illei PB, Rusch V, & Ladanyi M (2004). Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet, 364 (9440), 1157-66 PMID: 15451223

PEDEN, K. (2008). Recovery of strains of the polyomavirus SV40 from rhesus monkey kidney cells dating from the 1950s to the early 1960s Virology, 370 (1), 63-76 DOI: 10.1016/j.virol.2007.06.045

The Immortal Life of Henrietta Lacks

immortal_lifeShortly after I wrote about my years of experience with HeLa cells, I was contacted by author Rebecca Skloot. One of her many questions was how I knew that I had produced 800 billion HeLa cells in my laboratory over 26 years. I learned that she was writing a book about Henrietta Lacks, whose tumor was the source of HeLa cells in 1951. Subsequently I had the privilege of reading an early draft of her book, The Immortal Life of Henrietta Lacks, which will be published next month.

I thought I knew enough about HeLa cells and their origins, but Rebecca’s book shattered that impression. I’ve worked with the cells all my career and have always appreciated them, and the fact that Henrietta gave science something fabulous, but the back story I didn’t appreciate. How the whole affair deeply affected that family, and what they went through. I want to thank Rebecca for working so hard to get the whole story. And for being nice enough that the family trusted her! She not only vividly portrays what the family went through, but shows what HeLa has meant to science, how unscrupulous people always want to take advantage of others, and the good and bad about science. In the end, I keep coming back to the same question: if we had informed consent laws back then, would Henrietta have said no? If so, it would have been a tremendous loss for science and medicine. Or should I say setback – because eventually there would have been others. That’s how science is: someone always makes the discovery, sooner or later.

There will be a public launch of the book on 1 February at 7pm at McNally Jackson Bookstore in New York City. Rebecca will read a bit from the book, talk about it, sign it, and answer questions. Below are the details of the public event. If you are in the New York area, and have an interest in science, I encourage you to attend. I will certainly be there!

Public Launch Event: Rebecca Skloot Discusses Her New Book “The Immortal Life of Henrietta Lacks”

Award winning science writer Rebecca Skloot discusses and signs her new book, The Immortal Life of Henrietta Lacks. Books available for sale at this launch event one day before the book’s official publication date. Free & open to the public.

Book description: Her name was Henrietta Lacks, but scientists know her as HeLa. She was a poor Southern tobacco farmer who worked the same land as her slave ancestors, yet her cells — taken without her knowledge — became one of the most important tools in medicine. The first immortal human cells grown in culture, they are still alive today, though she has been dead for more than sixty years. If you could pile all HeLa cells ever grown onto a scale, they’d weigh more than 50 million metric tons — more than 100 Empire State Buildings. HeLa cells were vital for developing the polio vaccine; uncovered secrets of cancer, viruses, & the effects of the atom bomb; helped lead to important advances like in vitro fertilization, cloning, and gene mapping; and have been bought and sold by the billions. Yet Henrietta Lacks remains virtually unknown, buried in an unmarked grave. Now Rebecca Skloot takes us on an extraordinary journey, from the colored ward of Johns Hopkins Hospital in the 1950s to stark white laboratories with freezers full of HeLa cells; from Henriettas small, dying hometown of Clover, Virginia — a land of wooden slave quarters, faith healings, and voodoo — to East Baltimore today, where her children and grandchildren live, and struggle with the legacy of her cells. Henriettas family did not learn of her immortality until more than twenty years after her death, when scientists began using her husband and children in research without informed consent. The story of the Lacks family — past and present — is inextricably connected to the dark history of experimentation on African Americans, the birth of bioethics, and the legal battles over whether we control the stuff we are made of. More information at rebeccaskloot.com.

“Skloot’s book is wonderful, deeply felt, gracefully written, sharply reported.” — Susan Orlean, author of The Orchid Thief

“This is an extraordinary book, haunting and beautifully told.” — ERIC SCHLOSSER, author of Fast Food Nation

When: Monday, February 1 2010, 07:00 PM
Where: McNally Jackson Books, 52 Prince Street, New York, NY, 1001
Full nationwide tour schedule and details