Oncolytic VSV
Oncolytic VSV (gold) infecting lung tumors1

Oncolytic viruses are a concept I’d like to be more excited by than I am.2 It’s an idea that seemed really exciting when I first came across it, but the more I thought about it the more dubious I was. But a recent paper helps me feel better about at least two of my worries.

The concept is a straightforward one. Viruses are good at killing cells.3 Why not have them infect cells that we want to die? That would be, for example, cancer cells. So all you need to do is find or make a virus that only grows in cancer cells, and you’re cured. Simple! Tomorrow we’ll fix global warming!

There’s the obvious problem with this: How can you find (or make) a cancer-specific virus? In principle the answer is the same as with chemotherapy; you use the ways cancer cells are different from normal as targets. This isn’t as hard as you might think. Lots of the things that make cancer cells cancerous are similar to the things viruses like. Viruses often drive infected cells into a cancer-like state that is more hospitable to the virus — friendly to nucleic acid replication, replication, unresponsive to death signals, independent of the signals that normally regulate growth. So lots of viruses are already kind of pre-adapted to replicate well in cells with a cancerous phenotype, and it doesn’t take all that much tweaking to make them adapted to only replicate well in cancer cells.

(After writing this post, it occurred to me that this is actually topical! I don’t usually do the topical blog post thing, but the background in “I Am Legend” has an anti-cancer virus, isn’t it? I haven’t seen it myself, with the grant-writing and the teaching and the two little kids,4 but have I actually tied a current entertainment topic into “Mystery Rays”? Fame and fortune is certain to come my way!)

Oncolysis through the ages

Jennerex Onolytic virusThe first runs at this technique that I knew of5 used mutant herpesviruses,6 but I think that much of the buzz came from work with defective adenoviruxes, especially the ONYX-015 virus.7 The approach here was based on the observation that adenoviruses (like many other viruses) normally inactivate p53 during infection. p53 is a multifunctional growth regulator that is very often also inactivated in cancers, for the same reason as viruses like to inactivate it:it oten triggers death in cells with unchecked growth. Adenoviruses lacking the gene that inactivates p53 (their E1B gene) can only efficiently infect cells lacking p53 — which would usually be, of course, cancer cells.

Blogging on Peer-Reviewed ResearchAs well as herpesviruses and adenoviruses, though, all sorts of other viruses have been used.8 One interesting approach is vesicular stomatitis virus. This is a very, very innocuous virus in normal people, partly because VSV is extremely sensitive to interferon. (VSV is used in bioassays for interferon release, because even tiny amounts of interferon completely block the virus’s replication.) So which kind of cells often aren’t responsive to interferon? Right; cancer cells, as part of their own immune evasion pathway, frequently disable their interferon responses. VSV doesn’t infect normal cells, but does infect, and kill, tumor cells.9

Questions and (maybe) answers

Anyway, the first question, of specificity, is more or less under control.10 Three questions that had made me rather dubious about the concept, though, still remained:

1. Getting the virus to the tumor …
2. Especially in the face of an immune response.
3. Killing all of the cancer cells, not a mere 99% of them (from which the cancer will rapidly recover).

Malignant melanoma cells in lymph node
Malignant melanoma cells in lymph node

A paper in Nature Medicine11 offers encouragement on all of those.

They used VSV as their cancer killer, and their twist here was to deliver it by loading it onto T cells. T cells naturally traffic to lymph nodes, and quite a few tumors metastasize through lymph nodes; the T cell therefore acts as a ferry to deliver its deadly viral cargo to the metastasizing tumor. (The goal here was not to clear the primary tumor, but to prevent metastases, which are often the major problem.  However, they did see some effect on the primary tumor, too, in some cases.) When it reaches the lymphoid tissue, it delivers the passenger virus to the cancer cells, the only ones that the VSV can productively infect (since the cancer cells are the only ones that have mutated their interferon pathway). This is an interesting idea, though limited in this form — I wonder about using antigen-specific T cells instead, to target the virus to a specific site — and it seemed to work quite well.

The two more interesting points to me were kind of peripheral to their main point. First, they find that once the virus killed some cancer cells, there was anti-tumor protection even after the virus was all cleared, and this was probably because of the immune response,12 which was triggered by the cell death initially caused by the virus:

In vivo tumor cell purging resulted both from direct viral oncolysis by virus released from the T cell carriers and from the priming of protective antitumor immunity, which prevents repopulation by further waves of cells metastasizing from the primary tumor.

— just as described in the paper by Apetoh et al13 that I talked about here. The authors suggest that because the cancer metastases are being killed in the lymph nodes, rather than in the bulk of the tumor (which is generally a highly immunosuppressive environment) the immune response was more efficient. That starts to get past my concern #3 above, because it offers multiple attacks on the tumor, not just the virus.

The other point is that the virus could reach the cancer reasonably well even in the face of an anti-viral immune response; the trick was to use just enough virus to kill the tumor cells, without getting enough on the T cells to trigger an immune response:

In virus-immune mice, T cells loaded with large amounts of VSV (MOI 1 or 10) could not keep DLNs or spleens free of tumors. However, T cells loaded with fewer viruses (MOI 0.1) still protected even virus-immune animals from tumor colonization of the DLN and spleen

The data are still very preliminary and inconclusive, but certainly it’s a step in the right direction, and I feel better about this whole approach than I did before reading the paper.

  1. Carrier Cell-based Delivery of an Oncolytic Virus Circumvents Antiviral Immunity. Anthony T Power, Jiahu Wang, Theresa J Falls, Jennifer M Paterson, Kelley A Parato, Brian D Lichty, David F Stojdl, Peter A J Forsyth, Harry Atkins and John C Bell. Molecular Therapy (2007) 15, 123-130. []
  2. That sentence needs a road map, but you got here eventually, didn’t you.[]
  3. At least, lytic viruses are.[]
  4. And the running and the screaming and the monkeys in the hair[]
  5. I realize now, though, that the concept arose long before that, apparently in the 1950s. For example: Love R, Sharpless GR. Studies on a transplantable chicken tumor, RPL-12 lymphoma. II. Mechanism of regression following infection with an oncolytic virus. Cancer Res. 1954 Oct;14(9):640-7.http://dx.doi.org/10.1126/science.1851332 though I don’t know much about those studies other than the titles []
  6. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. Science. 1991 May 10;252(5007):854-6. []
  7. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH. Nat Med. 1997 Jun;3(6):639-45.
    An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F. Science. 1996 Oct 18;274(5286):373-6. []
  8. And I have no idea which, if any, is the most promising.[]
  9. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. David F. Stojdl, Brian Lichty, Shane Knowles, Ricardo Marius, Harold Atkins, Nahum Sonenberg & John C. Bell. Nature Medicine 6, 821 – 825 (2000) http://dx.doi.org/10.1038/77558 doi:10.1038/77558[]
  10. One other point is that you can probably get away with a virus that isn’t completely restricted to tumor cells, because these are usually viruses that cause very mild disease anyway, so even if they can spread to normal cells it’s no more worry than exposure to a standard subway car. Maybe more concern for immunosuppressed cancer patients, of course, but likely not an insurmountable worry.[]
  11. Qiao, J., Kottke, T., Willmon, C., Galivo, F., Wongthida, P., Diaz, R.M., Thompson, J., Ryno, P., Barber, G.N., Chester, J., Selby, P., Harrington, K., Melcher, A., Vile, R.G. (2007). Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy. Nature Medicine DOI: 10.1038/nm1681[]
  12. The short-term clearance worked in immune-deficient mice, but the long-term did not[]
  13. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., Mignot, G., Maiuri, M. C., Ullrich, E., Saulnier, P., Yang, H., Amigorena, S., Ryffel, B., Barrat, F. J., Saftig, P., Levi, F., Lidereau, R., Nogues, C., Mira, J. P., Chompret, A., Joulin, V., Clavel-Chapelon, F., Bourhis, J., Andre, F., Delaloge, S., Tursz, T., Kroemer, G., and Zitvogel, L. (2007). Nat Med 13, 1050 – 1059. []