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Will cancer immunotherapy fail?

Ira Mellman1 paints rosy prospects for cancer immunotherapy, if only the field receives more support. We?ve repeatedly heard such promises over the past 40 years. Yet despite continuing strong support, progress has been minimal and I expect it will be so in the future. To be effective, cancer immunotherapy requires that cancer cells have antigens on their surface (i) different than on normal cells and, (ii) constantly expressed during the cell cycle and essential for cell survival. Both requirements are mutually inclusive. If cancer-specific antigen(s) are not essential for cell survival, cancer resistance to immunotherapy by antigen shedding or downregulation of its synthesis will evolve during the treatment. To shed or not express a particular antigen is mechanistically simpler and thus more likely to occur compared with mechanisms that generate...

Although instructive and supportive of the field, Ira Mellman?s article in the January issue1 follows an unfortunate tendency to selectively recognize certain academic studies, while simultaneously omitting sponsored research. The 2004 review article by Steven Rosenberg 2 is cited often, as it is by Mellman, as evidence that therapeutic cancer vaccines have been largely unsuccessful in clinical trials. A fundamental omission of Rosenberg?s article, however, is the mention of several successful clinical studies from numerous companies and universities, such as UCLA and Cedars-Sinai, in glioblastoma multiforme.

Numerous late-state trials are currently underway or planned (from Northwest Biotherapeutics, Dendreon, Therion, Biovax, Antigenics, Cell Genesys, among others) ? trials that would not have moved past pilot studies if potential efficacy had not been shown. Had such studies been included in Rosenberg?s review, the objective clinical response rate would have been much higher. As a former cancer vaccine developer both at NIH and in biotech, I?ve noticed that there is too often a bias in the academic world that nothing much can be learned from research coming out of commercial entities.

Mellman also mentions the promise of dendritic cell-based strategies, yet mistakenly states that commercial attempts have taken ?little care to characterize the population of cells.? In reality, companies using cell-based vaccines must strictly characterize the cell-surface and functional characteristics of their cells. This is critical in order to obtain FDA clearance, in which the ?active component? of the treatment must be identified. It is also critical in order to obtain the intellectual property that forms the protective core of a company?s technology. That some companies were able to avoid or reverse being put on FDA clinical hold by better characterizing their vaccine also provides evidence that such companies are not merely administering some murky cocktail of ingredients.

There?s much progress to be made, but it paints a pessimistic and partially inaccurate picture to omit those studies that have already moved into promising human trials.

Michael L. SalgallerToucan Capital Corp.Bethesda, Md.msalgaller@toucancapital.com

Ira Mellman responds:It is comforting that Dr. Darzynkiewicz feels that I have painted too ?rosy? a picture while Dr. Salgaller feels that I have been unfairly glum. I guess I struck the right balance.

Dr. Darzynkiewicz is correct that there are challenges to successful immunotherapy that I did not have space to mention. One of these is the prospect of antigenic heterogeneity or MHC down regulation among tumor cells, even in a single patient. However, I am unaware of any data to support his certainty that such heterogeneity negates a priori the potential utility of immune based therapies. Indeed, the immune system and therapeutic strategies can be mobilized to cope with such problems, should they manifest themselves, and should we learn to develop optimized approaches to eliciting anti-cancer immunity.

Dr. Darzynkiewicz is of course correct that cancer cells do exhibit important alterations in signaling and growth control mechanisms. However, for the majority of cancers, targeting this feature alone has not yet proved very successful either. We need more basic research in all relevant areas, not to cut one in favor of another, as at present, we simply do not know which ? or which combination ? will be most effective.

There is indeed much important work in the area of immunotherapy conducted in the biotech and pharmaceutical sector, as Dr. Salgaller points out. As a founder of two biotech companies, however, I am well aware that the realities of financing and responsibilities to investors or shareholders prevent most commercial ventures from taking the type of systematic, reductionist scientific approach that is needed to learn even from failure. More likely, failure in a trial leads to termination of a project, or sometimes the company. Moreover, many have not been willing or able to devote sufficient funds to collect all potentially useful data when running their trials. To claim otherwise, especially given the examples Dr. Salgaller noted, is simply incorrect. Having said that, I view commercial and academic efforts as complimentary. I only wish that they could be more closely coordinated. Companies have the resources to develop new agents that academics may never have. Why not make these more readily available to the scientific community for unrestricted study, even at an early stage? I well understand that there are legal, institutional, and financial barriers, but these are all problems of our own making, not problems of science. We should render unto Caesar that which is Caesar?s, and do it bidirectionally.

The science of a banned pesticide

Alison McCook gives a balanced account of the economic and political aspects of the ongoing debate on how fast to phase out the use of methyl bromide as a fumigant.3 She mentions the vast sums being spent to develop substitutes, none of which work as well or are as economic as methyl bromide. What is left out of her discussion is the science.

Consider these basic facts:

? About two-thirds of the methyl bromide entering the atmosphere is of natural origin, mainly from the oceans.

? The atmospheric lifetime of methyl bromide is only a few months. This has two important consequences: First, most of it is destroyed before it can reach the stratosphere, where it can attack the ozone layer. This is especially true for human-produced methyl bromide, which first has to travel from mid-latitudes to the equator before being transported into the stratosphere. Second, if ever a problem is found, production can be turned off and anthropogenic methyl bromide would disappear from the atmosphere within a year or two.

By contrast, chlorofluorocarbons have lifetimes of decades or a century.

? New data from ice cores show that atmospheric methyl bromide started to increase more than a century ago, long before it was manufactured and used commercially. Other measurements show that rice paddies in Asia are a source of the chemical, suggesting that rice cultivation to feed a growing population could be an important human-related source.

? Finally, I know of no measurements that show a gradual increase of bromine in the stratosphere. This would indicate that the human component is still insignificant.

? Taken together, this suggests that opposition to the use of methyl bromide as a fumigant is based on ideology and not on science.

S. Fred SingerScience & Environmental Policy Project Arlington, Va. singer@sepp.org

I?m surprised that in your article on methyl bromide,3 you made no mention of methyl iodide. It is a drop-in replacement for methyl bromide that my colleagues from the University of California, Riverside, and I have patented and have published on extensively. Methyl iodide is being developed by Arista as a product called Midas. It is currently nearing EPA registration. Methyl iodide is no threat to the atmosphere since it is quickly destroyed by sunlight.?

Jim Sims University of California, Riverside james.sims@ucr.edu


1. I. Mellman, ?Where next for cancer immunotherapy?? The Scientist, 20(1):47?53, January 2006. 2. S.A. Rosenberg et al., ?Cancer immunotherapy: moving beyond current vaccines,? Nat Med, 10:909?15, 2004.? 3. A. McCook, ?The banned pesticide in our soil,? The Scientist, 20(1):40?5, January 2006.

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