August 2013, Vol 2, No 5

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Immunotherapy in Cancer Care: Personalized or Population-Based Medicine…and the Janusian Factor

Robert E. Henry

The Last Word

Is immunotherapy a type of personalized medicine (PM) or just useful population-based medicine? Look in different directions and you’ll get different answers, but whatever we do, let’s avoid oversimplification. For when we get down to specifics, the accurate answer is, “It depends.” When in doubt, it is often useful to consult cutting-edge researchers and, every now and then, the Classical tradition. I offer the findings of a study published in Nature, “Cancer Immunotherapy Comes of Age,” the evaluation of a leading prostate cancer expert concerning sipuleucel-T (Provenge), and finally, the perspective of Janus, that obscure Roman god who insisted on looking both ways. In the end, we wind up with answers to the practical clinical management of cancer and some much-needed clarification of what is meant by PM.

First we turn to the fact that immunotherapy is now capturing the imagination of the oncology world. The study in Nature by Mellman, Coukos, and Dranoff exults in “…the ability of the anti-CTLA4 antibody, ipilim­umab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.”

But wait…the authors may be ecstatic at the use of ipilimumab within the context of PM, but they do not describe it as PM itself. That makes it perhaps a semi-PM regimen component, at least for now. And the recent FDA approval of sipuleucel-T for advanced prostate cancer has raised hopes for these patients, but when I asked a leading expert in prostate cancer, he stated categorically that it is not PM: “It is given to everybody that fits a clinical profile, and one day we might choose it on the basis of a personal trait or tumor trait, but not yet.”

This brings us back to the realities of PM in oncology (and elsewhere): it is the preferred quality of a medication or procedure, but meanwhile we operate in a “split system” of population-based and PM. The former is a game of chance, the latter an enriched patient base where we know (to a certain degree) whether a particular patient is capable or incapable of responding to a drug or procedure. And the latter is the criterion for PM.

We might have expected this answer in the case of sipuleucel-T (though we shouldn’t expect anything either way!). The common thinking in vaccine therapy is mass administration in the hope of helping some of the recipients, without having any idea which are the best candidates and which should be ruled out a priori. The topic helps reinforce our awareness of what PM is and how today’s practicing oncologists are forced to structure treatment strategies: a mixed bag of personalized and population-based medicine.

While it may seem that because PM is a diffuse constellation of screening tactics ranging from hard science to soft personal patient considerations, all new therapies fall within its boundaries. But the truth of PM is that its broad scope does not make its boundaries sloppy. The core PM criterion is fiercely simple, in fact, as described in stark simplicity by the aforementioned prostate cancer expert. It is treatment chosen “on the basis of a personal trait or tumor trait.” This principle may be simple, but the determinants are anything but. The enriched patient base that takes the guesswork out of drug or procedure choice for an individual patient is dizzyingly deep; it simply has to meet this core condition.

So the vaccine administered solely on the basis of the disease’s stage of progression, the patient’s raw symptoms, or demographic niches, remains outside the pale of PM. Such a drug is being administered on population-based criteria: average response rates to the drug regimen for anyone with advanced prostate cancer. But the moment a biomarker or other qualifying predictor (eg, nomogram – quite popular in prostate cancer, which has a paucity of biomarkers) is proven to predict the likelihood of response/nonresponse, the regimen crosses over into PM. It is that simple.

So much for the attempt to oversimplify the dual issue of immunotherapy and PM, to equate all progress with PM, and demoting population-based medicine – immunotherapy or otherwise – as passé or antiquated. The advent of PM has been, and will remain, an iterative one, putting a Janusian face on cancer treatments. Yes, Janusian – I haven’t forgotten my promise to bring in the Classics. Janus was the ancient Roman god of beginnings and endings, doorways and transitions. This two-faced god looked to the future and the past, whence we derive the month January. Cancer treatment is a pragmatic business, looking desperately in multiple directions at once for any remedy – PM or non-PM – that will conquer the cancer destroying its human host. The sage oncologist is cognizant of the superiority of PM-advised regimens over conventional ones, just as today’s savvy shopper seeks organic produce over conventionally raised food. But where organic produce is unavailable, the shopper does not cease to eat. In both scenarios, medical and shopping, the real-world resources available require the perfect and imperfect to be used side by side to sustain life. In this pragmatically run race against time and cell replication run amuck, the clinical oncologist welcomes every assist that increases the chance to outrun the killer disease.

Thus, the answer to the question of whether immunotherapy is part of PM in cancer is not to be confused with whether immunotherapy is good or bad medicine. Immunotherapy is not inherently PM or non-PM; it can achieve PM status as readily as any other drug, providing it meets the aforementioned criterion of being targeted treatment. Where it remains outside the pale of PM, this should only spur researchers to find that qualifying “personal trait or tumor trait” needed to enhance its usefulness, its predictability.

When the ancient Romans devised the Janus myth, they were extolling the need to look ahead and behind for answers to vexing problems. That dynamic is alive and well in cancer care.

Robert E. Henry

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