Personalized Cancer Immunotherapy: Will Big Pharma Hold Us Hostage?
It’s only been about 50 years since biologists really started more fully appreciating the complexity of our immune systems, and one must admit that it’s pretty impressive how far and fast clinical cancer immunologists and oncologists have run with this knowledge. The field traces its earliest efforts to the observations of William Coley, a 19th-Century American surgeon who recorded his observations that after surgery to remove tumors, patients who contracted microorganismal infections showed improved outcomes, presumably owing to increased activation of their immune systems.
T Cells
For as long as we’ve known about T Lymphocytes (often simply referred to as “T Cells”), the question has been posed once, twice, repeatedly: shouldn’t our immune systems kill cancer cells, assuming that they’re abnormal enough. Over the subsequent decades, the answer has come up “yes . . . and no.” But we’ve recently reached the point at which there have been enough successes in urging the immune system to aspire to greater cancer defenses so that immunotherapy targeted not to any old cancer, but to your specific form of the disease is fast becoming reality, should you be unfortunate enough to find yourself in that condition. Following, I’ll summarize, very simply, three main approaches. Their range of successes raises the questions of what is likely to be their availability — and their cost per patient, raising the related question of who, if anyone (other than you), will pay.
A Biomedical Revolution or another Revolting Development in US HealthCare?
The advances in cancer immunotherapy have come in at least three general areas. Checkpoint blockade, T Cell modification & Mutanome Cancer Vaccines. Readers interested in more-detailed descriptions of these therapies are advised to consult the 23 March, 2018 issue of the journal Science, for reviews that point to many of the original research reports.
Checkpoint Blockade
This is the least-personalized therapy, and it remains to be seen whether or not it’s applicable for use in a diversity of cancers and patients.
It comes into play because of observations by researchers that cancer cells possess at least two methods for shutting down the responses of a patient’s own killer (Cytotoxic) T Cells (or CTLs), thereby stopping them from killing those cancer cells. Immunologic-oncologists called these “checkpoints,” that is, points at which the activities of these T cells can be checked (or checkmated). The strategy developed was to employ monoclonal antibodies (whose names always logically end in “mab,” for example “nivolumab,” and “pembrolizumab”) as checkpoint inhibitors. This involves the use of such monoclonal antibody molecules to recognize, bind to and block restraining molecular signals sent to the T Cells by cancer cells. Blocking the restraining (checking) signals allows T Cells to become activated (thus “checkpoint blockade”). With such restraining signals blocked by the monoclonal antibodies, the T cells are released from the checkpoints, leaving them free to attack and induce killing of those cancer cells that previously held them in check. This is analogous to rescuing and re-arming a prisoner-of-war soldier, thus creating a newly effective fighter. The strategy has proven quite effective in cancers like Hodgkins’ lymphoma and a subtype of melanoma, with some moderate successes in some cancers related to cigarette smoking. Importantly, most patients suffer only mild side-effects, an important issue because for patients taking more conventional anti-cancer drugs, side-effects can be debilitating.
One telling observation is that some of the cancers against which checkpoint blockade has had successes are avoidable; for example, melanoma (sun block/avoidance) and some lung cancers (cigarette smoking). Others have a more sinister origin in terms of some contribution from inherited predisposition.
T Cell Genetic Modification
A more-personalized and also more technically elaborate approach entails the collection (removal from the patient), genetic modification, and re-infusion of an individual patient’s T Cells to render them more able to recognize and kill their cancer cells. The most technically manipulative version of this approach goes by the name chimeric antigen receptor–T cell therapy (or ACT). Although there are several potentially serious side-effect concerns, the fact that long-lasting cures have been achieved in melanoma patients makes this approach quite attractive, as underlined by the fact that, worldwide, there were over 200 clinical trials either completed or in-progress as of the beginning of 2018. The high levels of biomedical manipulation leading to extreme costs (despite the relative ease of DNA sequencing and editing) is a potential prohibitive factor in this general approach, as are possible side-effects such as the undesired induction of T Cell attack and killing of normal cells.
Personalized Cancer Vaccines (Mutanome Vaccines)
The basis for this approach is the biological knowledge that cancer cells carry genetic mutations, frequently scads of them. In fact, patients with more severely mutated cancer cells may be the best candidates for this approach. This is understandable if one considers that the more mutated a cancer cell, the more molecular (particularly RNA and protein) differences it will show, compared to a normal body cell of the same type (for example, a cancerous melanoma cell compared with a normal skin pigment cell (melanocyte). In general, the approach is to harvest this array of mutant molecules (“the mutanome”) and create a potent multifaceted (terminology you may hear is “multiepitope”) vaccine to immunize the patient. The goal is to activate numerous immune defenses against the patient’s own cancer cells. Theoretically, the more mutant the cancer cell, the more susceptible it should be to being recognized and killed.
How Much: Who’s Going to Pay?
Estimates are that, in 1995, the cost of cancer drugs to promote an extra one-year patient survival was $54,000 (US). Currently, that figure has skyrocketed five-fold to about $250,000, with really no ceiling in sight. And given the current relatively sparse use of immunotherapies, that figure is weighted toward mostly conventional cancer-drug therapies. In other words, Americans are being held hostage by Big Pharma, no surprise to many of us.
More pertinent to this discussion: current costs for the aforementioned cancer immunotherapies run from an estimated $150,000 for checkpoint blockade to as much as $650,000 for genetic modification of your T Cells. Quoted in that 23 March issue of Science, Dr. Peter Bach, of the reknowned Memorial Sloan Kettering Cancer Center in New York City opines, with respect to cancer-therapy costs: “This is a chase after riches, and it doesn’t advance science.” Contrasting drug costs in the U.S. compared to other developed countries in Europe, Bach also expresses the concern that many of us have undoubtedly entertained, namely that we are rapidly moving toward the seemingly inevitable conclusion that health care will become a luxury item for the wealthy. To spotlight these issues, Bach and others at Sloan Kettering created a tool called DrugAbacus (https://drugpricinglab.org/tools/drug-abacus/).
One may ask how it comes to be that much of the science underlying the development of immunotherapies is publically funded by our tax dollars (often through NIH [National Institutes of Health]), while the beneficiaries currently appear to be rapacious drug companies and the ultra-rich.
If there is any focus to bring people together in opposing the inequalities in U.S. society, this would seem to be a particularly auspicious one because all of us beyond a certain age can picture ourselves — directly or through a loved one’s travails — in the position of needing medical intervention that we’re told will be unaffordable and/or not covered by insurance.
