Chapter Eight
After the Gold Rush
The new cancer drugs with four-syllable names are now products sold during Super Bowl ads, and, remarkably, the new Jimmy Carter drug isn’t new anymore. But the surprise, excitement, and hope surrounding that first breakthrough in cancer immunotherapy triggered a flood of new interest and funding to the field, and a multiplier effect for the pace of scientific progress. The result is what biologist E. O. Wilson has referred to as a “consilience”—an intellectual synergy that comes when specialists from very different disciplines are able to examine a common topic and find a common language to share their ideas. It’s no longer an argument between cell biologists and immunologists and virologists and oncologists; it’s a conversation. For the first time we all glimpse the whole of the cancer-immunity cycle. The blind men and women examining the elephant have suddenly gained sight and can get to work.
The result is billions of dollars and scores of talented specialists now devoted to cancer immunotherapy. The funding torchbearers of the field such the Cancer Research Institute, started more than seventy years ago by William Coley’s daughter, have been joined by new organizational infrastructures to support that work, among them the Biden “moon shot” Cancer Initiative, to rethink medicine as a whole, and cancer most specifically; the Parker Institute for Cancer Immunotherapy to fund and coordinate researchers and clinical trials as never before; public appeal drives such as Stand Up to Cancer (SU2C), which directs hundreds of millions of donated dollars directly into research and clinical trials; and a gold rush for commercial pharmaceutical companies and startups and the dozens of biotech venture capitalists that fund them. Several researchers have quipped that there are now two types of drug companies: those that are deep into cancer immunotherapy, and those that want to be.
For everyone—the organizations, the individuals, and most especially the patients—the goal is to change what it means to have cancer and to render the disease a chronic condition, serious but manageable, like diabetes or high blood pressure. Or, just maybe, to cure it.
Cure isn’t a word thrown around lightly by oncologists, but now the top scientists in the cancer field are willing to bandy the word about aloud, publicly and often. In fact, they remind us, we already have cured cancer in a subset of patients. The work now is to enlarge that cohort. The classes of cancer immunotherapies described below are among the ones that might help accomplish that goal.
Checkpoint inhibitors may be the purest articulation of cancer immunotherapy, because they simply unleash the immune system. The first was the anti-CTLA-4 antibody ipilimumab, which won FDA approval for metastatic melanoma in 2011.1
That drug was an immediate game changer, reducing deaths from late-stage melanoma by 28 to 38 percent. The first phase 1 clinical trials started in 2001, long ago enough to qualify 20 to 25 percent of those patients with “long-term survival” benefit. That’s still less than half of the patients, but a great deal better than the low single-digit survivor percentages only the year before.
Anti-CTLA-4 drugs have some serious toxic side effects, but they set the stage for other immunotherapies, including more selective checkpoint inhibitors, such as the anti-PD-1 / PD-L1 drugs.
There are now at least half a dozen approved anti-PD-1 / PD-L1 drugs.2 Each blocks one or the other side of the handshake. Whether it matters which side of the handshake you block, only further trials will tell. The anti-PD-1 / PD-L1 drugs seem to work best if a patient’s tumor is expressing PD-L1. For that subset of patients, the drug has worked well, providing durable and sometimes complete responses.3
Both types of checkpoint inhibitors prevent cancer from turning down or off the immune response, but there are important differences between these drugs, having to do with when cancer uses the checkpoints they inhibit. CTLA-4 is a more general checkpoint; it happens earlier, preventing T cell activation, and when you block it, the response may be more general, too.4 Cancer uses the PD-1 / PD-L1 checkpoint later, after the T cell is activated. Blocking these checkpoints has a more specific response, like removing handcuffs only from specialized soldiers already on the battlefield and face-to-face with the enemy. As you might expect, the anti-PD checkpoint inhibitors are better tolerated and have far fewer toxic side effects than anti-CTLA-4, which is now understood to both up-regulate T cell activity and down-regulate the specialized regulatory T cells, or T regs, that keep the immune system from overreacting.
Both of these drugs—but especially the anti-PDs—are proving to be even more effective in combination with other therapies. As the data rolls in, it seems that most cancer therapies work better when coupled with a PD-1 / PD-L1 checkpoint inhibitor. That includes chemotherapy, which kicks off the immune battle with some dead tumors for the unleashed T cells to recognize and activate against. For example, over the course of one week in July 2018, data from phase III trials showed that a combination of an anti-PD-L1 drug and a chemotherapy agent showed meaningful improvements against both small-cell lung cancer and triple-negative breast cancer—the first advances against either disease in decades.
Cancer immunotherapies that previously failed are now being reevaluated to see if they work better with the brakes off (i.e., in combination with a checkpoint inhibitor). Most of those combinations are with anti-PD-1 / PD-L1 drugs. And future cancer therapies are now being planned with checkpoint inhibition in mind. The net result is that most drug companies with cancer therapies in their portfolio want a PD drug to pair it with. There are now reportedly 164 PD-1 / PD-L1 drugs in the pipeline between preclinical testing and consumer marketing, and industry insiders suspect there may be many more being developed in China. This redundancy isn’t the best use of intellectual or physical resources; one hopes it will result in more competition and lower prices.
(A question not addressed in this book is how anyone’s going to afford this bright shiny future. Pricing for Yervoy—the trade name for the anti-CTLA-4 drug ipilimumab—is typical, costing more than $120,000 for a four-course treatment. Merck’s anti-PD-1 drug Keytruda, for advanced melanoma, costs $150,000 for a yearlong treatment. Behind the good news is a pressing need for better answers about how we pay for the inevitability of illness and decline. Cancer is an equal opportunity disease; if progress against it isn’t for everyone, even a breakthrough becomes a step back for our humanity.)
When I ask immunology researchers what’s next, the answer is always “more”: more tools, more targets, more therapeutic agents. More drugs, more FDA approvals and fast tracks, more biomarkers to better describe cancer with molecular specificity (as opposed to classifying it by the organ the mutation started in, be it liver, lung, or breast), combined with more “immune profiling” of the specifics of a patient’s immune system (to determine who will receive the greatest benefit from exactly what type of immunotherapy).
Such personalized cancer immunotherapy, which pairs an individual’s unique immune profile and unique tumor genotype with the right immunotherapy combination, is presumed to be the future of cancer treatment.5
It’s not reasonable to guess at what will work next, but as of this writing the greatest demonstrated promise—the closest to a sure thing in terms of what’s been demonstrated in the clinic—seems to come from the expanding CAR-T therapies and CD3 bispecifics. Watch this space. It’s moving fast.
As of June 2018, there were reported to be some 940 new immuno-oncological drugs being tested for breakthrough designation and FDA approval. Another 1,064 new immunotherapy drugs are in the labs in preclinical phase.
That’s 2,004 new cancer drugs in just a few short years. This speed of change is highly unusual in medicine, and totally unprecedented in cancer. And by the time you read this, those numbers and the science behind them will have advanced again.
It’s worth noting that a study published in the Proceedings of the National Academy of Sciences of the United States of America found that every single one of the drug approvals since 2010—210 of them—can be traced back to the $100 billion NIH budget for drug development. The breakthrough is built on tax dollars, and it’s yours.