Immunotherapies are beginning to revolutionize clinical care and to revolutionize the way we think about cancer therapy — that it can and should be curative. However, current approaches do not provide all patients with the long-lasting, safe, accessible cures that are needed. There is so much more to be done.
I am encouraged by the pace of discovery at Fred Hutchinson Cancer Research Center, where I serve as president and director, and at other major cancer centers in the U.S. As we fine-tune current immunotherapies, which harness the immune system to kill cancer, we are progressing toward the kind of success I know is possible. That is why it is not too soon to talk about a next generation of immunotherapies and how, with a concerted effort, we can bring them into being.
Expanded reach: curative approaches for all cancers
First, the next generation will have to treat more types of cancer. It has been one year since the FDA approved the first of two “living drug” chimeric antigen receptor T cell (CAR T-cell) therapies for patients with certain blood cancers; more are in the pipeline. Yet blood cancers account for only 10 percent of cancers in the U.S. To reach the other 90 percent of patients, including those with breast, colon, lung and pancreas cancers, to name a few, advances are needed to pry into harder-to-treat solid tumors.
It is also important to note that immunotherapies include a very exciting class of drugs known as checkpoint inhibitors. They disable a tumor’s capacity to avoid demolition by tricking the immune system into putting on its brakes. Checkpoint inhibitors release those brakes and have been remarkably effective. They appear to offer curative potential, but they do not benefit all patients with cancer. We must clarify why these drugs work for some individuals but not for others.
This effort to understand who responds to treatment will also require leverage of technology capabilities and “big data” to sort out why different people respond differently to immunotherapies. With these technological advances, we in Seattle have the capability to develop new platforms for diagnosis and patient-specific treatment of cancer, with the goal of curative therapies for all.
Potent and precise
Second, to improve the potency of next-gen therapies, they will have to be more precisely targeted to the cancer and tailored to the individual patient. One approach is to pair current checkpoint inhibitors with conventional chemotherapy, radiotherapy, other checkpoint drugs or engineered T cells. More than 1,000 clinical trials are underway to explore these options for both blood cancers and solid tumors. Results so far are mixed, but developing the right treatment combinations offers the possibility of helping significantly more patients.
It will take ingenuity and persistence to overcome the barriers that solid tumors put up against the immune system. We need a better understanding of the complex microenvironment that surrounds and shields these tumors from immune attack. We also need to identify, and then overcome, the ways in which these cancers become resistant to immune-based treatments that initially work.
This summer, we learned from National Cancer Institute researchers that a combination of T-cell therapy, a checkpoint blocker and an immune stimulator caused remission — going on two years — in a woman with metastatic breast cancer. This unheard-of response is a sign that researchers may be onto something — certainly something worth pursuing further. But we must also be mindful that while one patient’s good result provides hope, it will take large clinical trials to be certain this same path will work for others.
We still need to understand more of the basic biology involved in today’s immunotherapies so we can dial in their effects. For example, the genetically engineered CARs in CAR T cells include many different molecular components. As shown in a recent study by my colleagues at Fred Hutch, we now understand in greater detail how these different parts work to trigger these cancer-killing cells. With continued research along these lines, I expect that we will be able to design highly precise next-gen CAR T cells that can take down a specific cancer with minimal side effects.
Third, next-gen immunotherapies must be safer. As researchers gain a greater understanding of side effects of the first wave of cell therapies, such as high fevers and neurotoxicity, we are also gaining the capacity to manage them better and to engineer features that reduce or prevent these worrisome reactions. At the Hutch, working with our collaborators, we have identified strategies for minimizing toxicities while preserving the effectiveness of treatment through the use of selected subsets of genetically re-engineered CAR T cells.
Fourth, if our progress is to be meaningful, we must make certain that these new therapies are affordable. In March, the President’s Cancer Panel called for urgent action to address the burden of “financial toxicity” for families due to the high cost of cancer care. I believe there is a compelling case for increasing access through value-based pricing, in which the cost of cancer care is tied to the benefits such as quality of life and survival time. Access should not be denied to those who cannot afford these treatments. If we cannot assure access to effective immunotherapies, then we will have failed.
I would suggest that the Centers for Medicare & Medicaid Services and other federal agencies that determine reimbursement consider the value proposition for patients and the argument for cost-effectiveness. While these are expensive treatments, they are potentially curative — with a single dose of medicine — and offer the only hope for patients with end-stage disease. This is a complicated issue, but there can be no debate over the value of a medicine with curative potential for patients for whom there are no other treatment options.
Fifth, next-gen immunotherapies need to be made more widely available. Researchers at the Hutch and our clinical care partner, Seattle Cancer Care Alliance, are working toward protocols to make CAR T-cell therapies safe enough to be administered in outpatient clinics rather than in a hospital. This will not only lower costs, it could make these cell therapies more widely accessible to patients who live far from academic medical centers.
Sixth, next-gen immunotherapies must be scalable. To that end, researchers are developing technologies to automate as much as possible the time-consuming and labor-intensive processes of reprogramming T cells. At Fred Hutch, some of our scientists are looking even further ahead, developing nanoparticles capable of reprogramming T cells inside the body, potentially sidestepping the complex steps required to modify and grow a patient’s blood cells in in the lab and then return them to treat the cancer.
This is a formidable list. The bar is set very high. Yet we have already seen seemingly incurable cancers melt away in some patients, and so we ask: Why not all? The impact we could have on world health is stunning.
The current generation of immunotherapies is the product of decades of discovery and hard-won lessons in understanding the complexities of the human immune system. Aided by the tools of modern biotechnology, genomics and data science, next-gen immunotherapies will be at hand in a fraction of that time. The path ahead is daunting, but I believe the goal is attainable with sufficient resources, willpower and a cancer research community fired up by a shared sense of urgency.
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