More than a century ago, the American surgeon William Coley noticed a correlation between cancer remissions and postoperative infections: some patients who had battled an infection also experienced a regression of their cancer. Because of these observations, Coley hypothesized that a patient’s immune response to a bacterial infection could be leveraged to treat cancer. To test his hypothesis, Coley injected live bacteria into an inoperable tumor of one of his patients. The patient’s tumor regressed, and Coley went on to experiment with direct injections of live, and later heat-killed, bacteria into more than a thousand patients over the next 40-plus years. Coley’s toxins never achieved widespread clinical success due to concerns over reproducibility, although a strain of mycobacterium, bacillus Calmette–Guerin, is still routinely administered to treat early-stage bladder cancers.
Also more than a century ago, Nobel laureate Paul Ehrlich proposed his immune surveillance hypothesis, which states that the immune system can recognize and suppress tumor growth. Ehrlich’s idea, which was controversial at the time, led many scientists to dream about using the immune system as a therapeutic agent. Thus, the framework for cancer immunotherapy was established long before radiation and chemotherapy became mainstay cancer treatments.
Unfortunately, the decades following Coley’s and Ehrlich’s initial hypotheses were not kind to cancer immunotherapy. There were numerous false starts, failed trials, and controversies. Critics of the immune surveillance hypothesis presented data that damaged but could not extinguish the field. A relatively small fraction of cancer researchers, committed to the idea of engaging the immune system to treat cancer, continued to toil away. In the late 1970s and 1980s, many new immune-stimulating proteins called cytokines were discovered. A couple of these cytokines, interleukin-2 and interferon-alpha, were later approved for a limited number of advanced cancers.
The 1990s and 2000s brought numerous discoveries in basic immunology that greatly improved our understanding of cancer–immune interactions. During this time, there was also a keen focus on the development of therapeutic cancer vaccines capable of training the immune system to recognize and destroy cells harboring tumor-associated antigens. However, although cancer vaccines were generally proven to be safe, clinical anticancer efficacies did not match what was observed preclinically.
The Long-Awaited Arrival of Cancer Immunotherapy
Finally, in 2010, the first therapeutic cancer vaccine (Provenge) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic prostate cancer. Although expensive (around US$100,000) for what it achieves (an approximately four-month increase in median survival), Provenge was a watershed approval because it proved that the immune system could be specifically trained to treat cancer. It also didn’t hurt that Provenge’s price tag signaled to pharmaceutical companies that effective cancer immunotherapies were worth a premium. This likely encouraged big pharma to invest heavily in immune-oncology pipelines. Whatever the reason, 2010 was an inflection point, as at least 30 other cancer immunotherapies have since been approved in the United States.
Thus far, most of the FDA-approved cancer immunotherapies belong to a category called immune checkpoint inhibitors. These inhibitors are antibody-based molecules that block an immune cell’s “off switch,” allowing it to remain in an activated state. These agents have the potential to induce miraculous results leading to complete remissions in some metastatic cancer patients. However, the majority of patients do not benefit from these new immunotherapies. Clinical response rates in most published studies fall within the range of 15–40%.
Interest in improving clinical outcomes has led to unprecedented increases in preclinical and clinical activities. There are now over 2,000 immuno-oncology agents in development, more than 940 of which have reached clinical testing . There are also more than 3,000 open or ongoing clinical trials, with planned enrollments approaching 600,000 patients . The global immune-oncology market is expected to reach US$100 billion per year by 2022 .
What’s All the Hype About?
As one can see from these staggering numbers, biopharmaceutical companies are betting big on immune-oncology development. As with most experimental therapies, there are bound to be great successes as well as spectacular failures. But one thing is clear: cancer immunotherapy is well on its way to becoming a mainstay treatment for cancer. This is due not to investments or media hype but rather to the scientific basis of immunotherapy and its mechanisms of action.
Unlike surgery, chemotherapy, or radiotherapy, cancer immunotherapies can train a patient’s immune system to find and eliminate cancer cells. While a large primary tumor would be an obvious target for immunotherapy, primary tumors are usually sufficiently controlled by surgery, radiation, or other ablative techniques. However, residual or hidden tumor cells that have been shed from primary solid tumors or are left behind after traditional chemotherapy are the real challenge, as they can lead to progressive recurrences and metastases. Ultimately, metastases are responsible for nine out of ten cancer deaths, even though most patients are diagnosed with localized disease.
Most of the clinical successes achieved by cancer immunotherapies to date have taken place against metastatic cancers, as new experimental treatments are typically evaluated first in advanced cancer patients. However, as immunotherapies continue to develop a safe and effective clinical history, it is only a matter of time before they are approved either as an adjuvant or as a stand-alone therapy in early-stage cancer patients. In fact, given that advanced cancer patients typically have weakened immune systems, these new cancer immunotherapies are expected to be more effective in early-stage patients, who are not immune suppressed. And, if cancer immunotherapies in nonmetastatic patients fulfill their promise of preventing or reducing lethal metastases, cancer mortality will drop dramatically.
Opportunities for Engineering and Technology
With more than 3,000 open or ongoing immuno-oncology trials, it would seem that the field is saturated or, at the very least, that everything about cancer immunotherapy will be known once these trials are completed. However, the rapid push for clinical studies has been criticized for leading to many overlapping and/or seemingly redundant research. In fact, some regard this bolus of clinical studies as an attempt by competing pharmaceutical companies to grab as much “territory” or as many approvals as quickly as possible—a “low-hanging fruit” period of cancer immunotherapy.
There is no doubt that a wider range of cancer patients will gain access to immunotherapies over the next few years. However, there will still be significant room for improving immunotherapy to achieve higher overall response rates. Those in the engineering and technology fields, in particular, have considerable opportunities, some of which are described here, to maximize the efficacy and/or efficiency of cancer immunotherapy while quickly determining which patient populations will benefit from immunotherapy.
- Big data/bioinformatics: Regardless of whether clinical trial enrollment targets will be met, there will be massive amounts of data generated from hundreds of therapy combinations in thousands of trials involving hundreds of thousands of patients and millions of clinical samples. These data need to be analyzed to understand which patient populations will benefit, which biomarkers or combinations of biomarkers are prognostic indicators, and which combinations of therapies are most successful. In addition, the rapidly decreasing cost of DNA sequencing has made feasible the routine sequencing of tumors. Thus, new computational and statistical analysis techniques will be needed to robustly interpret the impending avalanche of noisy genomic data. Of particular interest is the identification of patient-specific mutations that can be used to predict immune responses or form the basis of novel personalized immunotherapies.
- Delivery systems: Over the last four decades, many billions of dollars have been spent developing platforms to deliver cytotoxic agents to cancer cells but not healthy cells. The development of hydrogels, polymer scaffolds, microparticles, and nanoparticles, both targeted and untargeted, has been widely published. Many of these same platforms have been adapted to cancer immunotherapeutics. However, large, fragile proteinaceous (and sometimes cellular) cancer immunotherapies are not the same as small, organic chemotherapeutics. New platforms that account for differences in size and lability are needed. Also, most clinical-stage immunotherapies are currently administered intravenously, similar to traditional chemotherapies. However, systemic delivery can lead to unintentional activation of immune cells that attack healthy tissues, resulting in autoimmune side effects. Novel delivery systems capable of controlling exposure and the spatiotemporal distributions of cancer immunotherapies are also needed.
- Biomanufacturing: Cancer immunotherapies and monoclonal antibody-based cancer drugs are significantly costlier to manufacture than small-molecule cancer drugs. While there have been significant advances in bio-manufacturing over the last decade to drive down the manufacturing costs of monoclonal antibodies, there remains significant demand for new technical advances in genetic engineering, including CRISPR-based editing, protein expression, and purification technologies. Another significant opportunity is the development of highly characterized, closed-loop processes for the cost-effective and reproducible manufacture of whole cell-based therapies, such as stem cell or adoptive T cell therapies.
- Imaging: The efficacy of traditional solid cancer treatments is assessed by quantifying tumor shrinkage via radiographic imaging. Unfortunately, standard tumor volume measurements are not appropriate for many cancer immunotherapies, as immune infiltration does not always cause immediate tumor shrinkage. Additional imaging modalities are needed to quantitatively assess immune responses in the tumor microenvironment. For instance, an approach capable of quantifying the activities or numbers of immune cells infiltrating a tumor would be useful for sorting responders and nonresponders to a particular immunotherapy at earlier stages.
Looking to the Future
Cancer immunotherapy has come a long way since the days of Coley and Ehrlich. And, while the last decade witnessed an explosion of research, FDA approvals, funding, “moonshots,” and so forth, there is still a long way to go before the promise of immunotherapy is fully realized. Yet, by the end of the next decade, about half of all cancer patients are expected to receive an immune-based therapy.
Biomedical engineers will play a major role in improving the effectiveness of these therapies by creating novel bioinformatics algorithms, developing better delivery systems for immunotherapeutic agents, streamlining complex biomanufacturing processes, and designing innovative cancer imaging modalities. In the following decades, when some form of immunotherapy is the standard of care for all cancer patients, our grandkids or great-grandkids will wonder why we ever exposed ourselves to disfiguring barbaric surgeries, cytotoxic poisons, or the burns of high-energy radiation.
- J. Tang, A. Shalabi, and V. M. Hubbard-Lucey, “Comprehensive analysis of the clinical immuno-oncology landscape,” Ann. Oncol., vol. 29, no. 1, pp. 84–91, 2018 . doi: 10.1093/annonc/mdx755.
- Hexa Research. (2016). Immuno-oncology market, by type [mAb (naked, conjugate), cancer vaccines, immune checkpoint inhibitors (PD-1, PD-L1, CTLA-4]), by application (lung, melanoma, leukemia, lymphoma): Global forecast to 2022. [Online].