In November 2010, the Pulitzer Prize-winning The Emperor of All Maladies, which chronicles the history of cancer, was published without a single mention of immunotherapy. By the end of the decade, however, the impact of these novel immune-based treatments would be impossible to ignore.
As of 2019, immunotherapy has permanently changed the cancer treatment landscape, resulting in FDA approvals for more than a dozen types of cancers, thousands of lives saved, and even a Nobel Prize. When it comes to cancer, it’s hard to deny that this was the decade of immunotherapy.
Therefore, as the 2010s draw to a close, we’ve picked one highlight from each year of the decade to capture immunotherapy’s journey into the medical mainstream and how it’s helped bring us closer to realizing the Cancer Research Institute’s vision of A Future Immune to Cancer™.
2010: The first therapeutic cancer vaccine is approved by the FDA.
In 2010, the FDA approved the first cancer vaccine—sipuleucel-T (Provenge®)—for the treatment of advanced prostate cancer. This first-of-its-kind treatment takes a patient’s dendritic cells (a type of immune cell) and trains them to recognize a certain marker—PAP—that is commonly overexpressed by prostate cancer cells. These dendritic cells are re-infused into a patient, with the goal of stimulating an immune response against tumors. The development of this treatment was made possible, in part, by the groundbreaking research of CRI scientist Dr. Ralph Steinman, of The Rockefeller University, who discovered dendritic cells. With the help of CRI fellows Drs. Jonathan Austyn, Kang Liu, and Nina Bhardwaj, who is now a member of the CRI Scientific Advisory Council, Steinman also helped describe the role that dendritic cells play in immune responses, which paved the way for their use in this groundbreaking cancer vaccine.
2011: The first checkpoint inhibitor immunotherapy received FDA approval.
Before 2011, no treatment had ever been shown to improve the survival of patients with metastatic melanoma in a phase 3 trial. That changed with the arrival of ipilimumab (Yervoy®), a checkpoint inhibitor immunotherapy that blocks the CTLA-4 pathway in order to unleash cancer-targeting T cells against tumors. In 1995, CRI scientists Drs. Arlene Sharpe and Frank Borriello showed that CTLA-4 acts as a “brake” on T cells that can restrain immune responses. The following year, Dr. James Allison, now director of the CRI Scientific Advisory Council, showed that blocking CTLA-4 could lead to elimination of tumors in mice. Subsequently, Allison’s dogged determination led to the clinical development of ipilimumab, which in 2011 became the first FDA-approved checkpoint immunotherapy. This important breakthrough would launch checkpoint immunotherapy as the most promising development in cancer treatment since the first chemotherapies and would eventually earn Allison the 2018 Nobel Prize in Physiology or Medicine.
2012: First proof-of-principle that next generation sequencing can characterize tumor neoantigens is demonstrated.
Tumor cells can be distinguished from normal cells by the mutated proteins—known as neoantigens—that they express. These mutated proteins make cancer cells “stand out,” and thus could serve as targets that enable the immune system to recognize and attack tumors. However, because each patient’s cancer is unique—and expresses different mutated proteins—this time- and resource-consuming process of identifying neoantigens must be done individually for each patient. Fortunately, in 2012, Dr. Robert Schreiber, an associate director of the CRI Scientific Advisory Council who has received multiple CRI grants, and Dr. Matthew Vesely, then a CRI fellow in Schreiber’s lab at Washington University in St. Louis, showed for the first time that next generation sequencing could quickly and efficiently identify these mutated tumor proteins. This work paved the way for the development of personalized cancer vaccines that are now demonstrating promising results in the clinic.
2013: Demonstration of a superior vaccine strategy is made.
Cancer vaccines can help educate the immune system about what tumors “look like”—so the immune system can launch a response and eliminate them. But what is the best way to vaccinate? In work at Leiden University Medical Center, CRI grantees Drs. Sjoerd van der Burg and Cornelis J. M. Melief, who is also a member of the CRI Scientific Advisory Council, showed that, compared to vaccines composed of whole proteins, vaccines composed of synthetic long peptides were more efficiently taken up by dendritic cells and led to superior activation of killer T cells. These scientists would leverage this insight later in the development of vaccines that have shown promise in the treatment of human papilloma virus (HPV)-associated cancers, such as cervical cancer and head and neck cancer.
2014: The first PD-1-targeting immunotherapies are approved by the FDA.
After the important discoveries relating to CTLA-4-targeting checkpoint blockade immunotherapy, scientists searched for other immune checkpoints that might also be targeted to improve cancer treatment—and found a pretty good one in PD-1. In 2014, the first two PD-1-targeting drugs—pembrolizumab (Keytruda®) and nivolumab (Opdivo®)—were approved by the FDA for patients with advanced melanoma. Since then, these and other checkpoint immunotherapies that target the PD-1/PD-L1 pathway have been approved for more than 10 cancer types. These treatments were made possible by the work of several CRI-funded scientists, including Drs. Arlene Sharpe and Gordon Freeman of Harvard Medical School, Dr. Lieping Chen of the Mayo Clinic and later Yale University, and Drs. E. John Wherry and David Masopust, who were both CRI postdoctoral fellows in the Emory University lab of Dr. Rafi Ahmed. (Wherry is now also an associate director of the CRI Scientific Advisory Council.) Drs. Jedd Wolchok, an associate director of the CRI Scientific Advisory Council at Memorial Sloan Kettering Cancer Center, and Antoni Ribas, a member of the CRI Clinical Accelerator Leadership at the University of California, Los Angeles (UCLA)—both of whom have been funded by CRI—led some of the pivotal clinical trials resulting in the approval of these game-changing immunotherapies.
2015: FDA approved the first oncolytic virus therapy.
While some viruses are known to cause certain cancers, more recently scientists have developed the ability to engineer viruses to become tumor-targeting cancer killers. In 2015, this research culminated in the FDA approval of T-Vec (Imlygic®) for patients with melanoma. This treatment, known as an oncolytic virus therapy, involves a modified herpes virus designed to selectively infect cancer cells. Once inside, the virus replicates, causing the cancer cell to burst and spill its interior contents into the surrounding area. This then alerts the immune system, which can come in, determine what the cancer “looks like,” and eliminate any other remaining cells.
2016: Immunotherapy is named “Clinical Advance of the Year” by ASCO.
By 2016, immunotherapy had become firmly established—alongside surgery, radiation, and chemotherapy—as the fourth pillar of cancer treatment. To recognize the impact that immunotherapy was making in the clinic, the American Society of Clinical Oncology (ASCO) named immunotherapy the 2016 “Clinical Advance of the Year.” But immunotherapy was still just getting started—and these immune-based approaches would lead ASCO to name immunotherapy the “Clinical Advance of the Year” in 2017 and 2018, too.
2017: The first CAR T cell immunotherapies are approved by the FDA.
T cells are perhaps the most powerful immune cells in our body. It’s largely because of them that checkpoint inhibitor immunotherapies have been so successful against so many types of cancers. However, our normal T cells, as powerful as they are, have some limitations that can impede their cancer-fighting ability. This led scientists to develop synthetic T cells known as CAR T cells—named for the Chimeric Antigen Receptor with which they’re equipped and that enables them to target cancer cells. In 2017, the FDA approved the first two CAR T cell immunotherapies—axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®)—for patients with leukemia or lymphoma. Many of the scientific breakthroughs that led to the development of these “living drugs” were made by CRI scientists, including Drs. Mark Dudley and Michael Kalos, CRI fellows at the National Institutes of Health (NIH) and University of Pennsylvania, respectively, as well as Memorial Sloan Kettering Cancer Center’s Dr. Michel Sadelain, a member of the CRI Clinical Accelerator Leadership, and University of Pennsylvania’s Dr. Carl June, a CRI grantee and member of the CRI Scientific Advisory Council.
2018: Drs. James Allison and Tasuku Honjo are awarded the Nobel Prize in Physiology or Medicine.
On October 1, Dr. James Allison, the director of the CRI Scientific Advisory Council, and Dr. Tasuku Honjo, were named the recipients of the 2018 Nobel Prize in Physiology or Medicine. In addition to other important discoveries, Allison and Honjo were instrumental in the development of checkpoint immunotherapy—Allison initially propelled the field with his work on CTLA-4, whereas Honjo played a key role in advances relating to PD-1. Coming on the heels of ASCO naming immunotherapy the “Clinical Advance of the Year” for three consecutive years, the Nobel Prize being awarded to two tumor immunologists served as validation of the mission that CRI has pursued since its founding in 1953: to harness our immune system's power to control and potentially cure all types of cancer.
2019: Potentially promising breakthrough against pancreatic cancer is revealed.
Pancreatic cancer remains one of the hardest cancers to treat, in part because it’s not usually found until it’s already reached an advanced stage. While immunotherapy alone has not worked well in pancreatic cancer, preliminary results from a CRI-funded clinical trial revealed that combining immunotherapy and chemotherapy may be a promising approach against this deadly disease. In this trial, which is being led by the University of Pennsylvania’s Dr. Robert Vonderheide, patients received a combination of PD-1 checkpoint immunotherapy, chemotherapy, and a novel immunotherapy targeting the CD40 pathway. Of 24 patients evaluated at the time the data was unveiled, 20 had their tumors shrink.
2020 and Beyond: We expand immunotherapy’s benefits to more cancer patients.
Immunotherapy has come far in the last decade, thanks to the decades of research that came before and made today’s breakthroughs possible. More work, however, remains to be done, as there are still many patients who do not benefit from current immunotherapies. Fortunately, CRI scientists and others remain committed to carry out research aimed at harnessing the full power of the human immune system to fight cancer.
So what’s next for immunotherapy in 2020 and beyond? To find out, be sure to watch our January “Cancer Immunotherapy and You” webinar with CRI Scientific Advisory Council member Dr. Padmanee Sharma of the University of Texas MD Anderson Cancer Center, who will discuss the most exciting and promising advances today in treating different types of cancer with immunotherapy.