By: Eliot Eton
The statistics are alarming: in 2012, there were about 14 million new cases of cancer, and 8.2 million cancer-related deaths (1). Over the next twenty years, the number of new cases is likely to increase by over 70% (1). Approximately 42% of men and 38% of women are expected to develop cancer over the course of his or her lifetime (2). In 2016, 1.7 million individuals will be newly diagnosed with cancer, and 600,000 individuals will die from the disease (1). Immunotherapy, which augments the power of the immune system to directly attack and eliminate tumors, has reinvigorated the search for safe and effective cancer treatment.
Making Cancer a Priority
The first known description of cancer is found on papyrus, on which an Egyptian physician, four thousand years ago, classified all known diseases and their known treatments (3). Case number 45 characterizes breast cancer, yet the description of treatment is pithy: there is none (3). Not until 1948 did Sidney Farber, a pathologist at Harvard Medical School, working on a study on the effects of aminopterin on childhood acute lymphoblastic leukemia, prove that clinically-induced tumor remission was achievable (3).
This discovery revitalized cancer treatment research and would soon ignite international efforts to eradicate the disease. With pushing by Mary Lasker and the Lasker Foundation, President Richard Nixon passed the National Cancer Act of 1971, which officially propelled cancer research to a top national priority, creating, as Dr. Jerome Groopman said, “an entity based on a promise and that was the cure of cancer” (4). With greater understanding of the causes and mechanisms of tumor development, innovation has skyrocketed. Between 1949 and 1971, about 30 drugs were approved and entered treatment clinics; today, more than 300 drugs are being used, and there may be as many as 700 in the pipeline (5).
Fundamentals of Immunotherapy
The concept that the immune system is capable of suppressing tumor growth is not new. In 1891, William Coley injected live or inactivated bacteria in order to stimulate antibacterial immune cells to kill nearby tumor cells (6). In the early 1900s, immunologist and future Nobel-Prize-recipient Paul Ehrlich went a step further and proposed the “immune surveillance” hypothesis, which suggested that the immune system’s cells can both naturally identify and destroy emerging tumors (6). Not until 2001, however, was this much-debated theory universally accepted, when Drs. Robert Schreiber and Lloyd Old showed that mice that could not synthesize interferon-gamma, an important protein involved in immune signaling, were more likely to develop B-cell lymphomas (6). One can hypothesize that cancers exist because they have already eluded the host immune surveillance system. In the past few decades, the challenge was to find how this could occur and reverse it.
In the late 1980s, to understand immune system-cancer cell interaction, Jean-François Brunet et al. sought to characterize the surface of cytotoxic T-lymphocyte cells (CTLs), also known as killer T cells, which are the soldiers of the immune system. If the environment and signaling are appropriate, CTLs will lyse and destroy infected, cancerous, or damaged cells. CTLs were already known to require two signals for activation: according to the Cancer Research Institute, the first signal, coming from the T cell receptor, is like an “ignition switch,” priming the cells for action, while the second signal, from co-receptor CD28, is like a “gas pedal,” driving the attack (7). When analyzing the different co-receptors, Brunet et al. discovered a surface peptide, cytotoxic T cell antigen-4 (CTLA-4), that seemed to play a critical role in immune system response.
Debate soon arose regarding the function of CTLA-4. While it appeared remarkably similar to CD28 in sequence, work by Dr. James Allison et al. showed that CTLA-4 actually had an opposing effect: it acted as a brake on the immune system (7). CTLA-4 blocked the second signal, without which CTLs could neither produce the cytokine interleukin-2 to initiate cytotoxicity nor stimulate the proliferation of CTLs to attack the cancerous cell target. Allison hypothesized that releasing the immune system from this break could allow it to mount a robust attack against cancer (7).
Soon afterward, a small biotechnology company, Medarex, later purchased by Bristol-Meyers Squibb, began developing ipilimumab, a monoclonal antibody against CTLA-4, which effectively blocks CTLA-4.7 First tested in a large trial in metastatic melanoma, ipilimumab showed tremendous potential: while metastatic melanoma had a two-year survival rate of only 12%, investigators discovered that between 20-25% of patients were alive two-plus years after just four doses three weeks apart (8). Now a decade following the trial, patients with no disease progression at two years have yet to relapse: as Dr. Allison says, in some, “their cancers are not growing” and “in others, tumors just pop up and then go away” (4). For these individuals, cancer does not mean certain death, instead, Allison adds, it is “something of a chronic condition” (4).
Given all the heterogeneity in cancer, the challenge moving forward is determining how these particular individuals had such successful responses. Indeed, some patients, as expected, had severe side effects such as severe diarrhea, attributed to the unleashed immune response attacking other unrelated targets. Appropriate management of patients could reduce the risk of such serious toxicity. Indeed, ipilimumab was a successus: in a 2011 Nature Review, Ira Mellman et al. writes how ipilimumab “provides realistic hope for melanoma patients, particularly those with late stage disease who otherwise had little chance of survival” (9). Furthermore, they wrote how ipilimumab “provides clear clinical validation for cancer immunotherapy in general” (9).
In 2000, Dr. Gordon Freeman et al. at the Dana-Farber Cancer Institute were investigating T-cell surface proteins. They discovered a protein on the surface of normal cells called programmed cell death 1 ligand 1 (PD-L1). This protein interacted with a T cell co-receptor, PD-1, preventing the T cell from driving its attack.10 Normally, PD-1 and PD-L1 help protect healthy cells from destruction: only cells lacking these proteins – i.e. foreign cells – will be recognized and lysed, while others will be ignored.
Yet, in 2001, Freeman et al. discovered that PDL1 is not only found on normal cells but also on cancerous cells (11). The PD-1/PD-L1 interaction effectively encourages tolerance, as cancerous cells expressing these proteins will be protected from destruction: as Freeman says, “Cancer cells have essentially stolen the PD-1/PD-L1 mechanism from normal cells in order to evade attack by the immune system” (12).
Drugs targeting the PD-1 receptor on T cells, including nivolumab (Bristol-Myers Squib), are outperforming standard chemotherapy and inducing major responses, even more so than ipilimumab. In the most recent (2013-14) randomized phase III study for metastatic, untreated melanoma, using nivolumab alone (N-group) resulted in a ~44% objective response rate (including both partial and complete responses; ORR), using ipilimumab alone (I-group) resulted in a ~19% ORR, and using a combination of nivolumab and ipilimumab (NI-group) resulted in a remarkable ~58% ORR (14). Additionally, the median change from baseline size (given as the sum of the longest diameters of target tumors) was ~ -34.5% in the N-group, 5.9% in the I-group, and ~ -52% in the NI-group (11). Notably, while 80-90% of those in each group suffered treatment-related adverse events, only ~8% of those in the N-group, ~15% of those in the I-group, and 36% of those in the NI-group discontinued treatment because of these events (13).
Work is being done now to augment immune response that result in eradication of the melanoma in a greater proportion of patient and also in earlier stages of the disease. Yet, the level of efficacy seen in the trial above is not limited only to melanoma. Similar results for the anti-PD1 agents have been observed in some of the hardest-to-treat cancers, such as lung cancer, head and neck cancer, kidney cancer, gastric and esophageal cancers, and liver cancer.
Immunotherapy aims to override immune tolerance of “altered-self,” or cancer, and is yielding unprecedentedly durable response in cancers heretofore deemed incurable. Scientists are racing to target more checkpoints and their ligands and to test new combinations in order to fulfill the ultimate goal of harnessing our own natural defenses to eradicate even the stubborn cancers that have yet to respond to immunotherapy. These agents are rapidly moving up the priority lists in treating cancer and perhaps may cure more patients in earlier disease stages. Additionally, returning to William Coley and the origins of immunotherapy, trials are now being conducted on viral constructs, which the immune system loves to attack. These constructs could potentially augment the antigenicity of tumors and could thereby cause increased CTL migration to these metastases, where infusing checkpoint antibodies could then potentially mount an even more robust immune response against cancer. After decades of visionary thinking and of perseverance by scientists, there is now a bright future ahead in the field of cancer immunotherapy.
Elliot Eton ‘19 is a freshman in Apley Court.
 World Health Organization. Cancer: Fact Sheet N297. http://www.who.int/mediacentre/factsheets/fs297/en/ (accessed Feb. 28, 2016).
 American Cancer Society. Lifetime Risk of Developing or Dying from Cancer. http://www. cancer.org/cancer/cancerbasics/lifetime-probability-of-developing-or-dying-from-cancer (accessed Feb. 28, 2016).
 “Episode One: Magic Bullets.” Cancer: The Emperor of All Maladies, directed by Barak Goodman. http://www.pbs.org/show/story-cancer-emperor-all-maladies/ (accessed Jan. 13, 2016).
 Groopman, J. The T-Cell Army. The New Yorker, Apr. 23, 2012. http://www.newyorker.com/ magazine/2012/04/23/the-t-cell-army (accessed Feb. 28, 2016).
 Vanchieri, C. National Cancer Act: A Look Back and Forward. J. Natl. Cancer Inst, 2007, 5, 342-345.
 Cancer Research Institute. Timeline of Progress. http://www.cancerresearch.org/our-strategy-impact/timeline-of-progress/timeline-detail (accessed Mar. 3, 2016).
 CRI’s James Allison to Receive Prestigious Lasker Award. http://www.cancerresearch.org/ news-publications/our-blog/september-2015/ cri-james-allison-to-receive-prestigious-lasker-award (accessed Mar. 3, 2016).
 James Allison: The Texas T Cell Mechanic. http://www.cancerresearch.org/our-strategy-impact/people-behind-the-progress/scientists/james-allison (accessed Mar. 3, 2016).
 Mellman, I. et al. Nature, 2011, 480, 480-89.
 Freeman, G. et al. J Exp Med., 2000, 7, 1027- 34.
 Nature Immunol., 2001, 2, 261-68.
 Levy, R. Unleashing the Potential. Dana-Farber Cancer Inst. Paths of Progress, Spring/ Summer 2014. http://www.dana-farber.org/ Newsroom/Publications/Unleashing-the-Potential.aspx (accessed Mar. 3, 2016).
 Larkin, J. et al. NEJM, 2016, 373, 23-34.  Buchbinder, E., et al. Amer. J. Clin. Oncol, 2016, 1, 98-106.