When Lisa Butterfield, PhD, began her clinical research at the University of Pittsburgh in Pennsylvania in 2003, a senior colleague asked her what she did. “I said, ‘I'm interested in cancer vaccines and immunotherapy,' and he said, ‘Oh, you're one of those voodoo people,'” she recalls. No one says that anymore. The field of cancer immunotherapy, which explores how a patient's own immune system can be coaxed into fighting tumors, is suddenly booming. The pharmaceutical industry is investing heavily in a broad range of strategies amid a surge in optimism, energy, and encouraging results. “I don't know of a large pharmaceutical company now that doesn't have an interest in this area, or isn't trying to get into it,” says Howard Kaufman, MD, professor of surgery and immunology and director of the Rush University Cancer Center in Chicago, Illinois. “I think it's very promising.” Immunotherapy advances are fueling excitement among cancer researchers. Many tumors are inherently resistant to the body's immune response. Because they develop from our own cells, they usually do not contain anything that the immune system would recognize as foreign and thus view as a potential threat. Researchers believe that other cancers can dodge our defenses by exploiting regulatory pathways that the immune system normally uses to prevent overactivity and autoimmunity. However, at many conferences, researchers are unveiling multiple strategies to keep the immune system active, identifying and targeting cancers as threats, and then eliminating them. “It is so refreshing to be able to sit and listen to talks where the punch line of the talk is no longer limited to, ‘And my therapy was safe and well-tolerated by the patients,'” Dr. Butterfield says. A professor of medicine, surgery, and immunology, she directs the University of Pittsburgh Cancer Institute's Immunologic Monitoring and Cellular Products Laboratory. “What you hear now is, ‘This is the high percentage of overall clinical responses of people's tumors melting away, and these are the breadth of tumor types that responded, and the duration of years of patients surviving,'” she says. So far, a therapeutic intervention that relies on T-cell checkpoint inhibitors or blockades has captured much of the early excitement. When responding to infections, the immune system normally tamps down its own activity after it has cleared a pathogen. This response, prompted by inhibitory signals, can be mediated by suppressor cells and by surface molecules on T cells themselves. “We try to release those blockades, get rid of the suppressor cells, remove these checkpoints where the T cells tell themselves, ‘I've been active for a while, I should turn myself off,'” Dr. Butterfield says. In 2011, the US Food and Drug Administration (FDA) approved a monoclonal antibody called ipilimumab for the treatment of metastatic melanoma. One of the first immunotherapy drugs on the market, ipilimumab allows T cells to remain active by blocking an inhibitory signal emitted by a surface protein called cytotoxic Tlymphocyte antigen 4 (CTLA-4). Although the drug's overall response rate of approximately 11% is relatively modest, Dr. Kaufman says the response in many patients has been surprisingly durable.1 “That's where a lot of the initial enthusiasm came from,” he says. The success comes with a caveat, however. By ramping up T-cell activity, checkpoint inhibitors can cause autoimmunebased side effects. As the therapies move forward in clinical trials, researchers concede that a major challenge will be boosting an anti tumor T-cell response while minimizing autoimmunity. As a next-generation strategy, researchers are designing monoclonal antibodies that bind to proteins in a similar signaling pathway named programmed death 1 (PD-1). Whereas the PD- 1 protein appears on the outer surface of T cells, a binding partner called programmed death ligand 1 (PDL-1) studs the surface of tumor cells. When the T cells arrive at the tumor site, crosstalk between the 2 proteins instructs the T cells to shut down. More than 6 companies are now developing antibodies against either PD-1 or PDL-1 to block these T-cell inactivating signals. In phase 1 clinical trials, the best response rate has been closer to approximately 30%, with less toxicity than ipilimumab.2 “So there's enormous interest,” says Dr. Kaufman. Phase 3 studies are already underway, he says. Most recently, a phase 1 study combining CTLA-4 and PD-1 antibodies found a response rate of more than 50% in patients treated at the highest doses of both drugs.3 “It was really quite dramatic,” he says. Multiple experts are citing the development of chimeric antigen receptors (CARs) as another major advance in the field. Led by Carl June, MD, at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, the strategy relies on 2 engineering elements. On 1 end of each CAR molecule, researchers fuse an antibody that binds to a specific tumor antigen. The other end attaches to and activates T cells, instructing them to kill whatever is stuck to the antibody. In interviews, Dr. June has explained that the engineered CARs turn killer T cells into “serial killers” that can bind to a tumor cell, kill it, disengage, and then successively hunt down and destroy others, thereby eating away a cancer. Based on promising trials in patients with leukemia, Dr. June and his colleagues are now exploring the same strategy in patients with pancreatic cancer. “I think it's going to be a very powerful tool,” Dr. Kaufman says. The immunotherapy field has likewise seen a flurry of developments in cancer vaccines. The FDA approved the first cancer vaccine, sipuleucel-T, in 2010 for the treatment of prostate cancer. The vaccine boosts the antitumor activity of the immune system's dendritic cells. Since then, multiple research groups have constructed cancer vaccines based on cells, peptides, proteins, and even oncolytic virus agents, or ones that can deliver immune stimulants while damaging tumor cells. Leisha Ann Emens, MD, PhD, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, favors the cellbased approach and its potential to induce a broad immune response against multiple targets. She and her colleagues are developing a vaccine based on tumor cells that have been engineered to secrete a molecule called granulocyte-macrophage– colony-stimulating factor (GM-CSF). The factor acts like a beacon for dendritic cells, drawing them to the tumor and allowing them to sense the cancer's full array of tumor-specific antigens. Once the threat has been identified, the dendritic cells can call upon the armada of cancer-killing T cells and show them the antigens, directing them to attack wherever those foreign proteins appear. Dr. Emens is testing the strategy in patients with breast cancer; her colleagues are trying out the same method in individuals with pancreatic cancer, prostate cancer, and melanoma. Dr. Kaufman and his colleagues are instead using a herpes virus that encodes GM-CSF. By design, the oncolytic virus cannot replicate in nontumor cells. However, it kills melanoma cells when injected directly into melanoma lesions. The GM-CSF molecule then draws in dendritic cells and spurs a broader immune response. Dr. Butterfield has opted for a personalized vaccine based on dendritic cells isolated from melanoma patients. She and her colleagues culture each patient's cells, load them with tumor antigens, and then inject them back into the patient. She describes the strategy as a “souped-up” way to turn on the killer T cells and activate multiple waves of a melanoma tumor-specific immune response. Although her own vaccine is still early in its development, Dr. Butterfield says data from other vaccine trials, including ones for prostate and colon cancer, have generated promising results. Adding to the excitement in the field, emerging data have suggested that combining 2 agents, such as vaccines and immune checkpoint inhibitors, might yield a synergistic effect in which the sum is greater than the parts. “We really think combination therapy is going to be where it's at,” Dr. Emens says. She compares vaccines to stepping on the accelerator to ramp up the immune response, whereas drugs that interfere with checkpoint blockades or inhibitors are akin to taking your foot off the brake. “I think there's a lot of optimism,” she says. “Everyone's very excited. We're starting to see clear evidence of durable responses in patients now. And we worked very hard to delineate the pathways by which the immune response is regulated at the cellular and molecular level.” With the growing body of molecular and cellular knowledge, Dr. Emens and other researchers say they can start to take more precisely targeted and personalized approaches to induce effective antitumor immunity. “I think this is the beginning of being able to really understand classes of tumors and individual tumors much better so that we can do the right thing,” Dr. Butterfield says.