Cancer immunotherapy— Science ’s 2013 breakthrough of the year—took off in 2014. Almost weekly, reports described patients on immunotherapies living longer than those taking combinations of chemotherapy and targeted drugs. One immunotherapy has reenergized the field. Ipilimumab (Yervoy), the first checkpoint inhibitor developed, approved in the U.S. in 2011, is the culmination of more than two decades of research. Ipilimumab is an antibody that inhibits cytotoxic T lymphocyte–associated protein 4 (CTLA-4), an immune checkpoint receptor found on T cells. CTLA-4 normally acts as a brake on the immune system’s ability to unleash T-cell attack on cancer cells. But ipilimumab releases the brake, allowing T cells to attack cancer. About 20% of patients with advanced melanoma who take the drug live 3 years or longer, whereas previously median survival was 7–8 months. However, ipilimumab works well only in one-fifth of patients. Scientists recently discovered the reason and, for the first time with any immunotherapy, could predict who will benefit. Jedd D. Wolchok, M.D., Ph.D., chief of the melanoma and immunotherapeutics service at Memorial Sloan–Kettering Cancer Center in New York, and team analyzed tumor samples from 64 patients treated with ipilimumab or a similar drug, tremelimumab ( N. Engl. J. Med. 2014;37:2189–99; doi:10.1056/NEJMoa1406498). The researchers discovered an association in many, but not all, patients, between mutational load and clinical benefit. “We then asked, What did the immune system ‘see’ to evoke a reaction in responders?” Wolchok said. A genetic signature in these patients caused tumors to express new antigens (neoepitopes) that T cells recognize and become more reactive to. The researchers then validated the signature in a second set of 39 melanoma patients treated with anti–CTLA-4 antibodies. The reactive antigens are similar to many viral and bacterial antigens to which the body normally reacts as well. “These data suggest that the neoepitopes in patients with strong clinical benefit from CTLA-4 blockade may resemble epitopes from pathogens that T cells are likely to recognize,” Wolchok said. “This is the first reliable way to predict which patients with melanoma will respond to ipilimumab, which will help guide upcoming trials and therapy design,” said coauthor Timothy A. Chan, M.D., Ph.D., vice chair of the radiation oncology department and director of the translational oncology division. The team is applying these techniques to study responses to other immunotherapies in trials, including PD-1 (programmed death protein 1) checkpoint blockers in melanoma and other cancers. “We are hoping to refine this into a test which will help inform medical decision making in the future, but this is a work in progress,” Wolchok said. He is considering several options to treat nonresponders, including combinations of immunotherapies, oncolytic viral therapies, targeted pathway inhibitors, and chemotherapy or radiation, he said. “Early results with checkpoint inhibitors offer both proofs of concept and some dramatic clinical results,” said Richard D. Klausner, M.D., chief medical officer and senior vice president of Illumina in San Diego. Many previous efforts to activate the immune system to fight cancer were less successful than recent trials with checkpoint blockers. “This is because it was thought that just turning on the T-cell receptor should be sufficient to produce a response,” said Padmanee Sharma, M.D., Ph.D., of the department of genitourinary medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston. “That did not pan out,” she said. But the discovery of CTLA-4 in the 1990s by James Allison, Ph.D., then at the University of California, Berkeley, now at M. D. Anderson, led to experiments to block this off-signal to increase antitumor immune responses and ultimately tumor rejection. That breakthrough led to ipilimumab and laid the basis for research on another T-cell–inhibitory pathway, PD-1. But broad patents on the CTLA-4 pathway, compared with those on the PD-1 and PD-L1 molecules, have limited efforts to develop other CTLA-4 inhibitors, Sharma said. Immunotherapy has several advantages over other treatments. Unlike chemotherapy and targeted therapies, immunotherapy is well suited to cancers with many mutations and may need to be given only once or a few times. Roy S. Herbst, M.D., Ph.D., chief of medical oncology and professor of medicine and pharmacology at Yale University, noted that the pluses of immunotherapies include “their specificity, memory or durability, and adaptability.” Still unresolved are questions including the best endpoints for trials and how best to deal with adverse effects (such as gastrointestinal and lung) and cytokine release syndrome, which can cause many complications and differ from side effects of other therapies. Until recently, most efforts focused on melanoma and renal cell cancer, long known to be immunogenic. But with new genetic research, such as Wolchok’s, that focus is changing. Most trials combine CTLA-4 inhibitors with several other treatments. F. Stephen Hodi Jr., M.D., director of the Center for Immuno-Oncology at Boston’s Dana–Farber Cancer Institute, recently led such a study. Patients with metastatic melanoma treated with ipilimumab survived significantly longer, a median of 17.5 months versus 12.7 months, if they simultaneously received granulocyte–macrophage colony-stimulating factor (GM-CSF), which stimulates growth of white blood cells ( JAMA 2014;312:1744–53; doi:10.1001/jama.2014.13943). In the 245-patient phase II study, 68.9% of those taking the combination survived for 1 year, compared with 52.9% of those taking ipilimumab only. In the 245-patient phase II study, 68.9% of those taking the combination survived for 1 year, compared with 52.9% of those taking ipilimumab only. Hodi said that he and his team had reason to believe that this combination would be beneficial from synergies seen in preclinical studies between CTLA-4 blockade and GM-CSF–secreting tumor vaccines. Improved antigen presentation with GM-CSF by recruiting macrophages and dendritic cells may account for the synergy. Early clinical research also shows that this combination could benefit patients with prostate and ovarian cancers. This trial showed two intriguing results beyond survival benefit. First, although overall survival differed, both arms had the same median progression-free survival, 3.1 months. One reason may be that some immunotherapies produce necrotic and/or inflammatory tissue around tumors, which may appear as tumor growth on a scan, Hodi said. “This effect was also seen with sipuleucel-T, or Provenge, in prostate cancer [an autologous cellular immunotherapy],” he added. Second, more patients on monotherapy reported serious side effects, 44.9%, than those on combination treatment, 58.3%. Two patients taking the combination died, from cardiac arrest and a perforated colon, whereas seven taking ipilimumab alone died, from colon, multiorgan, respiratory, and liver failure. The combination regimen’s improved adverse-effect profile contributed to overall survival rates, the authors observed. As for why the combination was superior, they noted that GM-CSF protected gastrointestinal mucosa from severe colitis in preclinical and clinical studies. Fewer toxic effects to the lung also occurred with the combination, which the authors attributed to GM-CSF’s lung-protectant qualities. Timothy A. Chan, M.D., Ph.D. In another combination study, Yale researchers tested ipilimumab with the PD-1 immune checkpoint inhibitor nivolumab in a phase I/II trial initially with 53 patients with advanced melanoma, with an update given at the 2014 American Society of Clinical Oncology (ASCO) meeting in a total of 94 patients ( N. Engl. J. Med. 2014;369:122–33; doi:10.1056/NEJMoa1302369). The updated trial yielded a 1-year overall survival rate of 82% and a 2-year overall survival of 75%. Patients responded similarly regardless of BRAF mutation status, and as of June 2014 the median duration of response had not been reached (ASCO 2014 abstract LBA9003). “It makes sense to combine them, as each had demonstrated considerable activity in this indication as monotherapies,” said lead author Mario Sznol, M.D., Yale professor of medical oncology. Of the original 53 patients in the trial, with more time, complete response rate increased from 10% to 17%. Sznol said that figure was probably an underestimate, since 22 (41.5%) of those patients experienced tumor reduction of more than 80%, with many experiencing near-complete responses. However, toxic effects with the combination increased, with 62% having grade 3/4 side effects, which were manageable and reversible. Twenty-two patients stopped treatment because of toxic effects, and one patient died from colitis-related multiorgan failure. Scientists at ASCO’s 2014 meeting discussed preliminary results of a phase I trial in metastatic renal cell cancer with the same combination at two doses. The objective response rate was 29% with a higher dose of nivolumab and 39% for a higher dose of ipilimumab; duration of response was 4.1–22.1 weeks and 6.1–18.3 weeks, respectively. An expansion trial at these doses and at a third, equal high dose is ongoing. A phase III trial comparing the combination with each drug alone is under way. Researchers are now seeing checkpoint blocker activity outside melanoma and renal cell carcinoma, Herbst said. Lung cancer, once thought nonimmunogenic, is also the subject of several ipilimumab trials. A phase II study combining ipilimumab with paclitaxel and carboplatin showed a median overall survival of 12.2 months for phased ipilimumab, 9.7 months for concurrent ipilimumab, and 8.3 months for control in untreated patients. Those results serve as the basis for an ongoing phase III trial in non–small-cell lung cancer (NSCLC) and SCLC. It is also in phase II testing with chemotherapy before surgery for NSCLC and in a phase I trial with the targeted drugs erlotinib or crizotinib for patients with stage IV NSCLC who also have mutations in the gene for epidermal growth factor receptor or anaplastic lymphoma kinase. A phase I trial of ipilimumab plus imatinib (Gleevec), a c-Kit inhibitor, is ongoing for patients with advanced cancers, including lung cancer. Ovarian cancer and other trials are also under way, including a phase II study with ipilimumab and a phase I with tremelimumab and MEDI4736, an anti–PD-L1 immunotherapy in advanced solid tumors, including colorectal cancers. Combination nivolumab and ipilimumab is in a phase II clinical trial for recurrent glioblastoma. Ipilimumab is also in two phase I trials in adults with Hodgkin lymphoma and a phase II trial in mesothelioma. “Despite many, many unanswered questions, I think that it is safe to say that we have finally, after decades of research, begun to open an important new chapter in the treatment of cancer via the manipulation of the immune system,” Klausner said. “That said, we are still in the early days of the therapeutic potential of immunotherapy—and the rules, the generalizability, and the persistence of therapeutic benefit are all questions whose answers are ahead of us,” he added.
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