cd4 t-cell immunotherapy shows early...
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JUNE 2016 CANCER DISCOVERY | 567
Based on this data, Drilon announced that a global phase II trial of entrectinib, for which he will serve as the principal investigator, has been launched. Only patients with an NTRK, ROS1, or ALK gene fusion will be enrolled.
“I want to emphasize that this [study outcome] is the product of many decades of very sophisticated research that was conducted to understand the genetic abnormalities that drive human cancers,” said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. “This work was basic, it wasn’t clearly going to lead anywhere when it started, it was persistent, it was expensive, it was hard to get done. . . . And here we are, witnessing what I would consider a glory moment, showing that all of us benefit from the patient research that was done.” –Suzanne Rose n
cD4 t-cell immunotherapy shows Early Promise
To date, T cell–based immunothera-pies for cancer have mostly involved introducing receptors (TCR) recogniz-ing specific tumor antigens to CD8 T cells, then exploiting the natural cytotoxicity of these cells to target and eradicate tumors. More recently, researchers have started applying this strategy to the “helper” population of CD4 T cells, which are not directly cytotoxic, but trigger an immune response by releasing cytokines.
“We wanted to see if, in terms of destroying tumors, helper T cells could also sit in the driver’s seat,” said Yong-Chen Lu, PhD, a research fellow at the NCI’s surgery branch. At the American Association for Cancer Research Annual Meeting 2016 in New Orleans, LA, April 16–20, Lu presented preliminary data from the first phase I study investigating the therapeutic potential of genetically modified CD4 T cells against metastatic cancer.
The study enrolled 14 patients with various treatment-refractory cancers positive for MAGE-A3, a protein that’s present during fetal development, lost in adult tissue, and frequently re-expressed in cancer. All study par-ticipants had the correct cell-surface protein, HLA-DPB1*0401, to present this tumor antigen for immune system surveillance and action. The researchers
Even though patients lacking NTRK fusions could enroll in the trial, none of them have had a response to LOXO-101, Hong noted. Consequently, a phase II trial of LOXO-101 now under way will enroll only patients who have tested positive for an NTRK gene fusion.
“The phase II study is important not only for generating additional data on LOXO-101 in patients with NTRK-fusion cancers, but we anticipate it will further broaden the range of tumor types that we’ve tested thus far,” explained Hong.
Responses to entrectinib were equally dramatic. Data reported in September 2015 from two phase I studies involving a total of 119 patients showed an objective response rate of 72% among the 18 whose tumors har-bored one of the five gene fusions.
Alexander Drilon, MD, assistant attending physician of the Developmen-tal Therapeutics Clinic and the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York, NY, provided additional data at the AACR meeting, reporting on 24 patients. Overall, 79% responded to the drug, including all three patients with NTRK rearrangements, 12 of 14 with ROS1 rearrangements, and four of seven with ALK rearrangements. Responses were seen in NSCLC, MASC, astrocytoma, colorectal cancer, renal cell carcinoma, melanoma, and infantile fibrosarcoma.
“Responses to entrectinib were brisk,” commented Drilon, “and the majority of them were really seen at the first time point patients were imaged—within the first 4 to 8 weeks.” In addition, the majority of the patients have had ongoing responses, with half responding for 6 months. One patient continues to respond after more than 2 years.
During preclinical work, researchers repeatedly refined entrectinib, aiming to get it to cross the blood–brain bar-rier in people, Drilon said. It worked. All three patients with a primary brain tumor or brain metastases experienced dramatic intracranial drug activity. In one case Drilon presented, a patient with NSCLC experienced just a 47% reduction in lung tumor volume after 26 days, but at that same time, all 15 to 20 of his brain metastases had com-pletely disappeared. After nearly a year, the lung tumors had decreased by 79%, and the brain lesions have not returned.
harvested CD4 T cells from these patients and redirected TCR specificity to recognize MAGE-A3. The cells were then amplified in the laboratory before being infused back into the patients.
The first eight patients received escalating doses of modified T cells—from 10 million to 30 billion—as the researchers waited to see if dose-limiting toxicities would develop. Because none occurred, “we were able to keep increas-ing the dose to the maximum of 100 billion cells,” Lu said, which the study’s final six patients received. He and his team observed significant tumor regres-sion in three patients with different metastatic tumors: cervical, esophageal, and urothelial. The objective responses for cervical and urothelial cancer are ongoing at 15 and 7 months after treat-ment initiation, respectively.
“I should emphasize that this immu-notherapy is much safer than, say, CAR [chimeric antigen receptor] T cells tar-geting CD19,” Lu added. None of the patients experienced cytokine release syndrome, which is common with CAR T-cell therapy, and the main side effect—a high fever that lasted from 1 to 2 weeks—was easily controlled.
Louis Weiner, MD, director of the Georgetown Lombardi Comprehen-sive Cancer Center in Washington, DC, called this study “a promising conceptual strategy” that has yielded “exciting early responses.”
Yong-Chen Lu presents results of a study investigating the potential of genetically modi-fied CD4 T cells to treat metastatic cancer.
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North Chicago, IL–based abbVie ac quired stemcentrx in a deal that could total nearly $10 billion. AbbVie aims to cash in on the five drugs that the South San Francisco, CA–based company currently has in clinical trials, including its antibody– drug conjugate Rova-T for the treatment of small-cell lung cancer.
Napster founder and former Facebook president sean Parker announced a $250 million grant to launch the Parker institute for cancer immunotherapy, which includes more than 30 industry partners, 40 labora-tories, and 300 researchers from six lead-ing cancer centers—Memorial Sloan Kettering Cancer Center (New York, NY); Stanford Medicine (CA); the University of California, Los Angeles; the University of California, San Francisco (UCSF); the University of Pennsylvania in Philadelphia; and The University of Texas MD Anderson Cancer Center in Houston. The collabora-tion aims to “broadly disseminate discover-ies” and “more rapidly deliver treatments to patients.”
For nonhematologic cancers, such as breast, colorectal, lung, and prostate can-cers, the global market for therapies will nearly double from $72.9 billion in 2014 to $140.8 billion in 2021, at a compound annual growth rate of 9.9%, according to a report from business intelligence pro-vider GBI Research.
the american society of hematology issued a list of six priorities to be included in the national cancer Moonshot. The prior-ities include improving early cancer detec-tion and prevention; improving access to clinical trials of novel targeted therapies; focusing on cancer immunotherapy; enhanc-ing data sharing and education; attacking pediatric cancers; and accelerating the approval of effective therapies.
the uK’s royal college of Physicians issued a report encouraging smokers of traditional cigarettes to switch to elec-tronic cigarettes, saying that the nicotine-delivery devices are less likely to cause harm and could aid in smoking cessation.
stand up to cancer announced a new research program called Catalyst that will use funding and materials from the pharmaceutical, biotechnology, and medi-cal devices industries to speed research on cancer prevention, detection, and treatment.
Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center in New York, NY, opined that the data so far are “intriguing, but not over-whelming.” However, he also expressed confidence that the burgeoning field of T-cell engineering will produce “many other tools to boost T-cell potency,” both individually and in concert.
Meanwhile, Lu and his group have started a phase II study of their MAGE-A3–targeting immunotherapy. He’s hopeful that it will continue to demonstrate effectiveness in patients despite GlaxoSmithKline’s decision in 2014 to shutter development of a vac-cine against MAGE-A3, after a phase III trial in non–small cell lung cancer failed to meet two primary endpoints.
“The problem isn’t MAGE-A3; it can be difficult to provoke a strong immune response with a vaccine,” Lu explained. “What we’ve done—infusing patients with greatly expanded num-bers of T cells primed to recognize their target—is far more aggressive and effective.” —Alissa Poh n
Drug combo curbs Duodenal Polyps in faP
Patients with familial adenomatous polyposis (FAP) aren’t just susceptible to colorectal tumors; they are also vulnerable to duodenal polyps, which form in the first section of the small intestine. A new study suggests that sulindac (Clinoril; Merck) and erlo-tinib (Tarceva; Genentech) can shrink these growths.
FAP results from germline muta-tions in the tumor suppressor gene adenomatous polyposis coli (APC). Because the risk of developing colo-rectal cancer in patients with FAP is close to 100%, physicians recommend removing the colon, which comprises most of the large intestine. Yet even people who have had a prophylactic colectomy face another risk: More than half of patients with FAP develop duodenal polyps, and up to 12% of them develop duodenal tumors, which typically require risky surgery.
Researchers have found that EGFR activity and APC-inactivating mutations
spur polyp formation by increasing expression of COX2. NSAIDs such as sulindac, a COX inhibitor, reduce colon polyp formation in patients with FAP, but they don’t work as well against duodenal polyps. Deborah Neklason, PhD, of the University of Utah in Salt Lake City, and colleagues tested whether pairing sulindac with the EGFR-blocker erlotinib would be more effective.
The scientists randomized 92 patients with duodenal polyps to receive sulindac and erlotinib or a placebo for 6 months. Endoscopies at the start and end of the trial allowed the researchers to track each patient’s polyp burden, the total diameter of all polyps in their duo-denum. They found that the median polyp burden increased by 8 mm in the control group but decreased by 8.5 mm among the treated patients (JAMA 2016;315:1266–75). Because the trial was brief, they don’t yet know whether the drug combination actually prevents duodenal tumors.
Sulindac and erlotinib triggered side effects in 93% of the treated patients, whereas 72% of the control patients reported them. The most common side effect was a rash, which occurred in 87% of the treated patients and 20% of the control patients. Other adverse effects from the drug combo included mouth sores, diarrhea, and nausea.
“It’s the first study to show effec-tiveness of chemoprevention in the management of duodenal polyposis,” says Carol Burke, MD, of the Cleveland Clinic, OH, who wasn’t connected to the research. The results are “provoca-tive and compelling,” she adds. Ernest Hawk, MD, of The University of Texas MD Anderson Cancer Center in Hou-ston, agrees. “It’s a first step, but it’s a promising first step because of the level of efficacy they have demonstrated.”
However, Hawk and Burke say they are concerned by the drugs’ side effects. Along with the side effects that occurred in the trial, studies have linked the drugs to cardiac toxicity and interstitial lung disease. Both researchers say future studies need to determine how to reduce these risks, perhaps by further decreasing doses or by treating patients intermittently. —Mitch Leslie n
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2016;6:567-568. Published OnlineFirst April 18, 2016.Cancer Discov CD4 T-cell Immunotherapy Shows Early Promise
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on June 21, 2018. © 2016 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from
Published OnlineFirst April 18, 2016; DOI: 10.1158/2159-8290.CD-NB2016-045