Fred Hutch studies advance methods to avert toxicity that can accompany immunotherapyOctober 12, 2017
SEATTLE - OCT. 12, 2017 -- Two new papers from researchers at Fred Hutchinson Cancer Research Center provide the most comprehensive data yet reported on side effects of the emerging cancer immunotherapy strategy known as CAR T-cell therapy.
Based on their data from 133 adult participants in one clinical trial, the researchers identified potential biomarkers associated with the development of the toxic effects, known as cytokine release syndrome and neurotoxicity. They also created algorithms aimed at identifying the rare patients whose symptoms were most likely to turn life-threatening.
The team's paper on neurotoxicity will be published online in Cancer Discovery at 12:05 a.m. Eastern Time Oct. 12. Their paper on cytokine release syndrome was published online in the journal Blood Sept. 18.
The researchers anticipate that their work could be the basis for an algorithm that doctors could follow to reduce the risk of the severe side effects and occasional deaths, which have been seen in clinical trials of various CAR T-cell products. They said that their findings will need to be tested and improved upon by further study, and noted that their results arise from a clinical trial of a particular CAR T-cell product, which is made by and at Fred Hutch.
"It's essential that we understand the potential side effects of CAR T therapies" said Fred Hutch's Dr. Cameron Turtle, who led the research. "While use of these cell therapies is likely to dramatically increase because they've been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn."
The first CAR T-cell product was recently approved by the U.S. Food and Drug Administration to treat certain leukemias. That product, like the one studied by the Fred Hutch team, reprograms patients' immune cells to kill blood cancer cells bearing a protein called CD19.
The 133 participants in the Fred Hutch clinical trial - believed to be the largest sample size in any published study of CAR T-cell therapy side effects - had advanced leukemias or lymphomas that had proven resistant to standard therapies. Over the last two years, Fred Hutch papers reported results from different groups of patients treated with the optimal regimen of chemotherapy and CAR T cells: 93 percent of participants with B-cell acute lymphoblastic leukemia went into complete remission; 64 percent with non-Hodgkin lymphoma experienced complete remission; and 86 percent of a subset of patients with high-risk chronic lymphocytic leukemia cleared disease from their bone marrow.
"These patients had highly resistant, refractory disease," Turtle said. "For many of them, it was their last option."
The two latest papers provide detailed descriptions of the clinical courses of cytokine release syndrome and of neurotoxicity in study participants, including the types of symptoms present, the timing of their occurrence and the course they ran to resolution. The neurotoxicity paper also includes detailed data from imaging and pathological studies.
As previously reported, complications of cytokine release syndrome, neurotoxicity or both were fatal for some participants. The new findings show that in the vast majority of patients (about 95 percent of participants) harms were either reversible or did not occur.
One of the studies' novel findings is that severe cases of both types of toxicities were associated with signs that the endothelial cells, or the linings of patients' blood vessels, were ramping up activity in response to injury. For example, the team found that the normally tight barrier between the blood and the brain had broken down in some patients with severe neurotoxicity, and cytokines and CAR T cells from the blood had entered the fluid bathing the brain. The researchers say that biomarkers for endothelial activation could help identify which patients are at greatest risk of CRS and neurotoxicity.
"It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but in terms of what triggers a person with cytokine release syndrome to get neurotoxicity -- that's something we need to investigate further," said Dr. Kevin Hay, a research fellow at Fred Hutch and a lead author of both papers.
As the research progressed, the study investigators adjusted their CAR T-cell dosing strategy. This change appears to correspond with a reduction in the frequency of the most serious forms of these toxic effects, though more research is needed to confirm this.
In treating clinical trial participants at Seattle Cancer Care Alliance, Fred Hutch's clinical partner, the researchers developed methods for monitoring and treating toxicities, as reported in these two papers, that allow study participants to receive the preparatory chemotherapy and subsequent CAR T-cell infusion as outpatients. Patients are admitted into the hospital if they spike a high fever in the days following the infusion.
"We have come a long way in understanding what these toxicity events are," Hay said. "That's really what these two papers demonstrate."
Cytokine release syndrome
The symptoms of cytokine release syndrome include high fevers and low blood pressure. Cytokine release syndrome developed in 93 of 133 of patients on the trial. In most of these patients, it resolved on its own with no treatment. But 10 patients, most of who were treated early in the trial, developed the most serious symptoms of cytokine release syndrome (grade 4 or 5).
The researchers identified five independent factors relating to participants' baseline health status upon trial enrollment and variation within the experimental treatment itself, such as cell dose, which predicted patients' risk of developing any grade of cytokine release syndrome.
The researchers developed a simple two-part method to identify the patients who would go on to develop severe cytokine release syndrome. Within the first day and a half after T-cell infusion, the red flags were a fever of at least 102 degrees Fahrenheit and high levels of one particular immune-signaling chemical, a cytokine known as MCP-1. The algorithm was relevant to all three cancer types included in the trial.
While an effective therapy for cytokine release syndrome is FDA-approved -- a cytokine-modulating drug and/or a steroid -- it's unclear what the best protocol is for early intervention in the development of side effects. The data from their study could inform the design of a clinical trial to test the best strategy for blunting the development of the most serious cases, the researchers say.
A wide range of neurologic side effects are included under the umbrella of neurotoxicity, which occurred in 53 of the 133 trial participants after CAR T-cell infusion. The most common type of neurologic side effect was delirium with maintained alertness (35 patients), the team reported. Other manifestations of neurotoxicity included headache, problems speaking, a decrease in consciousness and, rarely, seizures (four patients) or coma (six patients). A total of seven patients experienced life-threatening neurotoxicity.
The researchers identified several preexisting factors that were associated with a higher risk of developing any level of neurotoxicity, such as patient age and cancer type. Only CAR T-cell dose was associated with later risk of developing the most serious neurotoxicity.
The team found that fever of at least 102 degrees Fahrenheit and high levels of two cytokines (IL-6 and MCP-1) in the first 36 hours after CAR T-cell infusion could identify, with high accuracy, those patients who would go on to develop life-threatening neurotoxicity.
There are no data that point toward the best treatment for neurologic toxicities of CAR T-cell therapy, and there are not yet any validated laboratory models to use for research to clearly elucidate their causes. The researchers hope that their comprehensive data provide a springboard for research teams to delve into its causes and best treatments.
The Cancer Discovery paper on neurotoxicity was led by Turtle (senior author) and co-first authors Dr. Juliane Gust of the University of Washington, Hay and Dr. Laïla-Aïcha Hanafi of Fred Hutch. Other authors are from Fred Hutch, UW, BloodWorks Northwest, Juno and the University of British Columbia.
The Blood paper on cytokine release syndrome was led by Turtle (senior author) and Hay (first author). Other authors are from Fred Hutch, the University of Washington, Juno, Seattle Children's Hospital and Bloodworks Northwest.
At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch's pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation's first cancer prevention research program, as well as the clinical coordinating center of the Women's Health Initiative and the international headquarters of the HIV Vaccine Trials Network.
Fred Hutchinson Cancer Research Center
Related Clinical Trial Articles:
A clinical trial funded by Arthritis Research UK and the National Institute for Health Research led by professors from the universities of Liverpool and Bristol has discovered a drug combination that could help thousands of children with arthritis.
The University of Liverpool, in partnership with AKL Research and Development Ltd, is to lead on a clinical trial to test a potential new drug treatment for osteoarthritis.
University of Tuebingen researchers in collaboration with the biotech company Sanaria Inc. have demonstrated in a clinical trial that a new vaccine for malaria called Sanaria® PfSPZ-CVac has been up to 100 percent effective when assessed at 10 weeks after last dose of vaccine.
A clinical trial of a smart bandage which changes color when it detects infections is beginning using samples from burns patients from four UK hospitals.
In the first controlled clinical trial of nicotinamide riboside (NR), a newly discovered form of vitamin B3, researchers have shown that the compound is safe for humans and increases levels of a cell metabolite that is critical for cellular energy production and protection against stress and DNA damage.
Behavioral economics may offer a powerful tool for improving patient enrollment in clinical trials, argue Eric VanEpps, Kevin Volpp, and Scott Halpern in this Focus.
A new study reports on the results of a randomized clinical trial that looked at whether the antidepressant citalopram would enhance complicated grief treatment psychotherapy, and if citalopram would be efficacious without it in an article published online by JAMA Psychiatry.
At the click of a button, health professionals and researchers will now be able to view all of the clinical trials referenced in the paper they are reading, and any related publications such as the protocol, statistical analysis plan, and results articles.
The Multiple Sclerosis Outcome Assessments Consortium (MSOAC), a global effort of the National MS Society and Critical Path Institute (C-Path), is launching a database, accessible to qualified researchers, containing trial data from nearly 2,500 patients from the placebo arms of nine MS clinical trials.
Results of the Wellcome Trust funded trial of the experimental anti-Ebola drug TKM-130803 published in PLOS Medicine.
Related Clinical Trial Reading:
Fundamentals of Clinical Trials
by Lawrence M. Friedman (Author), Curt D. Furberg (Author), David L. DeMets (Author), David M. Reboussin (Author), Christopher B. Granger (Author)
This is the fifth edition of a very successful textbook on clinical trials methodology, written by recognized leaders who have long and extensive experience in all areas of clinical trials. The three authors of the first four editions have been joined by two others who add great expertise. A chapter on regulatory issues has been included and the chapter on data monitoring has been split into two and expanded. Many contemporary clinical trial examples have been added. There is much new material on adverse events, adherence, issues in analysis, electronic data, data sharing and... View Details
Clinical Trials: A Methodologic Perspective (Wiley Series in Probability and Statistics)
by Steven Piantadosi (Author)
Presents elements of clinical trial methods that are essential in planning, designing, conducting, analyzing, and interpreting clinical trials with the goal of improving the evidence derived from these important studies
This Third Edition builds on the text’s reputation as a straightforward, detailed, and authoritative presentation of quantitative methods for clinical trials. Readers will encounter the principles of design for various types of clinical trials, and are then skillfully guided through the complete process of planning the experiment, assembling a... View Details
Clinical Trials, Second Edition: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines
by Tom Brody PhD (Author)
Clinical Trials, Second Edition, offers those engaged in clinical trial design a valuable and practical guide. This book takes an integrated approach to incorporate biomedical science, laboratory data of human study, endpoint specification, legal and regulatory aspects and much more with the fundamentals of clinical trial design. It provides an overview of the design options along with the specific details of trial design and offers guidance on how to make appropriate choices. Full of numerous examples and now containing actual decisions from FDA reviewers to better inform trial... View Details
A Concise Guide to Clinical Trials
by J. Rick Turner PhD (Author)
Biopharmaceutical drugs improve the health and well-being of people across the globe on a scale that is unrivaled by any other medical intervention. Before these drugs can be prescribed for patients by their doctors, they have to be approved for marketing by a regulatory agency. To gain marketing approval, drugs must go through an extremely rigorous process that investigates their safety and efficacy, the process of New Drug Development. The last stage of this long, complex, and expensive process involves conducting clinical trials, the topic of this book. Successfully conducting clinical... View Details
A Practical Guide to Managing Clinical Trials
by JoAnn Pfeiffer (Author), Cris Wells (Author)
A Practical Guide to Managing Clinical Trials is a basic, comprehensive guide to conducting clinical trials. Designed for individuals working in research site operations, this user-friendly reference guides the reader through each step of the clinical trial process from site selection, to site set-up, subject recruitment, study visits, and to study close-out. Topics include staff roles/responsibilities/training, budget and contract review and management, subject study visits, data and document management, event reporting, research ethics, audits and inspections,... View Details
Clinical Trials in Oncology, Third Edition (Chapman & Hall/CRC Interdisciplinary Statistics)
by Stephanie Green (Author), Jacqueline Benedetti (Author), Angela Smith (Author), John Crowley (Author)
The third edition of the bestselling Clinical Trials in Oncology provides a concise, nontechnical, and thoroughly up-to-date review of methods and issues related to cancer clinical trials. The authors emphasize the importance of proper study design, analysis, and data management and identify the pitfalls inherent in these processes. In addition, the book has been restructured to have separate chapters and expanded discussions on general clinical trials issues, and issues specific to Phases I, II, and III. New sections cover innovations in Phase I designs, randomized Phase... View Details
Clinical Trials: What Patients and Healthy Volunteers Need to Know
by Lorna Speid Ph.D (Author)
Every year, hundreds of thousands of healthy volunteers and patients worldwide undertake the journey through the maze that can be clinical trials. Research participants take part in clinical trials for a variety of reasons. The healthy volunteers may be seeking extra money to pay off college tuition, or they may know someone who is suffering and would potentially benefit from the results of the trial. The patient who is terminally ill might participate in a clinical trial simply as a last hope for a cure. Whatever the goals, though, most participants will experience the same sense of... View Details
Gynecologic Oncology Clinical Trials Review: Landmark Studies in Uterine Cancer
by Joshua Kesterson (Author), Rebecca Phaeton (Author)
Gynecologic Oncology Clinical Trials Review: Landmark Studies in Uterine Cancer represents a comprehensive review and synopsis of pivotal trials in uterine cancer. It is designed for ease of use and ready comprehension, with its topics divided into disease stages and studies in chronological order. Its reader-friendly format, condensation of entire clinical trials into salient highlights, discussion of limitations, areas of controversy and the clinical impact of the trial provides a succinct yet detailed synopsis of important studies. This Gynecologic Oncology Clinical Trials Book aims to... View Details
Clinical Trials: A Practical Approach
by Stuart J. Pocock (Author)
This comprehensive, unified text on the principles and practice of clinical trials presents a detailed account of how to conduct the trials. It describes the design, analysis, and interpretation of clinical trials in a non-technical manner and provides a general perspective on their historical development, current status, and future strategy. Features examples derived from the author's personal experience. View Details
A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons from a Horse Named Jim
by Margaret Liu (Author), Kate Davis (Author)
"The publication of the second edition of this manual comes at an important juncture in the history of clinical research. As advances in information technology make it possible to link individuals and groups in diverse locations in jointly seeking the answers to pressing global health problems, it is critically important to remain vigilant about moral and ethical safeguards for every patient enrolled in a trial. Those who study this manual will be well aware of how to ensure patient safety along with fiscal responsibility, trial efficiency, and research integrity."
—Robert... View Details