New technique of cellular vaccination against HIV

Scientists at The Scripps Research Institute have found a way to tether HIV-fighting antibodies to immune cells, creating a cell population resistant to the virus. Researchers have used membrane-tethered, receptor blocking antibodies to achieve this outcome.

Here, cells protected from rhinovirus by membrane-tethered,
receptor-blocking antibodies survive well and form colonies.
Credit: Jia Xie, Lerner lab, The Scripps Research Institute.

Their experiments under lab conditions show that these resistant cells can quickly replace diseased cells, potentially curing the disease in a person with HIV. “This protection would be long term,” said Jia Xie, senior staff scientist at TSRI and first author of the study published today in the journal Proceedings of the National Academy of Sciences.

The new TSRI technique offers a significant advantage over therapies where antibodies float freely in the bloodstream at a relatively low concentration. Instead, antibodies in the new study hang on to a cell’s surface, blocking HIV from accessing a crucial cell receptor  called CD4, and thereby preventing spreading of infection. With the antibodies monopolizing that site, the virus cannot enter the cell to spread infection. “This is really a form of cellular vaccination,” said study senior author Richard Lerner, M.D.

The scientists further confirmed that these tethered antibodies blocked HIV more effectively than free-floating, soluble antibodies in experiments led by study co-authors Devin Sok of the International AIDS Vaccine Initiative (IAVI) and TSRI Professor Dennis R. Burton.

Citation: Xie, Jia, Devin Sok, Nicholas C. Wu, Tianqing Zheng, Wei Zhang, Dennis R. Burton, and Richard A. Lerner. “Immunochemical engineering of cell surfaces to generate virus resistance.” Proceedings of the National Academy of Sciences, 2017, 201702764.
doi:10.1073/pnas.1702764114.
Adapted from press release by The Scripps Research Institute.

New approach to Multiple Sclerosis treatment using immunosuppression and stem cells shows promise

New clinical trial results provide evidence that high-dose immunosuppressive therapy followed by transplantation of a person’s own blood-forming stem cells can induce sustained remission of relapsing-remitting multiple sclerosis (MS).

Five years after receiving the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), 69 percent of trial participants had survived without experiencing progression of disability, relapse of MS symptoms or new brain lesions. Notably, participants did not take any MS medications after receiving high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT). Other studies have indicated that currently available MS drugs have lower success rates.

The trial, called HALT-MS, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN). The researchers published three-year results from the study in December 2014, and the final five-year results appear in Neurology, the medical journal of the American Academy of Neurology.

“These extended findings suggest that one-time treatment with high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging results support the development of a large, randomized trial to directly compare high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) to the standard of care for this often-debilitating disease.”

In HALT-MS, researchers tested the safety, efficacy and durability of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) in 24 volunteers aged 26 to 52 years with relapsing-remitting multiple sclerosis (MS) who, despite taking clinically available medications, experienced active inflammation, evidenced by frequent severe relapses, and worsened neurological disability.

The experimental treatment aims to suppress active disease and prevent further disability by removing disease-causing cells and resetting the immune system. During the procedure, doctors collect a participant’s blood-forming stem cells, give the participant high-dose chemotherapy to deplete the immune system, and return the participant’s own stem cells to rebuild the immune system. The treatment carries some risks, and many participants experienced the expected side effects of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), such as infections. Three participants died during the study; none of the deaths were related to the study treatment.

Five years after high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), most trial participants remained in remission, and their MS had stabilized. In addition, some participants showed improvements, such as recovery of mobility or other physical capabilities.

“Although further evaluation of the benefits and risks of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) is needed, these five-year results suggest the promise of this treatment for inducing long-term, sustained remissions of poor-prognosis relapsing-remitting MS,” said Richard Nash, M.D., of Colorado Blood Cancer Institute and Presbyterian-St. Luke’s Hospital. Dr. Nash served as principal investigator of the HALT-MS study.

If these findings are confirmed in larger studies, high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may become a potential therapeutic option for patients with active relapsing-remitting multiple sclerosis (MS), particularly those who do not respond to existing therapies,” said Daniel Rotrosen, M.D., director of NIAID’s Division of Allergy, Immunology and Transplantation.

Citation: Nash, Richard A., George J. Hutton, Michael K. Racke, Uday Popat, Steven M. Devine, Linda M. Griffith, Paolo A. Muraro et al. “High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.” JAMA neurology 72, no. 2 (2015): 159-169.
DOI: 10.1212/WNL.0000000000003660
Research funding: NIH/National Institute of Allergy and Infectious Diseases.
Adapted from press release by NIH/National Institute of Allergy and Infectious Diseases.

Animal study shows combination of antibodies are effective in HIV

Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body’s ability to control it. But a small group of infected individuals called elite controllers possess immune systems capable of defeating the virus. They accomplish this by manufacturing broadly neutralizing antibodies, which can take down multiple forms of HIV.

Now a study using antibodies from one of these elite controllers has shown that a combination of three such antibodies can completely suppress the virus in HIV-infected mice. The findings, from the laboratory of Michel Nussenzweig, who is Zanvil A. Cohn and Ralph M. Steinman Professor at Rockefeller University and head of the Laboratory of Molecular Immunology, are reported in Science Translational Medicine.

“Some people with HIV produce these antibodies, but most of the time the virus eventually escapes them through mutations in the antibody’s corresponding epitope,” says postdoctoral fellow Natalia Freund, the study’s first author. The epitope is the part of the virus that antibodies recognize and attach themselves to, and this ability to mutate makes HIV particularly tricky to tame. It ensures that once the virus is in their bodies, people remain infected forever, and this may be the biggest roadblock in developing immune therapies to overcome the virus.

“What we’ve shown in this study is that after several rounds of escape from these particular antibodies, the virus seems to run out of options,” Natalia Freund adds. “In this particular case, HIV eventually loses this arms race.”

An elite controller’s immune system can defeat the virus by coming up with new broadly neutralizing antibodies, and also by producing cytotoxic T cells immune cells that can recognize and destroy infected cells to immobilize the virus. The patient whose HIV response created antibodies for the study has been working with the Rockefeller team for ten years, contributing his blood serum for their research. He was infected at least three decades ago, and has developed three different types of broadly neutralizing antibodies that bind to three different sites on the virus.

The remarkable thing about his antibodies is that they seem to complement each other’s activity, completely shutting down HIV.

The investigators gave the three antibodies, called BG18, NC37, and BG1, to HIV-infected mice whose immune systems had been modified to more closely resemble those of humans. They found that the trio rendered the virus undetectable in two-thirds of the mice three weeks after it was administered.

“This study validates the approach of using three different antibodies to control HIV infection,” Freund concludes, “pointing the way toward a potential new treatment for people infected with HIV.”

Citation: Freund, Natalia T., Haoqing Wang, Louise Scharf, Lilian Nogueira, Joshua A. Horwitz, Yotam Bar-On, Jovana Golijanin, Stuart A. Sievers, Devin Sok, Hui Cai, Julio C. Cesar Lorenzi, Ariel Halper-Stromberg, Ildiko Toth, Alicja Piechocka-Trocha, Harry B. Gristick, Marit J. van Gils, Rogier W. Sanders, Lai-Xi Wang, Michael S. Seaman7, Dennis R. Burton, Anna Gazumyan, Bruce D. Walker, Anthony P. West Jr, Pamela J. Bjorkman and Michel C. Nussenzweig. “Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller.” Science Translational Medicine 9, no. 373 (2017): eaal2144.
DOI: 10.1126/scitranslmed.aal2144
Research funding: Robertson Foundation, Bill and Melinda Gates Foundation, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, National Institutes of Health, Gordon and Betty Moore Foundation, California HIV/AIDS Research Program.
Adapted from press release by Rockefeller University.

Multiple Sclerosis medication alemtuzumab can trigger severe B cell mediated brain inflammation

The multiple sclerosis (MS) therapy alemtuzumab can trigger severe, unpredictable side effects. This was the finding by a team led by Prof Dr Aiden Haghikia and Prof Dr Ralf Gold from the Department of Neurology of the Ruhr-Universität Bochum at St. Josef’s Hospital. In the journal Lancet Neurology, the scientists report on two patients for whom the infusion of alemtuzumab significantly worsened symptoms. The team also describes a treatment that successfully curbed the harmful side effects.

Alemtuzumab is a therapeutic antibody that docks to the protein CD52 on the surface of certain immunocytes, mainly T and B lymphocytes, leading to the depletion of almost all lymphocytes. It was already known from the approval studies that a quarter of the treated patients display mostly minor side effects, called secondary autoimmune processes: immunocytes turn against cells produced naturally in the body, predominantly in the thyroid gland; but the kidneys and platelets can also be affected.

The two patients described in the Lancet Neurology study received alemtuzumab because they had highly active MS, i.e. despite numerous previous treatments, they suffered from severe illness relapses with inflammation in the central nervous system. Six months after the treatment, these symptoms had worsened significantly. Using MRI, the researchers discovered a kind of new inflammation mode: they found vast areas in the brain with numerous ring enhancing lesion. The patients had not displayed this pattern in their previous medical history.

It is currently unclear whether the observed adverse events represent increased MS activity or an independent secondary autoimmune process.

In both cases, the neurologists were able to curb the side effects, and the observed ring-shaped deposits in the brain receded. Even a year after the treatment, the patients were still in a stable condition. Besides a blood plasma exchange, they treated both with the antibody rituximab that is directed against B lymphocytes. The researchers suspect that precisely these immunocytes were responsible for the observed side effect.

The authors propose that the measures they applied could also benefit other patients who develop similar adverse events under alemtuzumab.

Citation: Haghikia, Aiden, Calliope A. Dendrou, Ruth Schneider, Thomas Grüter, Thomas Postert, Mike Matzke, Heike Stephanik, Lars Fugger, and Ralf Gold. “Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy.” The Lancet Neurology 16, no. 2 (2017): 104-106.
DOI: 10.1016/S1474-4422(16)30382-9

Adapted from press release by Ruhr-Universitaet-Bochum.

Local chemotherapy delivered directly to the brain preserves immune system for further immunotherapy in mouse models of glioblastoma multiforme

In experiments on mice with a form of aggressive brain cancer, Johns Hopkins researchers have shown that localized chemotherapy delivered directly to the brain rather than given systemically may be the best way to keep the immune system intact and strong when immunotherapy is also part of the treatment. The researchers say their study results, reported in Science Translational Medicine, could directly affect the design of immunotherapy clinical trials and treatment strategies for people with a deadly form of brain cancer called glioblastoma.

Brain. Credit: Ashton University.

“We understand that our research was done in a mouse model and not in humans, but our evidence is strong that systemic chemotherapy alters the immune system in a way that it never fully recovers,” says Michael Lim, M.D., associate professor of neurosurgery and director of brain tumor immunotherapy at the Johns Hopkins University School of Medicine, and member of the Johns Hopkins Kimmel Cancer Center. “With aggressive cancers like glioblastoma, it is important that we don’t handicap the defenses we may need to add alternative treatments, such as immunotherapy, to chemotherapy,” he adds.

Lim’s laboratory in neurosurgery and a team from the Bloomberg~Kimmel Institute for Cancer Immunotherapy led by Drew Pardoll, M.D., Ph.D., performed their studies in a mouse with glioblastoma. In people, glioblastoma is a particularly aggressive form of cancer, with a typical survival time of just over a year after diagnosis. Current treatments include surgical removal of the visible tumor, radiation and chemotherapy. Because the disease is so lethal, even after aggressive standard treatment, neurosurgeons like Lim are looking to add newer immunotherapies that use the body’s own immune system cells to fight the tumor.

However, one challenge to immunotherapy, Lim says, has been the potential toxic effects of systemic therapies that could damage or interfere with the immune system and weaken the chances for success of immunotherapy approaches. With clinical trials being designed to integrate standard of care with immunotherapy, Lim and his team sought to create a way to accurately assess the impact of localized versus systemic chemotherapy on the immune system’s ability to stay healthy, and to see which kind of chemotherapy would actually improve survival time in the test mice.

To determine if one method of chemotherapy delivery was better over another when combined with immunotherapy, the researchers first gave a group of mice with glioblastoma clinically relevant doses the immunotherapy drug anti-PD-1 (200 milligrams per kilogram) and then treated the mice with chemotherapy either throughout the whole body or directly to the brain over two weeks.

For the whole-body, or systemic, chemotherapy, the mice were injected in their bellies with 30 milligrams per kilogram of the chemotherapy drug carmustine the same drug used against glioblastoma in people three times a week. Each treatment group contained 15 mice. For the local chemotherapy, the researchers directly implanted a wafer covered in molecules that bound carmustine, allowing sustained release of the drug over a week, into mice with established brain tumors.

The researchers first took blood samples from the rodents’ lymph nodes, brain, bone marrow and blood a couple of days after the end of the chemotherapy treatments, almost two weeks later and at the four-month mark. They focused on counting the number of white blood cells called lymphocytes (T cells) as a way to measure immune system integrity. The mice given systemic chemotherapy had much lower levels of lymphocytes than the mice given the local, long-lasting chemotherapy. For example, two weeks after treatment, mice with systemic chemotherapy had only about a third of the lymphocytes in their circulating blood as mice given the local chemotherapy. The researchers say their findings align with what is observed clinically in patients who received systemic chemotherapy. Lim says the suppression is suggested that the lymphocyte depletion caused by systemic chemotherapy is likely counterproductive to producing an effective antitumor immune response.

Next, the team wanted to see if local versus systemic chemotherapy in conjunction with immunotherapy affected survival in the mice with glioblastoma. The scientists found that when they gave the mice chemotherapy locally, it acted together with the immunotherapy drug to improve survival to about 80 percent after 100 days when compared to mice receiving immunotherapy alone, local chemotherapy alone, or combined systemic chemotherapy and immunotherapy, with a survival rate of about 50 percent after 100 days. Then, they followed up these experiments by assessing the immune system’s memory. They gave mice local chemotherapy or systemic chemotherapy in conjunction with immunotherapy and then implanted them with more tumors. The mice with the systemic chemotherapy and immunotherapy all died when injected with extra tumors. But the mice with local chemotherapy and immunotherapy survived, essentially immunized against their glioblastoma. The researchers say this suggests that the systemic chemotherapy profoundly weakens the immune system. The researchers showed that the immune system weakening phenomenon isn’t specific to carmustine and happens in multiple types of systemic chemotherapy, such as temozolomide.

The researchers also reversed the treatment protocols, giving the chemotherapy before the immunotherapy to see if that worked better and improved survival. They didn’t notice a difference in survival time whether the immunotherapy was given before or after the brain-specific chemotherapy.

Citation: Mathios, Dimitrios,  Jennifer E. Kim1, Antonella Mangraviti1, Jillian Phallen1, Chul-Kee Park1, Christopher M. Jackson1, Tomas Garzon-Muvdi, Eileen Kim, Debebe Theodros, Magdalena Polanczyk, Allison M. Martin, Ian Suk, Xiaobu Ye, Betty Tyler, Chetan Bettegowda, Henry Brem, Drew M. Pardoll and Michael Lim. “Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM”. Science Translational Medicine 2016 vol: 8 (370).
DOI: 10.1126/scitranslmed.aag2942
Research funding: Arbor Pharmaceuticals, Agenus, Altor, BMS, Immunocellular, Celldex and Accuray.
Adapted from press release by Johns Hopkins Medicine.

Making T-Cell receptor gene therapy safer by domain swapping

The human body produces T cells to recognize and fight disease. Each T cell has a unique T cell receptor (or TCR) on its surface that surveils small fragments of proteins presented by other cells. Upon detecting evidence of cancer or infection, a subset of T cells binds the diseased cells and orchestrates their elimination. When tumors and infections cannot be eradicated naturally, researchers employ immunotherapies to boost the immune system’s effectiveness.

By inserting genes encoding a tumor-specific T cell receptor (TCR) into a patient’s T cells, researchers can engineer a large population of T cells to target tumor cells. This approach, called T cell receptor gene therapy, has yielded clinical successes where conventional cancer treatments have failed. However, T cell receptor gene therapy is not without risk. The introduced receptor can become tangled with the resident receptor in each engineered T cell, causing some of these cells to attack healthy cells. A new technique developed by Caltech researchers prevents this from happening, increasing the safety of T cell receptor gene therapy.

The technique, called domain swapping, was developed in the laboratory of David Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology. A paper describing the findings appears in the November 8 issue of the journal eLife.

The specificity of the T cell receptor (TCR) in each T cell results from the pairing of two protein chains–called an alpha chain and a beta chain–each of which has constant domains (shared between all TCRs) and variable domains (unique to each T cell). Normally, each T cell encodes only one alpha chain and one beta chain, which pair to form a single TCR. In T cell receptor gene therapy, the introduction of genes encoding a tumor-reactive TCR results in T cells that express two alpha chains and two beta chains, with four possible pairings. This non-physiological situation poses a risk of autoimmunity.

The group’s solution was to generate hybrid genes encoding T cell receptor (TCR) chains with their alpha and beta constant domains swapped in a compensatory fashion. When correctly paired, these domain-swapped TCRs retain all of the domains necessary to function. Indeed, the group found that domain-swapped TCRs and unmodified TCRs both function in human T cells, and they prevented tumor growth in mice to a similar extent. However, whereas unmodified TCRs mispaired with resident TCR chains in both mouse and human T cells, and caused autoimmunity in mice, domain-swapped TCRs did not.

In addition to preventing mispairing, domain-swapped TCRs highlight a surprising robustness to the function of the TCR complex. The Caltech group teamed with Mike Kuhns at the University of Arizona to determine that domain-swapped TCRs assemble in a similar manner to unmodified TCRs despite significant structural rearrangement of the constituent protein chains. Domain-swapped TCRs may be useful tools for further study of the structure and function of the TCR complex.

Finally, in collaboration with Wolfgang Uckert at the Max Delbrück Center for Molecular Medicine in Berlin, the researchers showed that domain-swapped TCRs were expressed at higher levels on the T cell surface when the resident TCR genes were silenced.

“Our paper focuses on the increased safety afforded by domain-swapping, but combining these two solutions may result in a therapy with improved safety and efficacy compared to current practice,” Bethune says.

Citation: Bethune, Michael T., Marvin H. Gee, Mario Bunse, Mark S. Lee, Eric H. Gschweng, Meghana S. Pagadala, Jing Zhou et al. “Domain-swapped T cell receptors improve the safety of TCR gene therapy.” eLife 5 (2016): e19095.
DOI: http://dx.doi.org/10.7554/eLife.19095
Research funding: National Institutes of Health, Prostate Cancer Foundation, Jane Coffin Childs Postdoctoral Fellowship, Pew Charitable Trusts.
Adapted from press release by California Institute of Technology.

HIV treatment with immunotherapy using VRC01 shows promise and limitations

Immunotherapy has revolutionized treatment options in oncology, neurology, and many infectious diseases and now there is fresh hope that the same method could be used to treat or functionally cure HIV, according to two related studies from Perelman School of Medicine at the University of Pennsylvania, the University of Alabama at Birmingham (UAB), and the National Institutes of Health (NIH).

Published online today in the New England Journal of Medicine, the research offers new insights into how immunotherapy could be used to develop a functional cure for HIV and eliminate the need for people living with the virus to take a daily regimen of medications.

The study, which examined chronically HIV-infected participants, found that injections of one broadly neutralizing HIV antibody (bNAb), known as VRC01, were safe, generated high levels of the antibody, and modestly delayed the time of HIV viral rebound compared to historical controls. However, suppression did not surpass 8 weeks in the majority of participants. By demonstrating that HIV-specific antibodies could be successfully administered as long-acting agents to suppress or even kill HIV-infected cells, this method is a first step toward the ultimate goal of durable suppression of HIV in the absence of antiretroviral therapy (ART).

Currently, most people living with HIV take a once-daily combination of antiretroviral therapy (ART), which prolongs life expectancy and improves overall health, but cannot completely eradicate the virus. Adherence to a daily HIV medication continues to be a challenge for many people living with HIV, especially in resource-limited settings. However, the vast majority of people living with HIV experience rapid rebound if absence of antiretroviral therapy (ART) is stopped or interrupted, making those people sicker and more likely to spread the virus to others.

Through broadly neutralizing HIV antibody (bNAb) immunotherapy, people living with HIV could potentially receive an injection of antibodies or another immunological intervention that would suppress the virus. The injection would remove HIV from a person’s blood and enable control of the virus without a daily absence of antiretroviral therapy (ART) regimen.

“For the near future, it is unlikely that we will be able to fully eradicate HIV once a person has been infected. But a functional cure is a reasonable intermediate goal,” Tebas said. A functional HIV cure means that while the virus would still exist in a person’s body in extremely small amounts, virus replication would be durably suppressed, disease progression drastically slowed, and symptoms of infection stopped – all without the need for daily medications.

“The goal of immunotherapy is to eliminate the need to take a pill every single day while simultaneously chipping away at the latent reservoir of virus-infected cells. However, we are still years away from that goal. And even if a person is able to be functionally cured of HIV, long-term follow-up will be essential to ensure that the virus doesn’t return to high levels,” Tebas said.

The bNAb tested in this trial did not provide long-lasting virus control in participants. Investigators tested historical blood samples from trial participants that were stored at both Penn and UAB’s Centers for AIDS Research (CFAR) in order to determine if there was pre-existing resistance to bNAb immunotherapy and reveal its limitations as a potential cure. They found that the trial participants with the shortest times of HIV suppression harbored viruses that were resistant to the broadly neutralizing HIV antibody (bNAb).

Bar notes that this study was a collaborative effort between several institutions. “The close collaboration between the Penn and UAB CFARs with the AIDS Clinical Trials Group (ACTG) enabled us to characterize the pre-existing resistance and identify it as a key barrier to developing broadly neutralizing HIV antibody (bNAb) immunotherapy as an HIV cure. Continued collaboration between CFARs and the ACTG will be instrumental as we continue to move this research forward.”

Future trials that are now in development will test whether combinations of more potent broadly neutralizing HIV antibody (bNAb) can provide durable virus suppression and potentially reduce the size of the persistent reservoir.

Citation: Katharine J. Bar, Michael C. Sneller, Linda J. Harrison, J. Shawn Justement, Edgar T. Overton, Mary E. Petrone, D. Brenda Salantes, Catherine A. Seamon, Benjamin Scheinfeld, Richard W. Kwan, Gerald H. Learn, Michael A. Proschan, Edward F. Kreider, Jana Blazkova, Mark Bardsley, Eric W. Refsland, Michael Messer, Katherine E. Clarridge, Nancy B. Tustin, Patrick J. Madden, KaSaundra Oden, Sijy J. O’Dell, Bernadette Jarocki, Andrea R. Shiakolas, Randall L. Tressler, Nicole A. Doria-Rose, Robert T. Bailer, Julie E. Ledgerwood, Edmund V. Capparelli, Rebecca M. Lynch, Barney S. Graham, Susan Moir, Richard A. Koup, John R. Mascola, James A. Hoxie, Anthony S. Fauci, Pablo Tebas, and Tae-Wook Chun. “Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption” New England Journal of Medicine. 2016 pp: NEJMoa1608243
DOI: http://dx.doi.org/10.1056/NEJMoa1608243
Research funding: NIH/National Institute of Allergy and Infectious Diseases
Adapted from press release by University of Pennsylvania

Research shows subopitmal reporting of adverse events in targeted therapy and immunotherapy trials

A significant number of trials of targeted therapies and immunotherapies in recent years show suboptimal reporting of adverse events, particularly the reporting of recurrent or late toxicities and the duration of the adverse events, researchers have told the ESMO 2016 Congress in Copenhagen.

“Reporting adverse events from clinical trials with new agents is a crucial point, as this will inform physicians and patients regarding the safety profile of that drug and what to expect when starting this therapy in a new patient in everyday clinical practice,” said principal investigator Dr Paolo Bossi, from the Head & Neck Unit at the Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan.

In this study, researchers reviewed publications from 81 trials of targeted therapies and immunotherapies approved by the US Food and Drug Administration between 2000-2015 for solid malignancies in adult patients. Each publication was assessed according to a 24-point score card based on the Consolidated Standards of Reporting Trials (CONSORT) guidance.

More than 90% of trials scored poorly in their reporting of recurrent and late toxicities, and in reporting the duration of adverse events; 86% of trials did not adequately report on the time of the adverse event occurrence; and 75% of trials only reported on adverse events that occurred at a frequency above a fixed threshold. More than half of the analysed papers showed limitations in the method for presenting adverse events, in describing the toxicities leading to therapy withdrawal, and in the follow-up interval assessment, while dose reductions due to adverse events were not reported in one-third of trials.

He highlighted the issue of duration of an adverse event – the so-called ‘third axis’ (the other being severity and frequency) in the evaluation of toxicities – which is not regularly considered with a new drug comes to market.

Dr Bossi said that it was encouraging to see a trend towards improved adverse event reporting in recent years. Moreover, there are new instruments available that can help physicians to improve the quality of adverse event reporting and help them discuss potential toxicities with their patients.

“The most important and innovative one is the PRO-CTCAE form, which is the patient-reported outcome version of the common toxicity criteria of adverse events, and which will allow physicians to collect the symptoms as reported by the patients, considering also the severity, intensity and influence of the symptoms on their quality of life.”

Press release from European Society of Medical Oncology”