FDA hits Cellectis’ off-the-shelf CAR-T program with clinical hold after first patient treated in phase 1 trial dies
Cellectis CEO Andre Choulika (By Ramon Martinez)
The FDA has placed a clinical hold on two phase 1 trials of Cellectis’ UCART123 after learning of the death of one patient. Development of the off-the-shelf CAR-T therapy is now in limbo while Cellectis works with the FDA to redesign the protocol to mitigate the risks identified in the first weeks of the trials.
Doctors at the MD Anderson Cancer Center dosed the first blastic plasmacytoid dendritic cell neoplasm (BPDCN) patient with CD123-targeting CAR-T UCART123 on August 16. The patient died nine days later.
Initially, the 78-year-old man responded to the lowest dose of UCART123 without complication. On day five the patient suffered a grade 2 cytokine release syndrome (CRS) and grade 3 lung infection. On day eight he experienced a grade 4 capillary leak syndrome (CLS) and a CRS that, despite treatment with corticosteroids and tociluzumab, played a central role in his death the next day.
The only patient treated with UCART123 in the other phase 1 trial experienced similar, albeit less severe, reactions. That patient, a 58-year-old woman with acute myeloid leukemia (AML), suffered a grade 3 CRS and grade 4 CLS nine days after treatment with UCART123. The adverse events put the patient in intensive care but had cleared up by day 12.
The list of adverse events suffered by the patients suggests UCART123 may be affected by safety issues both general to CAR-Ts and specific to its targeting of CD123. CRS is a known and, in the case of autologous products, generally manageable side effect of CAR-Ts. The process for managing the events is well established enough for Roche to have won approval for tocilizumab—also known as Actemra—as a treatment for CAR-T-induced CRS.
It is conceivable Cellectis can prevent further patient deaths by lowering the dose of UCART123 and follow the example set by other CAR-T trials by intervening earlier and more aggressively to treat CRS.
“We think one of the key learnings from the CD19 CAR-T trials is the early administration of steroids; however, we think early administration of steroids was withheld due to potential negative impact on cell persistence. In our view, [Cellectis] may need to re-evaluate the timing of steroid administration and be more aggressive in treating CRS,” analysts at Jefferies wrote.
The way to manage the adverse events that may be tied the candidate’s targeting of CD123 is less clear.
Stemline Therapeutics’ SL-401 is the precedent in this case. Three patients in clinical trials of CD123-directed therapy SL-401 have died after experiencing severe cases of CLS, a syndrome characterized by the leaking of blood plasma through capillary walls and into the surrounding tissue. Stemline added dosing and safety parameters to the lead-in stage of the study following the first two grade 5 cases of CSL. But those precautions failed to prevent the third death.
Cellectis now needs to figure out its own precautions before it can resume enrolling the 71 BPDCN patients and 155 AML patients it plans to treat across the two phase 1 trials. The data safety monitoring board has already proposed lowering the dose of UCART123 and capping the amount of the chemotherapy cyclophosphamide patients receive during the preconditioning stage. The two patients treated to date received cyclophosphamide alongside fludarabine.
The one bright spot for Cellectis in the otherwise grim safety data is the lack of reports of graft-versus-host disease (GvHD), a complication that arises when the immune system rejects an allogeneic transplant. Cellectis’ use of T cells from donors, rather than patients themselves, means GvHD is a potential concern. Cases of the condition would scuttle Cellectis’ ambition to capture the CAR-T market from Novartis and soon-to-be Gilead unit Kite Pharma by industrializing the CAR-T production process.
Shares in Cellectis opened down about 30% in Paris.
When it comes to treating cancer, surgeons want to get rid of as much cancerous tissue as possible during tumor removal. Now a new technology—the size of a pen—is attempting to make that easier by distinguishing between tumors and healthy tissue in just 10 seconds.
The MasSpec Pen is a real-time diagnostic tool created by researchers at the University of Texas at Austin. In a new study published Wednesday in the journal Science Translational Medicine, the researchers report that their handheld device (which is not yet FDA-approved) uses tiny droplets of water to analyze human tissue samples for cancer with 96% accuracy.
“It’s a gentle, simple chemical process,” says study author Livia Schiavinato Eberlin , an assistant professor of chemistry at UT Austin. “It’s highly specific and highly sensitive. The fact that it’s non-destructive brings a new approach to cancer diagnosis.”
Getting rid of all cancerous tissue while also preventing any harm to healthy tissue is a delicate process. When operating on a woman with breast cancer, for example, a doctor needs to remove the tumor and other affected tissues while maintaining the rest of the breast. Currently there are other tools available to surgeons for tissue diagnosis, but many use gases or solvents that can be harmful for the human body. In 2016, researchers in Massachusetts reportedthat they developed a probe that can find and light up cancer cells, making them easier for surgeons to see. But other methods currently available to surgeons today are slower than the MasSpec Pen, the study authors say, in some cases by 30 minutes or more.
Human cells produce a variety of small molecules, and cancer creates a unique set of them that can be used for pattern identification. The MasSpec Pen produces a small drop of water that extracts molecules from a person’s cells during surgery. Through machine learning, the MasSpec Pen is able to determine what molecular fingerprint is normal and what is cancer, Eberlin says.
In the study, the researchers tested 253 human tissue samples from lung, ovary, thyroid and breast cancer tumors and compared them to samples of healthy tissues. The device was 96% accurate at identifying cancerous tissues. The researchers also tested the MasSpec Pen in live mice with tumors and found that the device was able to identify the presence of cancer without harming healthy surrounding tissues. The device can also identify different subtypes of lung and thyroid cancer, and the team hopes to make it more specified for other types of cancer, too.
The researchers say they need to continue validating their work and that they plan to start clinical testing in humans in 2018. Until then, it’s unclear how exactly the device will work when integrated into surgery. While the pen-sized device that the surgeon would use is small, the device is connected to a large mass spectrometer, which helps the process of analyzing individual molecules . That large machine would need to be wheeled in and out of a surgery room for each procedure. The pen is disposable, so surgeons would replace it with each surgery.
“This is a good example of a tool that empowers our transition to precision medicine where the treatment can be done with much higher levels of confidence,” says study author Thomas Milner, professor of biomedical engineering in UT Austin's Cockrell School of Engineering . “Treatment can be planned and given where the outcomes are known. This is one tool along that path.”
A harmful virus that can cause devastating brain damage in babies could offer up a surprising new treatment for adult brain cancer, according to US scientists.
Until now, Zika has been seen only as a global health threat – not a remedy.
But latest research shows the virus can selectively infect and kill hard-to-treat cancerous cells in adult brains.
Zika injections shrank aggressive tumours in fully grown mice, yet left other brain cells unscathed.
Human trials are still a way off, but experts believe Zika virus could potentially be injected into the brain at the same time as surgery to remove life-threatening tumours, the Journal of Experimental Medicine reports.
The Zika treatment appears to work on human cell samples in the lab.
Image copyrightGETTY IMAGESImage captionThe virus would need to be delivered directly to where it is needed in the brain
There are many different types of brain cancer. Glioblastomas are the most common in adults and one of the trickiest to treat.
They are fast growing and diffuse, meaning they spread through the brain, making it difficult to see where the tumour ends and the healthy tissue begins.
Radiotherapy, chemotherapy and surgery may not be enough to remove these invasive cancers.
But the latest research, in living mice and donated human brain tissue samples, shows Zika therapy can kill cells that tend to be resistant to current treatments.
It is thought that these glioblastoma stem cells continue to grow and divide, producing new tumour cells even after aggressive medical treatment.
Different, healthy stem cells are found in abundance in baby brains, which probably explains why regular Zika can be so damaging to infants, say the researchers.
Adult brains, however, have very few stem cells. This means Zika treatment should destroy only the cancer-causing brain stem cells without causing much collateral damage.
As an extra safety precaution, the team, from Washington University School of Medicine and the University of California San Diego School of Medicine, have already begun modifying the virus to make it more tame than regular Zika.
Researcher Dr Michael Diamond said: "Once we add a few more changes, I think it's going to be impossible for the virus to overcome them and cause disease.
"It looks like there's a silver lining to Zika. This virus that targets cells that are very important for brain growth in babies, we could use that now to target growing tumours."
Dr Catherine Pickworth, from Cancer Research UK, said: "This promising research shows that a modified version of the Zika virus can attack brain tumour cells in the lab.
"This could one day lead to new treatments for this particularly hard to treat type of cancer."
Zika
Image copyrightREUTERSImage captionZika infections in pregnancy have been linked to cases of microcephaly in newborns
Zika is a virus people can catch if they are bitten by an infected mosquito
Most people will have few or no symptoms, but the disease can pose a serious threat to babies in the womb
Affected infants have been born with abnormally small heads and underdeveloped brains – a condition known as microcephaly
The infection has been linked to severe birth defects in almost 30 countries
Although Zika is no longer "an international medical emergency", the World Health Organization says it is closely monitoring the infection
BiliScreen is a new smartphone app that is designed to screen for pancreatic cancer by having users snap a selfie. It’s shown here with a 3-D printed box that helps control lighting conditions to detect signs of jaundice in a person’s eye.Dennis Wise/University of Washington
Pancreatic cancer has one of the worst prognoses — with a five-year survival rate of 9 percent — in part because there are no telltale symptoms or non-invasive screening tools to catch a tumor before it spreads.
Now, University of Washington researchers are developing an app that could allow people to easily screen for pancreatic cancer and other diseases — by snapping a smartphone selfie.
BiliScreen uses a smartphone camera, computer vision algorithms and machine learning tools to detect increased bilirubin levels in a person’s sclera, or the white part of the eye. The app is described in a paper to be presented Sept. 13 at Ubicomp 2017, the Association for Computing Machinery’s International Joint Conference on Pervasive and Ubiquitous Computing.
One of the earliest symptoms of pancreatic cancer, as well as other diseases, is jaundice, a yellow discoloration of the skin and eyes caused by a buildup of bilirubin in the blood. The ability to detect signs of jaundice when bilirubin levels are minimally elevated — but before they’re visible to the naked eye — could enable an entirely new screening program for at-risk individuals.
In an initial clinical study of 70 people, the BiliScreen app — used in conjunction with a 3-D printed box that controls the eye’s exposure to light — correctly identified cases of concern 89.7 percent of the time, compared to the blood test currently used.
“The problem with pancreatic cancer is that by the time you’re symptomatic, it’s frequently too late,” said lead author Alex Mariakakis, a doctoral student at the Paul G. Allen School of Computer Science & Engineering. “The hope is that if people can do this simple test once a month — in the privacy of their own homes — some might catch the disease early enough to undergo treatment that could save their lives.”
BiliScreen builds on earlier work from the UW’s Ubiquitous Computing Lab, which previously developed BiliCam, a smartphone app that screens for newborn jaundice by taking a picture of a baby’s skin. A recent study in the journal Pediatrics showed BiliCam provided accurate estimates of bilirubin levels in 530 infants.
In collaboration with UW Medicine doctors, the UbiComp lab specializes in using cameras, microphones and other components of common consumer devices — such as smartphones and tablets — to screen for disease.
BiliScreen provides estimates of bilirubin levels in a person’s blood. Elevated levels can be an early warning sign for pancreatic cancer, hepatitis and other diseases.Dennis Wise/University of Washington
The blood test that doctors currently use to measure bilirubin levels — which is typically not administered to adults unless there is reason for concern — requires access to a health care professional and is inconvenient for frequent screening. BiliScreen is designed to be an easy-to-use, non-invasive tool that could help determine whether someone ought to consult a doctor for further testing. Beyond diagnosis, BiliScreen could also potentially ease the burden on patients with pancreatic cancer who require frequent bilirubin monitoring.
In adults, the whites of the eyes are more sensitive than skin to changes in bilirubin levels, which can be an early warning sign for pancreatic cancer, hepatitis or the generally harmless Gilbert’s syndrome. Unlike skin color, changes in the sclera are more consistent across all races and ethnicities.
Yet by the time people notice the yellowish discoloration in the sclera, bilirubin levels are already well past cause for concern. The UW team wondered if computer vision and machine learning tools could detect those color changes in the eye before humans can see them.
“The eyes are a really interesting gateway into the body — tears can tell you how much glucose you have, sclera can tell you how much bilirubin is in your blood,” said senior author Shwetak Patel, the Washington Research Foundation Entrepreneurship Endowed Professor in Computer Science & Engineering and Electrical Engineering. “Our question was: Could we capture some of these changes that might lead to earlier detection with a selfie?”
BiliScreen uses a smartphone’s built-in camera and flash to collect pictures of a person’s eye as they snap a selfie. The team developed a computer vision system to automatically and effectively isolate the white parts of the eye, which is a valuable tool for medical diagnostics. The app then calculates the color information from the sclera — based on the wavelengths of light that are being reflected and absorbed — and correlates it with bilirubin levels using machine learning algorithms.
The UW team tested two different accessories for BiliScreen: a 3-D printed box to control lighting conditions and glasses that help the app calibrate colors. The goal is to remove the need for additional accessories, potentially by mining data from facial pictures.Dennis Wise/University of Washington
To account for different lighting conditions, the team tested BiliScreen with two different accessories: paper glasses printed with colored squares to help calibrate color and a 3-D printed box that blocks out ambient lighting. Using the app with the box accessory — reminiscent of a Google Cardboard headset — led to slightly better results.
Next steps for the research team include testing the app on a wider range of people at risk for jaundice and underlying conditions, as well as continuing to make usability improvements — including removing the need for accessories like the box and glasses.
“This relatively small initial study shows the technology has promise,” said co-author Dr. Jim Taylor, a professor in the UW Medicine Department of Pediatrics whose father died of pancreatic cancer at age 70.
“Pancreatic cancer is a terrible disease with no effective screening right now,” Taylor said. “Our goal is to have more people who are unfortunate enough to get pancreatic cancer to be fortunate enough to catch it in time to have surgery that gives them a better chance of survival.”
Co-authors include Allen School undergraduate student Megan A. Banks, research study coordinator Lauren Phillipi and assistant professor of medicine Lei Yu.
The research was funded by the National Science Foundation, the Coulter Foundation and endowment funds from the Washington Research Foundation.
In 2015, scientists from Rice University revealed they had created light-driven nanosubmarines. These tiny molecular machines were activated by ultraviolet light and based on earlier work from Nobel laureate Bernard Feringa, whose ground-breaking research won the prize for chemistry in 2016. These single-molecule machines have now been shown to be able to target, and drill into, specific cancer cells, paving the way for a variety of highly targeted future nanomedicine treatments.
These molecular machines consist of 244 atoms with a tail-like propeller that creates propulsion when exposed to UV light. After proving the concept worked back in 2015, the team moved on to exploring whether the molecular motor could penetrate an individual cell.
"We thought it might be possible to attach these nanomachines to the cell membrane and then turn them on to see what happened," explains chemist James Tour.
First the team needed to attach the molecular motor to a component that allowed it to target a specific cell. In these early experiments a peptide was utilized that drove the molecule to attach itself to the membrane of human prostate cancer cells. The molecules were shown to effectively locate and attach to the targeted cells, but not drill into them until specifically triggered by UV light. Once triggered, the motors spun up to two to three million rotations per second to break through the cell membrane and kill the cell within one to three minutes.
The obvious challenge that needs to be overcome is to develop an activation trigger other than ultraviolet light, which currently limits the molecular motors to being controllable when concentrated at the surface of tissue. Other triggers are currently being investigated, with near infra-red (IR) light looking like the best option to control these motors when delivered deep into a body.
"In this process, the motor will absorb two photons simultaneously and get enough energy to start the rotor," says Gufeng Wang, a chemist on the Rice University team. "Since near IR light has deep penetration depth, we are no longer limited to the surface of the tissue."
There is much work that still needs to be done before these molecular motors become a real, clinical treatment, but there are a variety of exciting outcomes this technology promises. As well as targeting and destroying cancer cells, the molecular motors could be utilized to deliver drugs directly into diseased cells.
As well as working on additional activation mechanisms, the team is embarking on a series of small animal tests to examine the effectiveness of the molecules on living organisms.
"The researchers are already proceeding with experiments in microorganisms and small fish to explore the efficacy in-vivo," says Tour. "The hope is to move this swiftly to rodents to test the efficacy of nanomachines for a wide range of medicinal therapies."
The research was published in the journal Natureand the video below provides a closer look at the team's breakthrough.
Cellectis CEO André Choulika。(圖：AFP)
法國生物製藥公司 Cellectis 使用的 CAR-T 療法 UCART123 造成患者死亡，5 日股價暴跌 3 成，逾 4 億美元市值蒸發。(圖截自 Google)
