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