CAR T cell therapy has revolutionized treatment for many people with blood cancers who had run out of other treatment options. While some patients experience long-term responses to CAR T cell therapy, it doesn’t work-or the cancer eventually returns-for others. The CD19 CAR T cell therapies that are currently approved all target CD19 through the same epitope (FMC63). To try and make CD19 CAR T cell therapy more effective for more patients, Marco Ruella, MD, an assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program, and his research team, along with the Korean company AbClon Inc, co-developed a CAR T product (AT101), using cells originating from the same patient, that targets CD19 through a different epitope, located closer to the cell membrane, via a novel antibody (h1218). In preclinical studies, the team previously demonstrated that h1218-CART19 had decreased T cell exhaustion and improved control compared to FMC63-CART19.

The Phase I first-in-human clinical trial (NCT05338931) was conducted in South Korea and enrolled 12 patients with relapsed or refractory B cell non-Hodgkin’s lymphoma (NHL). The study was designed to increase the dose level of AT101 after safety was confirmed in the first six patients. After a median follow-up of 6.5 months, all six patients who received dose level 2 or higher experienced a complete response and their cancer has not relapsed.

“We’ve learned that the way you design your CAR really matters. Designing a different CAR might drastically change the way the T cells work, potentially allowing that CAR T cell product to work where other CAR T cell products have failed,” Ruella said. “We were not expecting such a drastic early difference in this study. The CART19 products that are already FDA-approved are very effective, and it’s not easy to do better. While there is not a randomized trial of this product yet, the initial results seem very promising, and we look forward to moving into the planned Phase II portion of the study.”

The drug was found to be safe, with manageable side effects, including cytokine-release syndrome in four patients and immune-cell-related neurotoxicity syndrome in three patients. One patient experienced grade 3 sepsis that resolved; the same patient later developed fatal neutropenic septic shock outside the dose-limiting toxicity time frame.

The Phase I study enrolled patients who had not previously received any other CAR19 therapy. In the Phase II expansion, the study will also include patients who have previously received CAR19 therapy.

Can AI save us from the arduous and time-consuming task of academic research collection? An international team of researchers investigated the credibility and efficiency of generative AI as an information-gathering tool in the medical field.

The research team, led by Professor Masaru Enomoto of the Graduate School of Medicine at Osaka Metropolitan University, fed identical clinical questions and literature selection criteria to two generative AIs; ChatGPT and Elicit. The results showed that while ChatGPT suggested fictitious articles, Elicit was efficient, suggesting multiple references within a few minutes with the same level of accuracy as the researchers.

“This research was conceived out of our experience with managing vast amounts of medical literature over long periods of time. Access to information using generative AI is still in its infancy, so we need to exercise caution as the current information is not accurate or up-to-date.” Said Dr. Enomoto. “However, ChatGPT and other generative AIs are constantly evolving and are expected to revolutionize the field of medical research in the future.”

Their findings were published in Hepatology Communications.

But integrating 2D materials into devices and systems like computer chips is notoriously difficult. These ultrathin structures can be damaged by conventional fabrication techniques, which often rely on the use of chemicals, high temperatures, or destructive processes like etching.

To overcome this challenge, researchers from MIT and elsewhere have developed a new technique to integrate 2D materials into devices in a single step while keeping the surfaces of the materials and the resulting interfaces pristine and free from defects.

Their method relies on engineering surface forces available at the nanoscale to allow the 2D material to be physically stacked onto other prebuilt device layers. Because the 2D material remains undamaged, the researchers can take full advantage of its unique optical and electrical properties.

They used this approach to fabricate arrays of 2D transistors that achieved new functionalities compared to devices produced using conventional fabrication techniques. Their method, which is versatile enough to be used with many materials, could have diverse applications in high-performance computing, sensing, and flexible electronics.

Core to unlocking these new functionalities is the ability to form clean interfaces, held together by special forces that exist between all matter, called van der Waals forces.

However, such van der Waals integration of materials into fully functional devices is not always easy, says Farnaz Niroui, assistant professor of electrical engineering and computer science (EECS), a member of the Research Laboratory of Electronics (RLE), and senior author of a new paper describing the work.

“Van der Waals integration has a fundamental limit,” she explains. “Since these forces depend on the intrinsic properties of the materials, they cannot be readily tuned. As a result, there are some materials that cannot be directly integrated with each other using their van der Waals interactions alone. We have come up with a platform to address this limit to help make van der Waals integration more versatile, to promote the development of 2D-materials-based devices with new and improved functionalities.”

Niroui wrote the paper with lead author Peter Satterthwaite, an electrical engineering and computer science graduate student; Jing Kong, professor of EECS and a member of RLE; and others at MIT, Boston University, National Tsing Hua University in Taiwan, the National Science and Technology Council of Taiwan, and National Cheng Kung University in Taiwan. The research will be published in Nature Electronics.

Advantageous attraction

Making complex systems such as a computer chip with conventional fabrication techniques can get messy. Typically, a rigid material like silicon is chiseled down to the nanoscale, then interfaced with other components like metal electrodes and insulating layers to form an active device. Such processing can cause damage to the materials.

Recently, researchers have focused on building devices and systems from the bottom up, using 2D materials and a process that requires sequential physical stacking. In this approach, rather than using chemical glues or high temperatures to bond a fragile 2D material to a conventional surface like silicon, researchers leverage van der Waals forces to physically integrate a layer of 2D material onto a device.

Van der Waals forces are natural forces of attraction that exist between all matter. For example, a gecko’s feet can stick to the wall temporarily due to van der Waals forces. Though all materials exhibit a van der Waals interaction, depending on the material, the forces are not always strong enough to hold them together. For instance, a popular semiconducting 2D material known as molybdenum disulfide will stick to gold, a metal, but won’t directly transfer to insulators like silicon dioxide by just coming into physical contact with that surface.

However, heterostructures made by integrating semiconductor and insulating layers are key building blocks of an electronic device. Previously, this integration has been enabled by bonding the 2D material to an intermediate layer like gold, then using this intermediate layer to transfer the 2D material onto the insulator, before removing the intermediate layer using chemicals or high temperatures.

Instead of using this sacrificial layer, the MIT researchers embed the low-adhesion insulator in a high-adhesion matrix. This adhesive matrix is what makes the 2D material stick to the embedded low-adhesion surface, providing the forces needed to create a van der Waals interface between the 2D material and the insulator.

Making the matrix

To make electronic devices, they form a hybrid surface of metals and insulators on a carrier substrate. This surface is then peeled off and flipped over to reveal a completely smooth top surface that contains the building blocks of the desired device.

This smoothness is important, since gaps between the surface and 2D material can hamper van der Waals interactions. Then, the researchers prepare the 2D material separately, in a completely clean environment, and bring it into direct contact with the prepared device stack.

“Once the hybrid surface is brought into contact with the 2D layer, without needing any high-temperatures, solvents, or sacrificial layers, it can pick up the 2D layer and integrate it with the surface. This way, we are allowing a van der Waals integration that would be traditionally forbidden, but now is possible and allows formation of fully functioning devices in a single step,” Satterthwaite explains.

This single-step process keeps the 2D material interface completely clean, which enables the material to reach its fundamental limits of performance without being held back by defects or contamination.

And because the surfaces also remain pristine, researchers can engineer the surface of the 2D material to form features or connections to other components. For example, they used this technique to create p-type transistors, which are generally challenging to make with 2D materials. Their transistors have improved on previous studies, and can provide a platform toward studying and achieving the performance needed for practical electronics.

Their approach can be done at scale to make larger arrays of devices. The adhesive matrix technique can also be used with a range of materials, and even with other forces to enhance the versatility of this platform. For instance, the researchers integrated graphene onto a device, forming the desired van der Waals interfaces using a matrix made with a polymer. In this case, adhesion relies on chemical interactions rather than van der Waals forces alone.

In the future, the researchers want to build on this platform to enable integration of a diverse library of 2D materials to study their intrinsic properties without the influence of processing damage, and develop new device platforms that leverage these superior functionalities.

This research is funded, in part, by the U.S. National Science Foundation, the U.S. Department of Energy, the BUnano Cross-Disciplinary Fellowship at Boston University, and the U.S. Army Research Office. The fabrication and characterization procedures were carried out, largely, in the MIT.nano shared facilities.

Hubs are critical for connectivity

Hubs are everywhere. The hub of a bicycle wheel, with spokes shooting out from the center, keeps the wheel from collapsing when the bicycle is ridden. Airport hubs connect cities across the world. And social hubs like coffee shops or online social networks are places people gather for interaction.

The human brain has hubs, too — the intersection of many neuronal pathways that help coordinate brain activity required for complex functions like understanding and responding to speech. However, whether highly interconnected brain hubs are irreplaceable for certain brain functions has been controversial. By some accounts the brain, as an already highly interconnected neural network, can in principle immediately compensate for the loss of a hub, in the same way that traffic can be redirected around a blocked off city center.

With a rare experimental opportunity, the UI neurosurgical and research teams led by Matthew Howard III, MD, professor and DEO of neurosurgery, and Christopher Petkov, PhD, professor and vice chair for research in neurosurgery, have achieved a breakthrough in understanding the necessity of a single hub. By obtaining evidence for what happens when a hub required for language meaning is lost, the researchers showed both the intrinsic importance of the hub as well as the remarkable and rapid ability of the brain to adapt and at least partially attempt to immediately compensate for its loss. The findings were reported recently in the journal Nature Communications.

Evaluating the impact of losing a brain hub

The study was conducted during surgical treatment of two patients with epilepsy. Both patients were undergoing procedures that required surgical removal of the anterior temporal lobe — a brain hub for language meaning — to allow the neurosurgeons access to a deeper brain area causing the patients’ debilitating epileptic seizures. Before this type of surgery, neurosurgery teams often ask the patients to conduct speech and language tasks in the operating room as the team uses implanted electrodes to record activity from parts of the brain close to and distant from the planned surgery area. These recordings help the clinical team effectively treat the seizures while limiting the impact of the surgery on the patient’s speech and language abilities.

Typically, the recording electrodes are not needed after the surgical resection procedure and are removed. The innovation in this study was that the neurosurgery team was able to safely complete the procedure with the recording electrodes left in place or replaced to the same location after the procedure. This made it possible to obtain rare pre- and post-operative recordings allowing the researchers to evaluate signals from brain areas far away from the hub, including speech and language areas distant from the surgery site. Analysis of the change in responses to speech sounds before and after the loss of the hub revealed a rapid disruption of signaling and subsequent partial compensation of the broader brain network.

“The rapid impact on the speech and language processing regions well removed from the surgical treatment site was surprising, but what was even more surprising was how the brain was working to compensate, albeit incompletely within this short timeframe,” says Petkov, who also holds an appointment at Newcastle University Medical School in the UK.

The findings disprove theories challenging the necessity of specific brain hubs by showing that the hub was important to maintain normal brain processing in language.

“Neurosurgical treatment and new technologies continue to improve the treatment options provided to patients,” says Howard, who also is a member of the Iowa Neuroscience Institute. “Research such as this underscores the importance of safely obtaining and comparing electrical recordings pre and post operatively, particularly when a brain hub might be affected.”

According to the researchers, the observation on the nature of the immediate impact on a neural network and its rapid attempt to compensate provides evidence in support of a brain theory proposed by Professor Karl Friston at University College London, which posits that any self-organizing system at equilibrium works towards orderliness by minimizing its free energy, a resistance of the universal tendency towards disorder. These neurobiological results following human brain hub disconnection were consistent with several predictions of this and related neurobiological theories, showing how the brain works to try to regain order after the loss of one of its hubs.

In addition to Petkov and Howard, the research team included researchers in the UI Departments of Neurosurgery, Radiology, and Psychological and Brain Sciences, as well as colleagues from Newcastle University, UCL, and University of Cambridge in the UK, and from Carnegie Mellon University, University of Wisconsin-Madison, and Gonzaga University in the United States.

The research was funded in part by grants from National Institutes of Health, the Wellcome Trust. and the European Research Council.