Tag: Biotech

Targeting solid tumors remains one of oncology’s most persistent challenges. Even when a therapeutic antibody is well‑designed, and its molecular target is clear, the drug often struggles to reach its destination inside the dense, heterogeneous architecture of human tumors. Understanding why these agents fail in patients has been a longstanding blind spot in cancer pharmacology.

A new study from Vanderbilt University Medical Center and Stanford University begins to close that gap. In work published in Nature Biotechnology, researchers developed a single-cell spatial pharmacology (SSP) platform, an experimental and analytical system that visualizes drug–tumor interactions directly in human solid tumors. The approach provides a high‑resolution view of drug delivery, target engagement, and the physical barriers that shape therapeutic response.

Eben Rosenthal, MD, the Barry and Amy Baker professor and chair of otolaryngology–head and neck surgery at Vanderbilt Health, is senior author of the paper, titled “Single‑cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors.” Rosenthal and co‑author Guolan Lu, PhD, of Stanford University School of Medicine, developed SSP to quantify how antibody‑based therapies behave once they enter the tumor microenvironment.

“Identifying the reason drugs fail in so many cancer patients is a high priority, and SSP can help,” Rosenthal said. “Current pharmacology tools and imaging methodologies do not provide the answers we need to understand which drugs fail due to poor delivery and which ones fail due to insufficient activity upon entering the tumor.”

Using SSP, the team found pronounced spatial heterogeneity in both drug delivery and target engagement across head and neck, pancreatic, and other solid tumor types. The data point to a consistent culprit: the stromal architecture, known as the dense, noncancerous tissue surrounding tumors, which acts as a physical barrier that limits antibody penetration.

“This approach allows us to examine how the drug distributes within the tumor, the cell types with which it interacts, how strongly it engages its molecular target, and how the architecture of the tumor microenvironment shapes its delivery and activity,” Rosenthal said.

The study included analysis of panitumumab‑IRDye800CW, an antibody used in Phase I trials and which is under investigation for fluorescence‑guided surgery. Rosenthal’s group has long been at the forefront of integrating fluorescence imaging into cancer research and surgical oncology.

“By directly measuring drug delivery at the site of targeted antibody therapy, SSP can distinguish tumor regions that are biologically unresponsive from those that are simply underexposed to the agent. We hope additional study in larger sample sizes of patients can help further validate the application of SSP to identify barriers to drug efficacy,” Rosenthal added.

By exposing the physical and biological barriers that shape drug performance in human tissue, the platform offers a path toward designing tools that account for the true complexity of the tumor microenvironment.

The post Spatial Single‑Cell Platform Reveals Barriers to Antibody Delivery in Solid Tumors appeared first on GEN – Genetic Engineering and Biotechnology News.

T cells are some of the immune system’s most important fighters. They can stop tumor growth and fight off severe infections. Scientists at La Jolla Institute for Immunology (LJI) have now reported a study indicating how T cells target paramyxoviruses, a viral family that includes measles virus and Nipah virus.

Paramyxoviruses are pathogens of pandemic concern. Measles virus is highly infectious, and Nipah virus has a high mortality rate. The new study shows how we might harness T cells to save lives. Headed by Alessandro Sette, PhD, the team systematically mapped human CD4+ T cell epitopes across Nipah and measles viruses, and analyzed T cells from donors who had previously received the MMR vaccine that protects against measles, and another paramyxovirus, mumps (as well as rubella), and who had not been exposed to Nipah virus. Their experiments showed that the two paramyxoviruses had conserved T cell epitopes (CTERs) in common, and that cross-reactive T cells can recognize multiple paramyxovirus species at once.

Instead of vaccinating against one virus at a time, the researchers found that activating these cross-reactive T cells may protect against the wider paramyxovirus family. This broad protection is essential when you don’t know which virus will strike next.

The discovery may guide the development of new vaccines and therapies that stop measles, Nipah, and other paramyxovirus infections before they turn deadly. “No one knows which particular viral species or strain of a virus might be responsible for an outbreak, as we’ve seen in the recent cases of Andes hantavirus,” Sette said.

Sette and colleagues reported on their findings in Cell Reports Medicine, in a paper titled “Comprehensive mapping of human CD4+ T cell epitopes for Nipah and measles as prototype Paramyxoviruses,” concluding, “Collectively, these findings support the concept that CTER-based immunogen design can both broaden protective coverage and strategically harness existing population immunity while complementing neutralizing antibody-based vaccine approaches.”

The Paramyxoviridae family, which includes measles and Nipah viruses, represents “… a plethora of viruses that impact global human health,” the authors wrote. “Understanding adaptive immune responses to these viruses is critical for characterizing host-pathogen interactions and evaluating vaccine performance.”

A part of the adaptive immune system T cells learn to target a specific threat. A T cell might respond to influenza virus infection but not malaria parasite infection. To do this T cells recognize specific epitopes on the pathogen. In general, T cell epitopes on one pathogen look very different from T cell epitopes on another pathogen.

But viruses may retain some “conserved” features that remain unchanged within viral families. LJI scientists have shown that some T cells can cross-react to different viruses, as long as the viruses share similar epitopes. In a series of landmark studies during the COVID-19 pandemic, Sette, LJI research assistant professor Alba Grifoni, PhD, LJI assistant professor Daniela Weiskopf, PhD, and professor and chief scientific officer Shane Crotty, PhD, showed that cross-reactive T cells can recognize the family resemblance between different coronaviruses. A person who had previously contracted a common cold coronavirus may already have T cells primed to recognize SARS-CoV-2, the coronavirus that causes COVID-19.

More recently, Sette and Grifoni demonstrated that cross-reactive T cells may offer broad protection against the deadly Lassa virus and the wider viral family of arenaviruses. Their findings suggested that future vaccines and therapies could activate these cross-reactive T cells to protect against many dangerous viruses at once. Each study makes it clear that cross-reactive T cells are key to stopping emerging viruses.

Measles is a threat worldwide, and while an effective vaccine is available, the authors cited figures indicating that there were over 10 million estimated infections worldwide in 2023. “Measles remains one of the main causes of morbidity and mortality in children, due to secondary infections from measles-induced immune suppression,” they noted. People in Southeast Asia also have to keep watch for a related paramyxovirus threat, Nipah virus, which is spread by bats. Cases are rare but can be deadly. “Nipah virus is another Paramyxovirus of concern due to high mortality rates, often mediated by fatal encephalitis,” the investigators wrote. Nipah virus has a fatality rate of 40-75%, which is much higher than measles. “Outbreaks are becoming more and more frequent, especially in the Malaysian region,” said Grifoni.

The new LJI study suggests cross-reactive T cells may be just the weapons we need to combat the dangerous paramyxovirus family. The scientists worked with LJI’s John and Susan Major Center for Clinical Investigation to collect and analyze T cells from the blood of 31 study participants. These study participants had received their MMR vaccines, which protect against severe infection from the measles and mumps viruses (both are paramyxoviruses) and the rubella virus. As a result, the blood samples contained T cells that were ready to fight measles infection.

LJI postdoctoral fellow Alison Tarke, PhD, and LJI senior staff scientist Ricardo Da Silva Antunes, PhD, led experiments to map the T cell epitopes on measles virus. These findings were important on their own. “Even though measles has been studied for quite some time, and there is a vaccine for measles, there was not a lot known about the specific T-cell response elicited by the measles vaccine,” Sette commented.

Tarke and the LJI team then tested how these same T cells reacted to Nipah virus. From blood tests, the scientists knew that the study participants had never been infected with Nipah virus, yet they found that measles-fighting T cells could cross-react and also recognize Nipah virus. The two paramyxoviruses had conserved T cell epitope regions (CTERs) in common. “Focusing immune responses on these conserved regions could have a broad, protective capacity for the whole viral family,” says Sette. The authors added,

The new study is the first to map T cell epitopes on Nipah virus. The researchers were able to zero in on a specific epitope shared between measles and Nipah viruses: a region of the viral fusion or “F” protein. A large number of cross-reactive T cells targeted this relatively small, conserved viral structure. “It appears that if someone is vaccinated against measles, their T cells will have some degree of cross-reactivity to Nipah,” said Sette. “That raises the possibility that during a Nipah outbreak, one could perhaps vaccinate people with a measles vaccine, and this cross-reactivity could potentially offer some benefit.”

The authors further noted, “In light of these findings, current Nipah vaccine candidates, many of which focus primarily on whole-protein antigens selected to maximize neutralizing antibody responses, particularly F and G glycoproteins, could potentially be optimized by incorporating conserved T cell epitope regions.” Added Grifoni, “Activating T cells can be your first line of defense when you don’t know what’s going to be thrown at you.”

In their paper the team concluded “With specific regard to vaccine strategies targeting Nipah or other paramyxoviruses, one anticipated outcome of focusing on CTERs, particularly those shared with measles and mumps viruses, is the potential to boost preexisting cross-reactive memory T cell responses in populations where MMR vaccination is widespread.”

The post Cross-Reactive T Cells Could Point to Broad Vaccines or Treatments for Measles, Nipah Virus appeared first on GEN – Genetic Engineering and Biotechnology News.

Fulcrum Therapeutics said today it is scrapping its lead pipeline program to develop pociredir as a treatment for sickle cell disease (SCD) and launching a “comprehensive” review of strategic alternatives, after the FDA told the company it had heightened concerns about the drug’s risks and benefits in fighting the disease.

Those concerns, which the agency raised with Fulcrum executives at a recent end-of-phase meeting, stemmed from an unexpectedly high rate of secondary blood cancers seen with another PRC2 inhibitor—Ipsen’s Tazverik^® (tazemetostat), indicated to treat follicular lymphoma and epithelioid sarcoma, the company disclosed, based on meeting minutes received May 28.

Ipsen voluntarily withdrew Tazverik from the market in March following adverse events of secondary blood cancers emerging from the ongoing Phase Ib/III SYMPHONY-1 trial (NCT04224493), which evaluated the drug in combination with lenalidomide plus rituximab (R²) vs R² in follicular lymphoma. Ipsen inherited the drug when it acquired its developer Epizyme in 2022 for $247 million. Tazverik last year generated €40.6 million ($47.2 million) for Ipsen and another $2.5 million for Hutchmed, which marketed the drug in China. The withdrawal also affected Eisai, since it marketed Tazverik in Japan and manufactured the drug there.

Pociredir is an oral small molecule polycomb repressive complex 2 (PRC2) inhibitor targeting embryonic ectoderm development (EED), and was discovered using Fulcrum’s discovery technology. Fulcrum has reasoned that inhibiting EED leads to potent downregulation of key fetal globin repressors including BCL11A, thereby causing an increase in fetal hemoglobin (HbF).

“Fulcrum submitted information to FDA supporting the position that mechanistic differences between EED (pociredir’s target) and EZH2 (tazemetostat’s target), which perform different biological roles, were relevant to the benefit-risk assessment,” Fulcrum said in a statement. “While no new safety signals have been observed to date with pociredir, the FDA raised concerns regarding the potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex.

The agency considered Fulcrum’s position before rebuffing the company, concluding that any drug intervention targeting the PRC2 complex carries equivalent malignancy risk “regardless of the specific subunit engaged,” Fulcrum continued, based on pociredir’s previously disclosed preclinical malignancy observations.

That left no viable regulatory path forward for further clinical development of pociredir, Fulcrum concluded.

No path forward

“Following a thorough review of regulatory feedback, the totality of available data, and the implications for a viable regulatory path, we have made the very difficult decision to discontinue development of pociredir,” stated Alex C. Sapir, Fulcrum’s president and CEO. “We arrived at this decision after discussion with the FDA, and despite robust elevations in fetal hemoglobin seen with pociredir and the potential for clinical benefit, we do not see a path forward with pociredir.”

“We know the SCD community has faced many disappointments and setbacks related to innovation for this devastating disease,” Sapir added. “We are not only humbled but forever grateful to the SCD warriors, investigators, and broader SCD community who have worked tirelessly alongside Fulcrum to evaluate new treatment options for this devastating disease.”

Pociredir is not the first SCD therapy to be scrapped. In 2024, Pfizer withdrew Oxbryta^® (voxelotor) from the market, citing deaths and vaso-occlusive crises occurring in patients given Oxbryta in clinical studies. Hours before Pfizer’s announcement, the European Medicines Agency (EMA) disclosed findings from two Phase III trials of Oxbryta in which a total of 18 deaths occurred—all but two of them reported in patients who were dosed with the drug.

Pfizer inherited Oxbryta when it acquired the drug’s original developer, Global Blood Therapeutics (GBT), for $5.4 billion, a deal completed in 2022.

Vijay Sankaran, MD, PhD, Professor of Pediatrics at Boston Children’s Hospital and a Howard Hughes Medical Institute investigator, called the outcome “unfortunate.” Sankaran told GEN: “There have been concerns about whether PRC2 inhibition could be sufficiently selective and without potential side effects.”

Much of the preclinical work on pociredir, Sankaran noted, was performed in cell models that might not have revealed the full range of potential effects.

Vivien Sheehan, MD, PhD, director of Translational Sickle Cell Disease Research at Emory University School of Medicine, told GEN Fulcrum’s data was “reasonable, although not game changing.”

“I don’t take it [Fulcrum’s halt to pociredir development] as an abandonment of SCD,” said Sheehan, who is also a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University. “There may not have been a path forward, and more efficacious drugs in the pipeline may have also influenced the decision.”

She expressed greater enthusiasm for a potential SCD treatment being developed by Bristol Myers Squibb (BMS)—BMS-986470, an oral HbF-activating cereblon (CRBN) E3 ligase modulator (CELMoD) agent designed as a potential first-in-class degrader of both transcription factors zinc finger and BTB domain containing 7A (ZBTB7A) and widely interspaced zinc finger (WIZ).

BMS-986470 is now under study in an ongoing Phase I/II trial (NCT06481306) designed to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, pH and food effect, and preliminary efficacy of BMS-986470 in healthy volunteers and participants with SCD. The study’s estimated primary completion date is January 6, 2027, according to ClinicalTrials.gov.

A 2024 preclinical study by a team of BMS researchers showed BMS-986470 to have generated “robust γ -globin induction activity leading to HbF levels predicted to significantly ameliorate SCD pathology.”

$1.5B peak sales forecast

In ending development of pociredir, Fulcrum has scrapped a drug that stood to generate as much as $1.5 billion in projected peak sales by 2038, according to BofA Securities, which predicted a 2029 commercial launch for the drug.

Investors responded to Fulcrum’s halt to development of pociredir with a stock selloff that sent shares of Fulcrum on the Nasdaq Global Market plummeting 51% Tuesday, to $3.13 from yesterday’s closing price of $6.42.

As a result of scraping development of pociredir, Fulcrum said, it will explore potential strategic alternatives, “including, but not limited to, a merger, acquisition, business combination, or other strategic transactions involving the company or its assets.”

Fulcrum said it has also begun efforts to “significantly” reduce its operating expenses and preserve capital. Fulcrum finished the first quarter with $333.3 million in cash, cash equivalents, and marketable securities.

“We believe that our existing cash, cash equivalents, and marketable securities as of March 31, 2026 will enable us to fund our operating expenses and capital expenditure requirements into 2029,” Fulcrum stated in its Form 10-Q regulatory filing for the first quarter.

“With a strong balance sheet extending our cash runway into 2029, we are well positioned to advance pociredir through the next phase of clinical development,” Fulcrum stated in its April 27 press release.

The company has not set a timeline for completing its strategic review, adding that it does not intend to provide further updates “unless and until the board of directors has approved a course of action, the review process is concluded, or other disclosure is otherwise determined to be appropriate.”

Positive interim data

As late as April 27, when it held its quarterly earnings call with analysts to discuss first quarter results, Fulcrum had conveyed optimism about pociredir’s clinical prospects.

During the call, Sapir cited Fulcrum’s announcement of positive interim data from its Phase Ib PIONEER trial (NCT05169580) in February, which showed:

• A mean absolute HbF increase of 12.2% at 12 weeks of treatment with pociredir, rising from a baseline of 7.1% to 19.3%—what the company said represented “a rapid, robust, and clinically relevant response,” with progression toward pan-cellular HbF induction as F-cells increased from 31% to 63%.
• Absolute HbF levels ≥20% in 7 of 12 patients (58%), with all patients achieving at least a 6.5% absolute increase in HbF.
• Improvements in markers of hemolysis, improved erythropoiesis, and a >1 g/dL increase in total hemoglobin.
• Zero vaso-occlusive crises (VOCs) during the treatment period reported in seven of 12 patients (58%).

“Importantly, pociredir has continued to be generally well tolerated with no treatment-related serious adverse events reported to date,” Sapir told analysts. “Taken together, these data reinforce our conviction in pociredir’s potential to address the underlying biology of sickle cell disease—and support our belief that pociredir has the potential to represent a differentiated, once-daily oral treatment option for patients.”

The post Fulcrum Halts Development of SCD Candidate Pociredir, Sets Strategic Review appeared first on GEN – Genetic Engineering and Biotechnology News.