Synovial sarcoma is diagnosed in fewer than 1,000 people in the United States each year. This cancer can develop in the extremities or in the soft tissues of the abdomen or lungs. It occurs most often in young adults. It is slightly more common in men than in women. New treatments for this cancer are currently being developed. Moreover, accelerated approval for a treatment for adults with synovial sarcoma, afamitresgene autoleuecel immunotherapy (Tecelra ®, also known as afami-cel), has been granted by the US Food and Drug Administration (FDA). The cancer-causing protein targeted by afami-cel is called MAGE-A4. It is the first modified T-cell therapy to receive FDA approval for a solid tumor cancer. The clinical trial was an international study involving 52 people with synovial sarcoma and Myxoid/Round Cell LipoSarcoma (MRCLS), another type of soft tissue sarcoma. These patients had not responded to other treatments. Around 37% of patients saw their tumors shrink after receiving a single dose. The drug helped around 39% of people with synovial sarcoma and 25% of those with MRCLS.

Stem-cell transplants have freed seven people of the virus, but researchers say most long-term interventions remain a distant prospect.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disease with sudden onset symptoms, including nerve damage affecting movement, sensation, speech, breathing, and heart rhythm. Treatments such as glucocorticoids, plasmapheresis, and intravenous gamma globulin (IVIG) can help manage symptoms but cannot completely eradicate the disease. However, a research team has reported using BCMA-CD19 bispecific CAR-T cells to treat relapsed/refractory CIDP, restoring the balance of immune responses by temporarily and profoundly eradicating B cells and plasma cells. After being treated with this therapy, one patient made significant progress in functioning according to the INCAT disability and MRC scores. Remarkably, almost complete recovery of muscle power was observed 180 days after administration of CAR-T, along with the ability to walk again. This study, therefore, highlights the evolution of patients' symptoms after treatment and confirms the safety of CAR-T cell therapy for CIDP. 

In a recent study of 30,000 patients treated with CAR-T therapy, second cancers reported are rare. However, the US FDA has monitored around 25 cases of CAR-T cell second cancers, generally lymphomas. Furthermore, researchers do not know how the CAR-T cells became a lymphoma. It is possible that the cells had lymphoma-causing mutations when they were initially collected from the patient and that CAR-T treatment caused the activation and expansion of these cells, that the mutations may have occurred when the CAR-T cells were prepared outside the patient, or that the CAR-T cells may have acquired the mutations after being returned to the patient. For future diagnostic and treatment purposes, the researchers note that switchable cell therapies could allow patients to take a drug to adjust the CAR-T cell activity daily, thereby reducing toxic side effects. 

According to a 2020 report by the Centers for Disease Control and Prevention (CDC), Florida has the second highest number of new cases of melanoma per year in the United States. However, these patients will soon have access to the first cellular therapy for this advanced form of skin cancer, following its recent approval by the Food and Drug Administration (FDA). This therapy, known as tumor-infiltrating lymphocyte therapy, or TIL, uses patients' own immune cells to fight their cancer. Trials testing TIL therapy, called lifileucel, prior to FDA approval showed a 32% response rate among 153 patients, and more than half of patients who responded favorably to treatment had maintained that response for more than three years. Lifileucel is approved for patients whose melanoma has progressed despite treatment with other forms of immunotherapy, including those involving checkpoint inhibitors, and targeted therapy for melanomas with a common BRAF gene mutation. 

Two blood biomarkers, pre-lymphodepletion C-reactive protein and ferritin, can help predict which lymphoma patients are at risk of poor outcomes after CAR-T cell therapy. Researchers analyzed data from 136 patients with relapsed or refractory diffuse large B-cell lymphoma. Almost all (93%) developed cytokine release syndrome, and 61% developed immune effector cell-associated neurotoxicity syndrome (ICANS). The researchers determined that patients with baseline blood levels of C-reactive protein (CRP) of at least 4 mg/dL and baseline ferritin of 400 ng/mL or more faced a higher risk of adverse outcomes, including shorter PFS, shorter OS and higher rates of severe toxicities. However, given that patients in the “low-risk” category are much less likely to experience severe toxicities or any type of major morbidity or mortality, these patients could be treated with CAR-T on an outpatient basis.

In the never-ending quest to discover previously unknown CRISPR gene-editing systems, researchers have scoured microbes in everything from hot springs and peat bogs to poo and even yogurt. Now, thanks to advances in generative artificial intelligence (AI), they might be able to design these systems with the push of a button.

This week, researchers published details of how they used a generative AI tool called a protein language model — a neural network trained on millions of protein sequences — to design CRISPR gene-editing proteins, and were then able to show that some of these systems work as expected in the laboratory1.

The integration of cleavable donor plasmids with hydrodynamic delivery opens up new avenues for treating genetic disorders. Cleavable donor plasmids imply that when the CRISPR-Cas system is directed to a specific location in the genome where a modification is desired, the Cas enzyme not only cleaves genomic DNA at the targeted site, but can also cleave the donor plasmid at the designated sites. This cleavage releases the donor DNA segment, which is then inserted into the genome at the cleavage site via the cell's natural DNA repair mechanisms. In addition, hydrodynamic delivery, a non-viral method, was used for its efficacy and safety compared to viral-based delivery systems. This approach mitigates the risks associated with the host immune response to viral vectors and undesirable mutations due to sustained nuclease expression. The research conducted precise in-frame knock-ins using CRISPR-Cas9 and Cas12a systems, successfully integrating reporter gene cassettes into targeted genomic loci in adult mouse liver. The results demonstrate the system's precise gene-editing capability and its potential applicability in therapeutic contexts. 

The study adapted the novel CRISPR-Cas Specific High-Sensitivity Enzymatic Reporter Unlocking (SHERLOCK) based diagnostic platform for species-specific detection of oral bacterial and human pathogens papillomavirus (HPV) nucleic acids. The investigators developed a computer pipeline capable of generating guide RNAs and species-specific genetic primers suitable for SHERLOCK. These constructs were synthesized by cell-free biosynthesis systems, and their specificity and sensitivity were experimentally validated by fluorescence readings of reporter RNAs. The study detected oral bacteria in the single-molecule range that remained specific in the presence of non-targeted DNA found in saliva. In addition, the assay was refined to detect common oral pathogens (e.g. P. gingivalis, F. nucleatum) directly from untreated saliva samples. Detection results, when tested on 30 patient saliva samples, are perfectly aligned with those of other detection methods such as qPCR and 16S rRNA sequencing. This oral pathogen detection method is highly scalable and can be easily optimized for point-of-care implementation. Detection takes around 35 minutes or less, is extremely inexpensive and requires no special skills or techniques.

Recurrent glioblastoma (rGBM) is an aggressive, treatment-resistant brain cancer with no conventional treatment options after chemoradiotherapy. Median overall survival (OS) is less than one year, indicating that effective treatment is an urgent unmet medical need in oncology. Despite limited therapeutic options, chimeric antigen receptor T cells targeting GBM-specific antigens have demonstrated tolerable safety but poor efficacy in adults. In the phase 1 clinical trial of a recent study, the use in cancer patients of intrathecally administered bivalent autologous chimeric antigen receptor (CAR) T lymphocytes targeting the epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2) was associated with early neurotoxicity, possibly the immune effector-associated neurotoxicity syndrome (ICANS). All six patients showed reduction in tumor size and enhancement, but none met criteria for objective response rate. The researchers identified CAR-T cell abundance and cytokine release in all patients, and all developed neurotoxicity. 

Muscular dystrophies are a group of congenital genetic diseases that affect muscle tissue, often resulting in severe disability and considerably reduced life expectancy. Despite intensive research, there is still no effective treatment for patients suffering from muscular dystrophy. It has already been discovered that the muscles that control eye movements are not affected by muscular dystrophy, even in otherwise serious disease processes. In people with muscular dystrophy, the muscles of the body atrophy, while the muscles of the eye remain strong despite the same genetic abnormality. A study has now shed light on this phenomenon. It turns out that a specific gene plays a key role. This gene, fhl2b, is expressed in eye muscles throughout life, but not in other muscles of the body. In the study, researchers used genetically modified zebrafish to investigate how muscular dystrophies affect eye muscles in relation to other muscles in the body. Using Crispr/Cas9 genetic scissors, new models of genetic diseases were created and used on zebrafish.

Currently, three CAR-T cell therapies (axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel)) are approved for the treatment of Diffuse Large B-Cell Non-hodgkin's Lymphoma (DLBCL). However, patients receiving these therapies are at high risk of developing either Cytokine Release Syndrome (CRS) or Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS). To monitor and manage these toxicities, the US Food and Drug Administration (FDA) has implemented a Risk Evaluation and Mitigation Strategy (REMS) requiring CAR-T therapy recipients to remain within two hours of their Authorized Treatment Center (ATC) for four weeks after therapy and to refrain from driving for eight weeks after treatment. However, a recent study showed that most patients who developed CRS or ICANS did so within the first two weeks after infusion. This would justify a shorter and more flexible toxicity monitoring period. The results also showed that after two weeks, infections, which developed in 14.5% of patients within 28 days of infusion, were the most common cause of death. This underlines the fact that infection is the main challenge following CAR-T treatment.  

Researchers have refined the primary editing (PE) method for correcting the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a significant cause of cystic fibrosis. They combined several efficiency improvements, including engineered PE guide RNAs and PEmax architecture. They achieved high correction efficiency in immortalized bronchial epithelial cells and substantial correction in patient-derived airway epithelial cells. In addition, they used strategic silent modifications to evade cellular mismatch repair and incorporated PE6 variants and dead simple guide RNAs (dsgRNAs) to improve targeting and editing efficiency. Results showed that these combined optimizations significantly increased the correction efficiency for CFTR F508del, reaching 58% in immortalized bronchial epithelial cells and 25% in primary airway epithelial cells derived from cystic fibrosis patients. Functional analyses indicated that corrected CFTR ion channels restored more than 50% of wild-type function, comparable to current drug treatments for cystic fibrosis. 

Nineteen genetic therapies have been approved by the U.S. Food and Drug Administration (FDA) to date, a number that now includes the first CRISPR genome editing therapy for sickle cell disease, CASGEVY (exagamglogene autotemcel). This extraordinary milestone is widely celebrated because of the promise for future genome editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding $4 million per patient.

CAR-T therapy, which harnesses a person’s own immune cells, racks up some astonishing success stories against deadly brain tumours in children. 

Activated T cells in patients with autoimmune diseases, cancer or viral infections expose large amounts of B7H6 on their surface. Co-culture experiments in the culture dish have shown that Natural Killer (NK) cells recognize activated T cells by their B7H6 expression. In contrast, T cells whose B7H6 gene was knocked out with CRISPR-Cas were protected from lethal NK cell attack. B7H6 can now be classified as another inhibitory immune checkpoint on T cells. Researchers have thus discovered that NK cells can thus alter the effect of cancer therapies using immune checkpoint inhibitors (ICIs). They may also be responsible for the rapid decline of therapeutic CAR-T cells. Interventions in this mechanism could potentially improve the efficacy of these cellular cancer immunotherapies. 

The European Commission has approved ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more previous lines of therapy (such as an immunomodulatory drug and a proteasome inhibitor), have progressed on their last line of therapy and are refractory to lenalidomide Revlimid. The expanded indication for cilta-cel was based on the results of the phase 3 CARTITUDE-4 trial (NCT04181827), which demonstrated that after a median follow-up of 15.9 months (range: 0.1-27.3), treatment with cilta-cel reduced the risk of progression or death by 74% compared with standard therapies in patients with relapsed or refractory disease who had received 1 to 3 prior lines of treatment (HR: 0.26; 95% CI, 0.18-0.38). Median progression-free survival (PFS) was not yet achieved in the cilta-cel arm versus 11.8 months (95% CI, 9.7-13.8) in the standard of care (SOC) arm. Estimated 12-month PFS rates were 76% (95% CI, 69%-81%) with cilta-cel versus 49% (95% CI, 42%-55%) with SOC.

The rise of RNA viruses such as SARS-CoV-2 highlights the need to find new ways of combating them. RNA targeting tools such as CRISPR/Cas13 are powerful but ineffective in the cytoplasm of cells, where many RNA viruses replicate. Scientists have developed a solution: Cas13d-NCS, a new system capable of transferring nuclear CRISPR RNAs (crRNAs) into the cytosol. crRNAs are short RNA molecules that guide the CRISPR-Cas complex to specific target sequences for precise modifications. In the cytosol, the protein/cRNA complex targets complementary RNAs and degrades them with unprecedented precision. With remarkable efficiency, Cas13d-NCS outperforms its predecessors in degrading mRNA targets and neutralizing self-replicating RNA, including the replication sequences of Venezuelan Equine Encephalitis (VEE) RNA virus and several variants of SARS-CoV-2, unleashing the full potential of Cas13d as a programmable antiviral tool. This new molecular tool enables crRNA molecules located in the nucleus of a cell to move into the cytoplasm, making it highly effective in neutralizing RNA viruses. This breakthrough opens the door to precision medicine and proactive viral defense strategies. 

In a study, researchers have developed a novel CRISPR-Cas9 delivery system using cryo-choked lung tumor cells to target Non-Small Cell Lung Cancer (NSCLC), particularly those with KRAS mutations. The technique involves using lung tumor cells treated by rapid shock with liquid nitrogen, effectively inactivating their pathogenicity while preserving their structure and surface receptors. These cryo-choked cells serve as carriers for CRISPR-Cas9, which aims to edit the CDK4 gene, a key player in the proliferation of KRAS-mutant NSCLC cells. In NSCLC carrier mice, in vivo injection of packaged CRISPR-Cas9 plasmids into cryo-choked lung cancer cells led to an almost four-fold higher concentration in the lungs compared with administration by lipofectamine. The new CRISPR delivery system showed a significant reduction in tumor size and prolonged survival, marking an important advance in the use of gene editing for cancer treatment.

Acute myeloid leukemia (AML) is an aggressive form of blood cancer. It is caused by mutations in a large number of genes acquired during a person's lifetime. One of these genes, the tumor suppressor gene TP53, plays a key role. Normally, TP53 helps prevent the development of tumors. However, blood cancer patients with this mutated gene face an extremely poor prognosis, as their genes are resistant to conventional chemotherapeutic agents. Intensive research is therefore being carried out into new therapeutic approaches, such as CAR T lymphocytes, already successfully used for other blood cancers. In particular, an international research team has shown that TP53 mutant AML cells are significantly more resistant to CAR T cell therapy than AML cells without the mutated gene. In their study, the researchers not only examined the mechanism underlying the resistance of mutated AML cells to CAR T cell immunotherapy, but also discovered how the endurance of CAR T cells can be increased, and how a weak point in TP53 mutant AML cells can be exploited to overcome this resistance. 

Researchers have carried out a study of CAR-T cells in breast cancer. However, this therapy doesn't always work on tumors, as their environment suppresses the immune response, and it can also be difficult to find specific features of breast cancer cells to target. To circumvent these challenges, the team directed CAR-T cells at cells surrounding the tumor's blood supply that make the protein endosialin, rather than at actual cancer cells. In experiments with mice, targeting endosialin successfully reduced the growth and spread of breast cancer. The team also tested the treatment on lung cancer tumors in mice and found similar results, suggesting that patients with other types of cancer could benefit from the new treatment too. Moreover, the researchers found that CAR-T therapy does not affect cells without endosialin, indicating that it could work as a cancer-specific treatment with potentially fewer side effects for patients.