 are collaborating to develop engineered regulatory T cell therapies (Treg) for the potential treatment of inflammatory bowel diseases (IBD) such as Crohn's and ulcerative colitis.

"We are thrilled to collaborate with Bristol Myers Squibb, a global leader in cell therapy and immunology drug development, to bring critically-needed, disease-modifying therapies to IBD patients," Adel Nada, MD, MS, co-founder and chief executive officer, GentiBio, said in a statement. "Unlike existing therapies, Tregs have the unique potential to re-establish immune tolerance in autoimmune and inflammatory diseases such as IBD. This strategic collaboration reflects our shared commitment to creating innovative immunotherapies that are designed to be potent, durable, selective and have the potential to significantly shift the standard of care for patients with autoimmune and autoinflammatory diseases."

The companies will develop Treg therapies with the goal of restoring immune tolerance and repairing tissue in patients with IBD. GentiBio is bringing their proprietary Treg platform and scalable manufacturing process to the table to improve the scalability, stability, specificity, and durability of the Tregs while Bristol Myers Squibb is bringing their leadership in cell therapies and immunology. The multi-year collaboration aims to produce Tregs selecting for multiple targets, 3 of which Bristol Myers Squibb will have the rights to develop and advance into clinical trials.

Sarepta, Broad Institute Strike Licensing Agreement for New Class of AAV Vectors for Gene Therapy

"Tregs have demonstrated the potential to suppress inflammation and autoimmune dysfunction in a tissue-restricted manner, thus avoiding widespread, and potentially harmful, immune suppression," Robert Plenge, MD, PhD, Senior Vice President and Head, Immunology, Cardiovascular and Fibrosis Thematic Research Center and Head, Translational Medicine, Bristol Myers Squibb, added to the statement. "We are excited to collaborate with GentiBio as we explore creating potentially promising Tregs for patients suffering from IBD."

GentiBio does not yet have any programs in the clinical stage. The company’s lead program is GNTI-122, an autologous engineered Treg product for treating Type 1 diabetes. The therapy, which expresses a pancreatic islet-specific T cell receptor is designed to restore immune tolerance to pancreatic islets as well as to support repair and improve function of inflamed and damaged beta cells. GNTI-122 also includes modifications to stabilize and increase expression of the FOXP3 protein and a chimeric IL-2 signaling complex to support proliferation and function and is tunable after administration.

GentiBio announces collaboration with Bristol Myers Squibb to pioneer engineered Treg therapies for inflammatory bowel diseases. News release. GentiBio. August 10, 2022. https://www.prnewswire.com/news-releases/gentibio-announces-collaboration-with-bristol-myers-squibb-to-pioneer-engineered-treg-therapies-for-inflammatory-bowel-diseases-301603092.html

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GentiBio will use their proprietary regulatory T cell platform to develop the engineered therapies against multiple targets. 

Bristol Myers to Fund Inflammatory Bowel Disease Treg Therapies 

This content originally appeared on our sister site, 

The phase 2 ELIANA study (NCT02435849) investigated the efficacy and safety of tisagenlecleucel in pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). A 5-year follow-up of these data was presented at the 2022 EHA Congress.

spoke with Shannon L. Maude, MD, PhD, attending physician, Division of Oncology, The Children’s Hospital of Philadelphia, and assistant professor, pediatrics, medical director, Center for Cellular Immunotherapies, Perelman School of Medicine, the University of Pennsylvania, to learn more about long-term safety data with tisagenlecleucel (Kymriah) in pediatric patients with B-ALL.

The study revealed common adverse effects (AEs) such as cytokine release syndrome (CRS) and neurotoxicity but no additional AEs of special interest were reported at the 5-year analysis. CRS incidence was significant, occurring in 77% of patients, including grade 3/4 in 48%, though many patients had a substantial disease burden at the time of treatment, Maude explained. Neurotoxicity was also seen in 40% of patients, Maude adds.

This longer-term follow-up of the ELIANA data provided the opportunity to look for late AEs, primarily infection and prolonged cytopenia, Maude says. Among patients in remission, any-grade infection occurred in 33% of patients, including grade 3 or higher in 20%, and hematological disorders of any grade, including cytopenia, occurred in 10% of patients, including grade 3 or higher in 6%. No other serious or unexpected late AEs have been reported, Maude concludes.

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The oncologist from Children's Hospital of Philadelphia discussed long-term safety data with tisagenlecleucel in pediatric patients with acute lymphoblastic leukemia.

Shannon L. Maude, MD, PhD, on Favorable Safety of Tisagenlecleucel in Pediatric B-ALL

 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

1. Zolgensma Gene Therapy Linked to 2 Deaths in SMA Patients, Novartis Reports

The 2 deaths, due to acute liver failure, occurred in patients treated in Kazakhstan and Russia.

2. Ide-Cel Shows Benefit in Earlier Use in R/R Multiple Myeloma

A recent comparison of health-related quality of life scores also favored ide-cel over belantamab mafodotin treatment.

3. UniQure Pauses High Dose of AMT-130 Huntington Disease Gene Therapy for Severe Adverse Events

No such adverse events have occurred in the lower-dose group.

4. First Patient Dosed in Sickle Cell Gene Therapy Clinical Trial From Graphite Bio

Nula-cel is intended to directly correct the mutation that causes sickle cell disease.

Frontotemporal Dementia Gene Therapy Trial Initiates Dosing

PBFT02, developed by Passage Bio, is delivered via intra cisterna magna administration to the brain.

Review top news and interview highlights from the week ending August 12, 2022. 

CGTLive’s Weekly Rewind – August 12, 2022 

Two children with spinal muscular atrophy (SMA) have died after being treated with

 (Zolgensma; Novartis) from acute liver failure, a known safety risk of the therapy.

Novartis has updated the FDA and other regulatory agencies in countries that Zolgensma is approved in, including Russia and Kazakhstan, where the deaths occurred. The company will also update the labeling of Zolgensma to include the deaths.

“While this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma, which to date has been used to treat more than 2300 patients worldwide across clinical trials, managed access programs, and in the commercial setting,” Novartis said in an emailed statement to BioPharma Dive.

Zolgensma’s labeling includes the risk of liver injury and instructs clinicians to assess liver function before treatment and to manage liver enzyme counts with steroid treatment. The 2 deaths occurred 5 to 6 weeks after the one-time infusion and 1 to 10 days after corticosteroid treatment was tapered, according to an initial report from Stat News.

Zolgensma Shows Efficacy in SMA With 3 SMN2 Copies

 that took place last fall identified risks of adeno associated virus (AAV) gene therapies including, specifically, Zolgensma.

 The committee recommended caution, but nothing that would hinder gene therapy development.

Zolgensma, which was approved in the US in May 2019, just recently demonstrated further positive data from SPR1NT (NCT03505099), a phase 3 multicenter, single-arm trial on its effect in 

All children in both the type 1 and type 2 cohorts achieved the ability to independently sit and most achieved other age-appropriate milestones including standing and walking. None of the children in the study required respiratory support or nutritional support, and there were no serious treatment-related adverse events observed.

"The robust data from both the 2- and 3-copy SPR1NT cohorts are being published together for the first time, further supporting the significant and clinically meaningful benefit of Zolgensma in presymptomatic babies with SMA," Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, said in a previous statement.

 "When treated with Zolgensma prior to the onset of symptoms, not only did all 29 patients enrolled in SPR1NT survive, but were thriving—breathing and eating on their own, with most even sitting, standing, and walking without assistance."

1. Silverman E. Novartis reports two children died from acute liver failure after treatment with Zolgensma gene therapy. STAT. August 11, 2022. https://www.statnews.com/pharmalot/2022/08/11/novartis-zolgensma-liver-failure-gene-therapy-death/
2. Pagliarulo N. Novartis reports deaths of two patients treated with Zolgensma gene therapy. BioPharma Dive. August 12, 2022. https://www.biopharmadive.com/news/novartis-zolgensma-patient-death-liver-injury/629542/
3. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. 

. Published online June 17, 2022. doi:10.1038/s41591-022-01866-42
4. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. 

 Published online June 17, 2022.doi: 10.1038/s41591-022-01867-3
5. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. https://firstwordpharma.com/story/5597735

The 2 deaths, due to acute liver failure, occurred in patients treated in Kazakhstan and Russia. 

Zolgensma Gene Therapy Linked to 2 Deaths in SMA Patients, Novartis Reports 

Israeli cell therapy company Kadimastem has been granted a patent from the United States Patent and Trademark Office for AstroRx, a cell therapy consisting of astrocytes derived from human embryonic 

 intended for the treatment of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

“The ALS program is progressing well," Michel Revel, MD, PhD, founder and chief scientist, Kadimastem, said in a statement regarding the news. "The company’s broad patent portfolio was strengthened today, and we are on track to begin the much anticipated clinical trial of AstroRx within months. I am excited to see our original vision come to fruition. The goal is to improve the treatment of ALS patients.”

Kadimastem previously announced positive results from cohort B of its phase 1/2a clinical trial of AstroRx (NCT03482050) in late 2020. During the 6 month post-treatment follow-up of the 5 patients dosed in the higher-dose cohort (Cohort B), there were no treatment-related serious adverse events nor dose limiting toxicities reported.

"The results after 6 months of follow up are encouraging, as they suggest a clinically meaningful signal of effect for a period of 3 months by a single administration of AstroRx and confirm the safety of AstroRx,” Marc Gotkine, head of the ALS Clinic at the Department of Neurology at Hadassah Medical Center, Jerusalem, and principal investigator of the trial, said in a statement at the time.

 “These results support a further, randomized-controlled, clinical trial with repeated doses of AstroRx in patients with ALS, in order to prolong the clinical effect observed by a single dose.”

AstroRx was shown to provide a clinically meaningful reduction in the rate of disease progression measured on the ALS Functional Rating Scale-Revised (ALSFRS-R), from -1.43/month in the 3 to 4 months prior to treatment to -0.78/month during the 3-4 months after treatment. However, this 45% decline (

 = .0023) in disease progression rate did not persist, and by the end of the 6-month period ALSFRS-R progression had returned to a rate similar to pre-treatment rates, indicating that continuous doses might be needed for sustained efficacy. Data from 5 patients in the lower dose cohort (Cohort A), reported earlier in 2020, displayed similar results in terms of efficacy and safety.

“The 6-month follow up data demonstrates the safety of AstroRx as a treatment for ALS,” Revel added to the statement.

 “The results also support the strategy of a repeated administration of the AstroRx cells using the intrathecal route. As such, we are planning to continue with this strategy during the next phase of the clinical development program.”

As of January 2021, the open-label, dose-escalation trial had recruited 16 participants between the ages of 18 and 70 years who had been diagnosed with probable or definite ALS. Participants were required to have an ALS-FRS-R score of at least 30 and an ALS diagnosis of 2 years or less, and patients being treated with Riluzole and/or Radicava were required to have been on a stable dose with these medications for at least 30 days. Patients who had past infections with or a positive test for HBV, HCV, or HIV were excluded from the study, as were patients in need of respiratory support, and those who scored lower than 10/12 in the ALSFRS-R respiratory parameters or below 70% of predicted slow vital capacity (SVC).

AstroRx was administered via intrathecal injection. Patients in cohort A were treated with a dose of 100x10

 AstroRx cells and patients in cohort B received a dose of 250x10

 AstroRx cells. The primary end point is the number of participants who experienced treatment emergent adverse events. Secondary end points include the change in the ALS functional rating scale, change in predicted SVC, changes in muscle strength grading measured by JAMAR grip strength and handheld dynamometer, and the change in the ALSAQ-40 quality of life questionnaire.

Kadimastem has announced their intention to submit an 

 by the end of 2022 and is currently preparing for the start of the phase 2a study in the US in 2023.

1. Kadimastem receives US patent for amyotrophic lateral sclerosis (ALS) treatment. News release. Kadimastem Ltd. August 9, 2022. 

https://www.kadimastem.com/post/kadimastem-receives-us-patent-for-a-treatment-of-amyotrophic-lateral-sclerosis-als

2. Encouraging results of Cohort B of its phase 1/2a clinical trial of AstroRx for ALS. News release. Kadimastem Ltd. December 15, 2020. 

https://www.kadimastem.com/post/encouraging-results-of-cohort-b-of-its-phase-1-2a-clinical-trial-of-astrorx-for-als

AstroRx previously demonstrated clinically meaningful reductions in the rate of disease progression. 

ALS Cell Therapy Receives US Patent 

The first patient in Graphite Bio’s phase 1/2 clinical trial (CEDAR; NCT04819841) for GPH101, an investigational sickle cell disease (SCD) gene editing therapy now known as nulabeglogene autogedtemcel (nula-cel), has been dosed.

 Nula-cel is an autologous CD34+ hematopoietic stem cell (HSC) therapy intended to directly correct the mutation that causes SCD, thus reducing the production of sickle hemoglobin (HbS) and increasing the production of adult hemoglobin (HbA).

“For decades, the goal of gene editing has been to precisely correct genetic mutations that cause disease,” Josh Lehrer, MD, chief executive officer, Graphite Bio, said in a statement.

 “Today, we took an important step toward achieving that goal by dosing our first patient with nula-cel, the first investigational therapy designed to correct a mutated gene to normal. This first use of high-efficiency precision DNA repair to correct a genetic mutation is an important milestone not only for our company but also for the gene editing field and, hopefully, for the sickle cell community.”

The open-label, multicenter trial aims to enroll around 15 participants aged 12 to 40 years with severe SCD. In order to be included, patients must either have experienced 4 or more episodes of recurrent severe vaso-occlusive crisis (VOC) in the past 2 years or have experienced 2 or more episodes of acute chest syndrome (ACS) in the past 2 years with at least 1 episode in the past year. Participants must additionally have a Lansky/Karnofsky performance status of 80 or greater. Patients who have an available 10/10 HLA-matched sibling donor or who have previously received HSCT or gene therapy will be excluded from the study, along with those who have a prior or current malignancy, myeloproliferative, significant coagulation, or immunodeficiency disorder.

Patients will receive a single dose of nula-cel via intravenous infusion after a myeloablative conditioning regimen. The primary end points are the proportion of patients who attain neutrophil engraftment in 42 days, incidence rates of treatment-related mortality at 100 days and 12 months post-infusion, overall survival at 24 months, and frequency and severity of adverse events and serious adverse events. Secondary end points include time to neutrophil engraftment, time to platelet engraftment, and evaluations of gene correction levels in peripheral myeloid cells, HbA as a percentage of total hemoglobin (Hgb), and HbS as a percentage of total Hgb. Total Hgb without disease-indicated transfusion support, the change in annualized packed red blood cell transfusion requirements for SCD indications, the proportions of patients achieving complete resolution of severe VOCs and HbS levels of less than 50% for at least 3 months, and the incidence rate of severe VOCs will also be examined.

“We continue to make tremendous progress with the development of nula-cel, which in preclinical studies successfully corrected the sickle cell disease mutation, directly reducing sickle hemoglobin and restoring healthy adult hemoglobin to potentially curative levels,” Lehrer added to the statement.

 “We believe nula-cel could be a definitive cure for sickle cell disease, with the potential to address all complications associated with this life-threatening disease. We look forward to reporting initial proof-of-concept data from the CEDAR trial in mid-2023.”

previously received FDA fast track designation in May 2022

FDA orphan drug designation in late 2021.

 The investigational therapy was developed using Graphite’s next-generation targeted gene integration platform, which relies on Cas9 technology and a non-integrating DNA template to correct the mutation in the β-globin gene through the homology-directed repair cellular pathway.

 to share more details about the CEDAR trial in SCD as well as Graphite’s other pipeline targets, including therapies for β-thalassemia and Gaucher disease. 

Graphite Bio doses first patient with investigational gene editing therapy GPH101 for sickle cell disease. News release. Graphite Bio, Inc. August 11, 2022. 

https://ir.graphitebio.com/press-releases/detail/76/graphite-bio-doses-first-patient-with-investigational-gene

Nula-cel is intended to directly correct the mutation that causes sickle cell disease. 