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Lysosomal Disorders

Oncology

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A number of molecularly targeted agents directed at critical cell survival and cell proliferation pathways have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while simultaneously diminishing acute and long-term toxic effects. Systematic evaluations of targeted agents are essential to achieving continued improvements in outcome for children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these and other agents in pediatric populations.

Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer, Part 2

A number of molecularly targeted agents directed at critical pathways involved in cell survival and cell proliferation have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while diminishing acute and long-term toxic effects. Systematic evaluations of agents such as these are essential if continuing improvements in outcome are to be achieved in children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these agents in pediatric populations

Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

For all of 2024, our team was following the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

Part of those conversations resulted in our long-form approaches to reporting on the latest cell and gene news in the form of feature stories. When you spend all year bringing the latest information to the website's front page, sometimes there's a longer story to tell. 

Here, we'll offer previews of some of the most-read features and long-form content from 

'scoverage this year. Click the buttons to read further into these stories.

Real-World Experience With Duchenne Muscular Dystrophy Gene Therapy

Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with Duchenne muscular dystrophy (DMD), was originally granted FDA approval under an accelerated approval pathway for a limited indication on June 22, 2023: ambulatory patients aged 4 to 5 years with DMD and a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9. Later, on June 20, 2024, the FDA approved the gene therapy for use in a broader indication: ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the 

 gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.

A Slow Embrace: Hemophilia's Gradual Adoption of Gene Therapy

The treatment landscape for patients with hemophilia has been enriched with one-time gene therapies, as of the November 2022 United States (US) approval of etranacogene dezaparvovec and the June 2023 US approval of valoctocogene roxaparvovec, both adeno associated virus (AAV) vector gene therapies.

UniQure and CSL Behring’s etranacogene dezaparvovec, marketed as Hemgenix, is approved for treating adults with hemophilia B who currently use Factor IX (FIX) prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. BioMarin’s valoctocogene roxaparvovec, marketed as Roctavian, is approved for the treatment of adults with severe hemophilia A defined as congenital factor VIII (FVIII) deficiency with FVIII activity of less than 1 IU/dL who do not have antibodies to adeno-associated virus serotype 5 (AAV5) according to an FDA-approved test.

Navigating a Novel Therapy Frontier: Gene Therapy's Stunted Impact on Leukodystrophies

Leukodystrophies are a group of inherited neurological disorders in which genetic mutations affect the myelin sheath, and are categorized as rare diseases, with a prevalence of around 1 in 7000 live births. Researchers have identified more than 50 types of leukodystrophies, with some common types including adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Krabbe disease or globoid cell leukodystrophy, and Canavan disease.

Despite their rarity, leukodystrophies are a prime target for gene therapy as most affected patients have a single gene mutation responsible for the disease phenotype. Substantial progress has been made in the field, with 2 gene therapies approved for leukodystrophies in the United States (US) in 2022 and 2024: bluebird bio’s elivaldogene autotemcel (eli-cel/Skysona) for cerebral ALD and Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel/Lenmeldy) for early-onset MLD.

Choosing the Right Treatment Path for Sickle Cell Disease

The molecular basis of sickle cell disease (SCD), an inherited blood disorder characterized by red blood cells (RBCs) that carry mostly an abnormal form of hemoglobin that sometimes results in sickle-shaped RBCs, has been well-understood since at least the 1950s.

 Despite this knowledge of its pathophysiology, treatment options for SCD were quite limited for many decades afterward. Up until about 10 years ago, the main treatment option for SCD was the small-molecule drug hydroxyurea.

Now, the landscape of care for SCD is rapidly changing. On a single day in 2023—December 8—the field of hematology was shaken by the FDA’s simultaneous approval of 2 gene therapy products for the treatment of SCD: Vertex Pharmaceuticals' and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy) and bluebird bio’s lovotibeglogene autotemcel (lovo-cel; marketed as Lyfgenia).

Cell Therapies Hope to Be Next Frontier for Alzheimer Disease

Alzheimer disease (AD) is a growing problem, affecting nearly 7 million people in the United States. In 2021, AD was the fifth-leading cause of death among people aged 65 years and older. Prior to 2023, the field of research for AD had stood relatively stagnant for 10 years until the FDA approved the controversial anti-amyloid therapy aducanumab (Aduhelm).

Take a look what stood out as pillars of progress and success from all of CGTLive's most popular feature stories in 2024.

CGTLive's 2024 Pillars of Progress: Most-Read Features

For all of 2024, our team was following along the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

The team spent all year bringing the latest information to the website's front page, from major data publications and presentations to FDA decisions and major medical meetings. Agency decisions were among the key portions of our coverage, with our team covering submissions, approvals, delays, and other actions across the breadth of medical specialties in search of the biggest news in cell and gene therapy.

Here, we'll highlight some of the most-read content from 

's FDA coverage this year. Click the buttons to read further into these stories.

FDA Approves Obe-Cel for Adults With R/R B-Cell Precursor Acute Lymphoblastic Leukemia

“Adult ALL is an extremely aggressive cancer, and there is a high unmet medical need that exists in the treatment of patients with this disease once they relapse, where historically they suffer from poor outcomes. This milestone approval, based on the demonstrated clinical benefit of Aucatzyl, brings new hope for adult patients with r/r B-ALL.”
—Elias Jabbour, MD

In November, the FDA announced that approved obecabtagene autoleucel (Aucatzyl; Autolus Inc), known colloquially as obe-cel, a CD19-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL). The therapy was approved based on the findings of the pivotal phase 1b/2 FELIX clinical trial (NCT04404660), which showed rates of overall complete remission (CR) above 60% and a median duration of remission beyond 12 months for those who achieved complete remission within 3 months.

FDA Approves Sarepta’s DMD Gene Therapy Elevidys for Expanded Indication

"Today’s expansion of the Elevidys label represents the culmination of my 50-year pursuit of a treatment for Duchenne patients and, along with my colleague Dr. Louise Rodino-Klapac, a nearly 20-year effort to optimize and develop a gene therapy that could be safely and effectively delivered to muscle. The initial approval of Elevidys was a significant milestone, and the expanded indication means clinicians now have a treatment option for the great majority of boys and young men living with Duchenne. This expansion speaks to the success of the science, the evidence, and the improvements in the trajectory of the disease we have seen to date across studies."
—Jerry Mendell, MD

In June, the FDA approved Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with Duchenne muscular dystrophy (DMD), for an expanded indication in the disease. The therapy is now approved for ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the 

 gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.

FDA Approves PTC Therapeutics’ Gene Therapy Kebilidi for AADC Deficiency

"PTC has once again pioneered a new approach to treating highly morbid neurologic diseases. I am proud of our team's unwavering commitment to achieve this important regulatory milestone. We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."
—Matthew B. Klein, MD

Also in November, PTC Therapeutics’ eladocagene exuparvovec, a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, was approved by the FDA for the treatment of children and adults with aromatic L-amino acid decarboxylase (AADC) deficiency. Notably, the indication covers the full spectrum of disease severity and the approval constitutes the first gene therapy for direct administration to the brain to be approved in the United States. The product will be marketed in the US under the name Kebilidi; in the European Union and United Kingdom, it is marketed as Upstaza.

FDA Approves Mesoblast’s Remestemcel-L for Steroid-Refractory GvHD

“Today’s decision marks an important milestone in the use of innovative cell-based therapies to treat life-threatening diseases with devastating impacts on patients, including children. This first mesenchymal stromal cell therapy approval demonstrates the FDA’s commitment to supporting the development of safe and effective products that could improve the quality of life for patients with symptoms that are unresponsive to other therapies.”
—Peter Marks, MD, PhD

Just this month, in December the FDA approved Mesoblast’s allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy remestemcel-L for the treatment of steroid refractory acute graft versus host disease (GvHD) in children aged 2 months or older. Notably, the product is the first MSC therapy to have been approved by the FDA. It will be marketed under the name Ryoncil. 

FDA Finalizes Sets of Guidelines for Both CAR-T Products and Genome Editing Products

"We first posted the draft guidance on considerations for the development of CAR T-cell products in March of 2022... [and] we received over 650 comments from approximately 85 stakeholders, and we really appreciate your thoughtful insights into where more clarity would be helpful. After consideration of each comment and with revisions as needed, the final guidance was then published at the beginning of 2024."
—Kim Schultz, PhD

After finalizing the guidance in January, in March, the FDA's Center for Biologics Evaluation and Research (CBER) hosted a webinar highlighting key points from the final version of the CAR-T guidance document on March 7, 2024. In the webinar, a recording of which is now available on the FDA's website, the speakers covered the main points from the general, CMC, nonclinical, and clinical considerations for CAR-T development from the document. The webinar also included a question-and-answer segment (which begins about 30 minutes into the presentation).

Click here to watch the FDA's webinar on the CAR T guidance.

Take a look at the stories that stood out as pillars of progress and success from all of CGTLive's coverage of FDA actions in 2024.

CGTLive's 2024 Pillars of Progress: Most-Read FDA News in Cell and Gene Therapy

What if the key to treating some of the most challenging diseases—ranging from cancer to neurological disorders—could lie within our immune system? Natural killer (NK) cells are the powerful yet often overlooked warriors of the immune system, playing a crucial role in defending us against infections and cancer. Traditionally known for their role in identifying and destroying infected or cancerous cells, NK cells are now being explored for a wide array of novel therapeutic applications. From tackling autoimmune diseases and fibrosis to offering new hope for conditions such as Alzheimer and Parkinson diseases, NK cells are proving to be more versatile—and more promising—than ever before.

NK cells are traditionally considered to be a key component of the innate immune system, their primary role being the cytotoxic control of invading pathogens, and cancerous cells and unhealthy cells expressing stress molecules due to infection or degeneration. They also have a regulatory role in interactions with T cells, macrophages, dendritic cells, and endothelial cells.

 Their ability to discriminate between healthy and pathogenic cells makes them a useful vehicle for targeting cancer, fibrosis, endometriosis, and autoimmune disorders, and controlling a broad spectrum of disease conditions that may be driven by inflammation. Recently, NK cells were serendipitously found to be capable of neural repair, heralding a completely new therapeutic role.

Allogeneic cancer therapies involving NK cells are developing and include the addition of chimeric antigen receptors (CARs) that target tumor cells.

 They may be isolated from adult and umbilical cord blood, followed by expansion ex vivo to clinically applicable levels. These systems have the disadvantages of batch-batch variability and cost. More recently, NK cells have been derived from induced pluripotent stem cells that can be functionally tailored by gene editing to introduce CARs and immune enhancement molecules or deleted of immune suppressive factors. The success of 

, however, is still evolving. One major distinguishing feature of CAR-NK cells relative to CAR-T cells is their high safety profile, making them an attractive prospect for pursuing other treatment modalities.

Expanding the Applications of CAR-T and CAR-NK Cells: From Fibrosis to Endometriosis

In this regard, the potential use of CAR-T therapies for lung and liver fibrosis is an important new development in these intractable diseases.

 The CAR targets fibroblast activation protein and appears to remove fibrotic lesions in models of cardiac failure in mice.

 These early studies are interesting because they may build wider applications of CAR-NK cells in the control of fibrosis.

Endometriosis is a challenging disease in women for which there are few therapeutic options beyond surgery and high-dose steroid treatment. Given that more than 10% of individuals assigned female at birth are affected by endometriosis, a condition that can lead to infertility, severe pelvic pain, and an increased risk of cancer, there is a critical need for effective therapies. In response to this growing demand, an Australian biotech company, 

., is exploring the possibility of CAR-NK therapy using targets that are specific to endometriosis.

NK Cells in Neurological Disorders: A New Frontier in Brain Disease Therapy

Potential applications of NK cells also extend to neurological disorders. Inflammation and pathological protein accumulation in brain tissue are properties of Alzheimer’s disease (AD), Parkinson’s disease (PD), and traumatic brain injury (TBI). Interestingly, the company NKGen Biotech treated AD patients with ex vivo–activated autologous NK cells intended to boost their immune system, but surprisingly revealed some remarkable improvements in their AD condition, including cognition.

 Given the role of NK cells in the control of inflammation, it is likely that this may be a component of the therapeutic benefit observed in AD patients treated with activated NK cells.

As a result of the encouraging response to activated NK cells in the NKGen Biotech clinical studies in AD patients, the company is now expanding into an FDA investigational new drug application for a phase 1/2a clinical study to test the safety, tolerability, and exploratory efficacy of autologous NK therapy in AD patients.

 It is crucial to start investigating in more detail the mechanisms through which NK cells could influence not only AD but also other brain diseases characterized by neurodegeneration and neuroinflammation. The potential for cell therapies to address these conditions is particularly significant, given the limited treatment options available for many of these challenging disorders. 

Indeed NK cells can be found in the central nervous system

 and form a major part of the innate immune system in the brain, together with microglia, which are macrophage-like. It has been shown that arming macrophages with a CAR specific for amyloid-b enables them to reduce plaques in vitro and ex vivo in mouse brain sections.

 Immune-deficient AD mice show increased amyloid pathology and an abundance of microglial cells with increased cytokine function, rather than phagocytosis ability, reflecting their dual role as part of the adaptive immune system.

 In a preliminary published report, the intravenous delivery of NK cells weekly for 5 weeks in AD model mice has shown reduced microglial activation, reduced amyloid precursor protein deposits, and reduced cognitive decline.

 These data further support a role of NK cells in AD. The logical next horizon is to potentiate the neurological specificity of these NK cells with a strategic CAR.

This growing understanding of NK cells' role in AD is paralleled by emerging research into their potential therapeutic effects in other neurological conditions, such as PD.

Allogeneic CAR-NK Therapy TAK-007 Achieves Responses in R/R B-NHL

PD is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy bodies. These Lewy bodies contain the aggregated ⍺-synuclein (α-syn) protein, which can propagate prion-like from cell to cell and throughout different regions in the brain. NK cells can help remove α-syn proteins, reduce autoreactive T cell–generated inflammation, and remove damaged neurons. Mouse models of PD have shown α-syn aggregates reduce NK cell toxicity and that NK cells can clear α-syn deposits without aberrant activation.

 NK cell depletion was associated with an increase in motor symptoms and ⍺-syn pathology, as well as dopaminergic neuron degeneration and increased neuroinflammation.

 NK cells have been found in the human central nervous system, in postmortem PD brains, including the substantia nigra, and leptomeninges.

NK cells can recognize and clear senescent cells, reducing ⍺-syn load and proinflammatory cytokines. However, the levels of NK cells between healthy and PD brain samples reportedly remain similar.

Similarly, depending on severity, TBI can manifest as neurodegeneration and is associated with some similarities to AD, such as elevated tau protein in the brain, pro-inflammatory microglial activation, and astrocyte reactivity. As such, investigations into the effects of CAR-NK cells on disease biomarkers, immune cell activity, and behavorial alterations are a logical next step in the characterization of their effects in neurological disease states.

Unlocking the Full Potential of NK Cell Therapies

In conclusion, the growing recognition of NK cells as a versatile therapeutic tool marks a transformative shift in the landscape of medicine. Beyond their traditional role in immune defense, NK cells are emerging as a promising solution for a wide range of challenging diseases, including cancer, autoimmune disorders, fibrosis, and neurodegenerative conditions. With advances in cell therapy, particularly the development of CAR-NK cells, we are witnessing a new era of targeted, safer, and more effective treatments. As research continues and clinical trials expand, NK cells may well become a cornerstone of next-generation therapies, offering hope for conditions that have long lacked effective treatment options. The potential for NK cell therapies to revolutionize health care is immense, and we are only beginning to scratch the surface of their true capabilities.

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1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. 

 2008;9(5):503-510. doi:10.1038/ni1582
2. Pupovac A, Cao H, Trounson A. CAR-NK cells: promising for cancer therapy. Drug Target Review. November 17, 2023. Accessed November 25, 2024. https://www.drugtargetreview.com/article/112476/car-nk-cells-promising-for-cancer-therapy/
3. Sobecki M, Chen J, Krzywinska E, et al. Vaccination-based immunotherapy to target profibrotic cells in liver and lung. 

. 2022;29(10):1459-1474.e9. doi:10.1016/j.stem.2022.08.012
4. Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. 

 2019;573(7774):430-433. doi:10.1038/s41586-019-1546-z
5. NKGen Biotech presents updated NK cell therapy data for neurodegenerative disease at the 12th Annual Alzheimer’s & Parkinson’s Drug Development Summit. News release. NKGen Biotech. April 25, 2024. Accessed November 25, 2024. https://nkgenbiotech.com/nkgen-biotech-presents-updated-nk-cell-therapy-data-for-neurodegenerative-disease-at-the-12th-annual-alzheimers-parkinsons-drug-development-summit/
6. NKGen Biotech’s positive phase 1 clinical data in moderate Alzheimer’s disease advances troculeucel into phase 2 with first patient dosed in phase 1/2a trial. News release. NKGen Biotech. September 12, 2024. Accessed November 25, 2024. https://nkgenbiotech.com/nkgen-biotechs-positive-phase-1-clinical-data-in-moderate-alzheimers-disease-advances-troculeucel-into-phase-2-with-first-patient-dosed-in-phase-1-2a-trial/
7. Qi C, Liu Q. Natural killer cells in aging and age-related diseases. 

2023;183:106156. doi:10.1016/j.nbd.2023.106156
8. Kim AB, Xiao Q, Yan P, et al. Chimeric antigen receptor macrophages target and resorb amyloid plaques. 

2024;9(6):e175015. doi:10.1172/jci.insight.175015
9. .Marsh SE, Abud EM, Lakatos A, et al

 The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. 

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 Natural killer cells improve cognitive function and support to induce amyloid beta clearance by functional recovery of impaired microglia in natural killer cell-treated Alzheimer’s diseases mouse model. 

2022;18(suppl 10):e061720. doi:10.1002/alz.061720
11. Earls RH, Menees KB, Chung J, et al. NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy. 

2020;117(3):1762-1771.doi:10.1073/pnas.1909110117
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 Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration. 

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Natural killer cells could redefine medicine and offer new hope for cancer, autoimmune diseases, and neurological disorders through advanced CAR-NK therapies.

The Power and Potential of Natural Killer Cell Therapies: A New Awakening

The FDA announced that has approved obecabtagene autoleucel (Aucatzyl; Autolus Inc), known colloquially as obe-cel, a CD19-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL).

 The therapy was approved based on the findings of the pivotal phase 1b/2 FELIX clinical trial (NCT04404660), which showed rates of overall complete remission (CR) above 60% and a median duration of remission beyond 12 months for those who achieved complete remission within 3 months.

The agency's total recommended dose of obe-cel is 410 × 10

 CD19 chimeric antigen receptor (CAR)-positive viable T-cells, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy and administered as split-dose infusion on Day 1 and Day 10 (±2 days) of treatment, based on bone marrow blast assessment.  No REMS was required by the FDA.

“Adult ALL is an extremely aggressive cancer, and there is a high unmet medical need that exists in the treatment of patients with this disease once they relapse, where historically they suffer from poor outcomes,” Elias Jabbour, MD, the lead investigator of the US-based portion of the FELIX study and a professor of Leukemia and ALL section chief at The University of Texas MD Anderson Cancer Center, said in a statement.

 “This milestone approval, based on the demonstrated clinical benefit of Aucatzyl, brings new hope for adult patients with r/r B-ALL.”

The biologics license application for obe-cel was originally submitted in November 2023, supported by data from FELIX. All told, among 65 patients in the trial with evaluable efficacy data, 63% achieved overall CR, including 51% who achieved it at any time and 12% with CR with incomplete hematologic recovery. CR within 3 months—the main efficacy end point—was achieved by 42% of patients with a median duration of remission of 14.1 months.

Updated data from this clinical trial were presented as part of 

 with data from the phase 1 ALLCAR19 trial (NCT02935257) last year, at 

the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition

, held December 9-12, in San Diego, California.

 ALLCAR19 was originally open to patients aged 16 years and older with r/r B-ALL, but later had its eligibility criteria expanded for an extension study that included patients with r/r B-cell chronic lymphocytic leukemia and r/r B-cell nonHodgkin lymphoma.

As for safety in FELIX, there were low levels of cytokine release syndrome (CRS) reported, with 3% of adverse events being deemed grade 3, and none labeled grade 4 or 5. Grade 3 or greater immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 7% of patients.

“Based on the experience in the FELIX trial Aucatzyl is highly active and can be well managed, offering an attractive risk benefit profile for B-ALL patients,”  

, the lead investigator of the FELIX study and Associate Professor of Haematology at the University College London (UCL) Cancer Institute, said in statement.

 “In the FELIX trial Aucatzyl has shown long term persistence and deep responses which we believe are critical for long term remissions in B-ALL.”

Obe-cel incorporates a novel fast off-rate CD19 binding domain intended to shorten the time that it takes for CAR T-cells bind to leukemia cells, which may simultaneously decrease the number of cytokines secreted and reduce the rate of T-cell exhaustion.

the American Society of Clinical Oncology (ASCO) Annual Meeting

 spoke with Roddie about the potential advantage of this design, where she noted that, “...We know that other products on the market for adult ALL have got significant toxicity profiles and that's actually really difficult for us physicians to manage and particularly difficult for the patients and their families.”  

“It makes it difficult to anticipate or imagine a clinical world where we can give these comfortably as outpatient therapies, which is obviously where [we want to go]—we want to be able to improve the patient experience, quality of life, etc.," Roddie told 

. "And so, I think that's where obe-cel comes into this because the toxicity profile is so much less difficult for patients to tolerate—even patients with lots and lots of disease—and I think that's its biggest selling point. From the perspective of just safely navigating patients through this therapy, it’s much more straightforward.”

Autolus noted that the CAR-T treatment will be manufactured at the company's dedicated site, called 'the Nucleus,' located in Stevenage, United Kingdom. It was granted a Manufacturer’s Importation Authorization and a GMP certificate from the UK's Medicines and Healthcare products Regulatory Agency in March 2024, and was inspected as part of the FDA's process. Cardinal Health will serve as Autolus’ commercial distribution partner in the United States.

REFERENCES
1. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. News release. FDA. November 8, 2024. Accessed November 8, 2024.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
2. Autolus Therapeutics Announces FDA Approval of AUCATZYL® (obecabtagene autoleucel – obe-cel) for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). News release. Autolus Therapeutics. November 8, 2024. Accessed November 8, 2024.https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-fda-approval-aucatzylr
3. Roddie C, Tholouli E, Shaughnessy P, et al. Long-term efficacy and safety of obecabtageneautoleucel (obe-cel) in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia ([R/R B-ALL]; pooled analysis from ALLCAR19 and FELIX phase Ib studies) or other B-cell malignancies (ALLCAR19 extension study). Presented at: 2023 ASH Annual Meeting & Exposition, December 9-12; San Diego, California. Abstract 2114.
4. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy ofobecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #7000

The CAR-T therapy was approved based on the pivotal phase 1b/2 FELIX clinical trial (NCT04404660), which showed good rates of overall complete remission and median duration of remission.

Malcolm A. Smith, MD, PhD

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