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Lysosomal Disorders

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1rem

Authors

Assistant professor of neurology, Harvard Medical School, and director, leukodystrophy service, Massachusetts General Hospital.

The neurologist at Massachusetts General Hospital discussed BBP-812, an investigational AAV vector-based gene therapy being evaluated for Canavan disease in a phase 1/2 trial.

Florian Eichler, MD, on Addressing Unmet Needs in Canavan Disease With Gene Therapy

The director of the leukodystrophy service at Mass Gen discussed progress dosing in the phase 1/2 trial. 

Florian Eichler, MD, on Promising Efficacy of AXO-AAV-GM2 in GM2 Gangliosidosis 

The director of the leukodystrophy service at Mass Gen discussed the phase 1/2 study of AXO-AAV-GM2. 

Florian Eichler, MD, on How Novel Gene Therapy Delivery Improved Targeting in GM2 Gangliosidosis

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 

Ultragenyx has received a complete response letter (CRL) from the FDA regarding its biologics license application (BLA) for UX111 (ABO-102), an adeno-associated virus (AAV) vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome).

According to Ultragenyx, the CRL relates to a need for additional chemistry, manufacturing and controls (CMC) information and improvements and observations from inspections of manufacturing facilities that were conducted recently. The company noted its perception that the concerns are related to facilities and processes rather than to the quality of the gene therapy product itself, and that the observations are “readily addressable”. Furthermore, Ultragenyx stated that it plans to work with the agency to address these observations and that it plans to resubmit the BLA thereafter. Once resubmitted, a review period of up to 6 months will take place.

Ultragenyx additionally noted that the FDA indicated that the neurodevelopmental outcome data it received in the original BLA are robust and that no concerns regarding the clinical data or clinical inspections were present in the CRL. The agency also indicated that additional supportive evidence is provided by the biomarker data included in the BLA. Although, the FDA requested that updated clinical data be included in the BLA resubmission.

“Our goal is to get UX111 to patients as quickly as possible knowing how critical this first therapy is to the Sanfilippo community,” Emil D. Kakkis, MD, PhD, the chief executive officer and president of Ultragenyx, said in a statement.

 “We have been diligently responding to the recent CMC observations and our priority is to resolve them so that we can resubmit the BLA as soon as possible. We believe the CMC observations are readily addressable and many have already been addressed. While the CRL will delay the potential approval of UX111 to 2026, we are working with urgency to respond and resubmit.”

 The company is seeking accelerated approval for the BLA based on the use of cerebral spinal fluid (CSF) heparan sulfate (HS) data from the phase 1/2/3 Transpher A clinical trial (NCT02716246), which will be used as a surrogate end point. In February 2025 the FDA accepted the BLA with priority review and the Prescription Drug User Fee Act action date for the BLA was set for August 18, 2025. According to 

, held February 3 to 7, 2025, a 65% median decrease in CSF-HS exposure (

 < .0001) was seen in the group of all patients who were treated at the study’s high dose (3x10

 vg/kg, n = 22), who had a mean posttreatment follow-up time of 34 months.

"...[I]deally with a biomarker such as CSF-HS, which is really intimately related to the disease—it's a disease-causing biomarker—we hope that by showing that CSF-HS is relevant in this particular neuronopathic MPS, that it will help accelerate drug development for all in this field—that we really shouldn't have to wait several years to see clinical benefit," Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx, told 

 in an interview held shortly after the conference. "We are supportive of this as a biomarker that is likely to predict clinical outcomes, which is the definition used in the accelerated approval pathway, at least in the United States. We really want to understand very quickly when a new drug comes on, does it work or not? So it's actually beneficial not only to show efficacy, but to fail fast, as well. I think the benefit here is we did show this clinical improvement, but we contend that this biomarker is useful in overall drug development for an ultrarare disease like this.”

REFERENCES
1. Ultragenyx receives complete response letter from FDA for UX111 AAV gene therapy to treat sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. July 11, 2025. Accessed July 14, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-complete-response-letter-fda-ux111-aav-gene
2. Ultragenyx submits biologics license application to the U.S. FDA for UX111 AAV gene therapy for the treatment of Sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. December 19, 2024. Accessed July 14, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-submits-biologics-license-application-us-fda-ux111
3. Ultragenyx announces new data demonstrating that treatment with UX111 AAV gene therapy significantly improved clinical function across multiple developmental domains in children with Sanfilippo syndrome type A (MPS IIIA) correlated with sustained reductions in CSF-HS. News release. Ultragenyx Pharmaceutical Inc. February 5, 2025. Accessed July 14, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-new-data-demonstrating-treatment-ux111-aav

According to Ultragenyx, the CRL relates to a need for additional CMC information and improvements and observations from inspections of manufacturing facilities.

Ultragenyx’s MPS IIIA Gene Therapy UX111 Met With CRL

The head of research at Mass General Brigham’s Gene and Cell Therapy Institute discussed how innovative research can be held back by financial considerations.

Nathan Yozwiak, PhD, on Commercial Bottlenecks in Gene Therapy Development

“How do you create a sustainable model for this? This has come up repeatedly throughout this conference and it's something that we as a field really need to tackle.”

Gene therapy has proven to be a remarkably promising new modality for a wide range of diseases. Although, in some cases, innovative technologies and research can be held back by the costs associated with development and potential financial viability as a commercial product. For example, many gene therapy candidates target very rare diseases, and thus would likely only be administered to a handful of patients each year if they were approved by the FDA.

the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting

, held May 13 to 17, 2025, in New Orleans, LA, Nathan Yozwiak, PhD, the head of research at the Gene and Cell Therapy Institute at Mass General Brigham, discussed this phenomena. He pointed out that while scientific breakthroughs are accelerating, commercial and financial models are lagging behind, and that this issue has been discussed often at ASGCT’s meetings.

To address the issue, Yozwiak emphasized the importance of continued innovation in technical aspects of gene therapy, such as improving vectors, utilizing AI for more efficient design, and refining delivery mechanisms. These innovations aim to lower costs and improve efficiency, potentially changing the economic feasibility of rare disease treatments. He noted that he sees the field approaching a major inflection point soon where several big advancements may push the field very far forward.

Yozwiak is especially excited about in vivo gene editing approaches, which allow direct treatment inside the body rather than requiring cells to be removed and reintroduced. He also notes progress in adeno-associated virus (AAV) vectors, particularly in engineering capsids for more targeted and cost-effective delivery. These advancements could replace the current high-dose, systemic approaches, improving safety and precision.

Click here to view more coverage of the 2025 ASGCT Annual Meeting.

Videos

Over the past 5 to 10 years, chimeric antigen receptor T-cell (CAR-T) therapy has firmly established itself as an effective treatment modality for blood cancers, with several products having been approved by the FDA for such indications, such as Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti) and Bristol Myers Squibb (BMS) and 2seventy bio’s idecabtagene vicleucel (ide-cel; marketed as Abecma). In light of this success, it only seems natural for investigators to seek to apply the same technology to solid tumor indications. After all, around 90% of cancers found in adult patients are varieties of solid tumors, and these malignancies can originate in myriad organs throughout the body.

Unfortunately, attempts to apply existing CAR-T approaches that proved effective in blood cancers to solid tumor indications has raised a number of difficulties related to key aspects of solid tumor biology.

 It has therefore become clear that a simple plug-and-play transfer of the technology is thoroughly insufficient. Indeed, a modified approach to CAR-T and/or other engineered cell therapy approaches will be necessary to make the modality of cell therapy able to provide clinically meaningful benefit for solid tumors.

This issue has been known for several years, and a number of biotech companies and academic institutions are already trying their hand at a variety of methods meant to overcome the barriers in place. Although some promising studies have been carried out, the task is still very much a work in progress, and it remains to be seen which, if any, of the approaches currently under evaluation will eventually become part of standard clinical practice. With the aim of getting a cross-section of the current state of progress in the field, 

 reached out to several experts to get their insight into several of the notable approaches currently being assessed.

Using Armored CAR T-Cells to Tackle Solid Tumors

The chair of the department of medicine at Roswell Park Comprehensive Cancer Center discussed the innovations necessary to make CAR-T therapy effective in solid tumor indications.

Renier Brentjens, MD, PhD, on Using Armored CAR T-Cells to Tackle Solid Tumors

“Over the brief 20-year span that I've been doing this work, I think we philosophically kind of changed how we look at [CAR T-cells as cytotoxic agents], and we realized that the CAR T-cell may be more of a spark rather than the actual explosion."

One noteworthy approach currently being applied is the concept of “armored CAR T-cells.” There are CAR-T products that have additional genetic modifications beyond the typical CAR modification itself that are intended to combat cancer cells in additional ways. The additional genetic modification can be almost anything. For example, a proinflammatory cytokine potentially capable of modulating the tumor microenvironment could potentially help to further elicit a patient's own endogenous immune response to aid in attacking the tumor.

Renier Brentjens, MD, PhD, the chair of the department of medicine and the deputy director at Roswell Park Comprehensive Cancer Center, spoke to 

 about how armored CAR T-cells may help bridge the gap necessary to make CAR-T effective in solid tumors. Brentjens pointed out that unlike blood cancers, solid tumors are more complex, and often surrounded by nontumor cells that block immune responses. He explained that armored CAR T-cells can reshape this environment and trigger the body’s natural immune system to help attack the cancer. 

“Over the brief 20-year span that I've been doing this work, I think we philosophically kind of changed how we look at [CAR T-cells as cytotoxic agents], and we realized that the CAR T-cell may be more of a spark rather than the actual explosion," Brentjens told 

. "It's the spark that sets off a downstream effect where an immune system that is actually quite reasonably sophisticated in recognizing cancer cells can overcome the defenses that cancer cells create around themselves to stop cell therapies from working.”

Furthermore, he emphasized that in solid tumors, armored CAR T-cells may help address antigen escape. He noted that this is typically an even greater challenge for solid tumors than it is in blood cancers.

Weber discussed the importance of these phenomena in the larger puzzle of making CAR-T effective in solid tumors, positing that addressing them may be a critical piece to enabling the therapies to be curative.

Addressing T-Cell Exhaustion

“...Overcoming this obstacle, I think, is going to be an important piece of designing and engineering T-cell engineered T-cell therapeutics that can actually cure patients.”

Despite the successes seen so far with CAR-T therapies in clinical trials and in the real-world setting for blood cancers, even in these hematologic malignancies, the modality continues to have a number of limitations. Among these are the phenomena of T-cell exhaustion, in which the CAR T-cells become less functional over time, and the limited persistence of CAR T-cells. It is thought that these phenomena may reduce the efficacy and durability of responses from CAR-T therapy, potentially leading patients to relapse.

 Although means of addressing these limitations are certainly of interest for improving the efficacy of CAR-T in blood cancer indications, tackling these same shortcomings may also give a much-needed boost to the efficacy of attempts to bring CAR-T to solid tumors.

On both these counts, methods to overcome T-cell exhaustion and enhance the persistence of CAR T-cells are a major area of focus for ongoing CAR-T research in the lab of Evan Weber, PhD, an assistant professor of pediatrics at Children's Hospital of Philadelphia, and his colleagues. In an interview with 

, Weber discussed the importance of these phenomena in the larger puzzle of making CAR-T effective in solid tumors, positing that addressing them may be a critical piece to enabling the therapies to be curative. 

“Overcoming T-cell exhaustion, which is exactly what it sounds like—it's a process whereby T-cells lose the ability to promote antitumor function both in liquid and solid tumors—overcoming this obstacle, I think, is going to be an important piece of designing and engineering T-cell engineered T-cell therapeutics that can actually cure patients," Weber told 

Weber also shared his thoughts on the broader array of cell therapy approaches currently being explored to treat solid tumors, such as tumor-infiltrating lymphocyte (TIL) therapies and T-cell receptor (TCR) T-cell therapy, and how improved CAR-T therapies may fit into that landscape. He suggested that different approaches may end up carving out different niches where they are shown to be most effective.

 Ben Creelan, MD, a medical oncologist at Moffitt Cancer Center who specializes in oncology cell therapy research, discussed how logic-gating may help CAR-T achieve a more favorable balance of efficacy and safety in solid tumors.

Targets, Logic-Gating, and Logistics

“For example, mesothelin-targeted CAR-T has been a very potent CAR T-cell. It does kill tumor cells that express mesothelin—mesothelioma, adenocarcinoma of the ovary, adenocarcinoma of the lung—and yet, it also attacks the peritoneum, it attacks the pleura, and has been essentially a nonstarter in phase 1 trials until recently.”

In hematologic malignancies, CD19 and BCMA have proven to be efficacious targets for CARs. These antigens exist in sufficient quantity on hematologic cancer cells and in low enough quantities in healthy cells to provide a favorable balance with regard to on-target cell killing. The application of CAR-T to solid tumors, however, requires identifying new antigen targets depending on the solid cancer type being addressed.

 Unfortunately, many antigens that could be potential candidates as targets for solid tumor cell therapies, such as mesothelin, come with higher levels of on-target, off-tumor toxicity than is seen with the targeting of CD19 and BCMA in blood cancers.

One approach aimed at getting around this conundrum is logic-gating.

 Unlike the CAR-T therapies that have been FDA-approved for use against hematologic malignancies that simply target and kill cells expressing a known tumor antigen, logic-gated CAR T-cells allow for more selective cell killing. Depending on the particular construct, they are designed to only activate in both the presence of a target antigen and the absence of a different marker expected to only appear on healthy cells (on-off switch construct) or to only activate in the presence of 2 target antigens (on-on switch construct).

, Ben Creelan, MD, a medical oncologist at Moffitt Cancer Center who specializes in oncology cell therapy research, discussed how logic-gating may help CAR-T achieve a more favorable balance of efficacy and safety in solid tumors by reducing off-tumor on-target toxicity. Creelan additionally spoke about the search for ideal antigen targets for solid tumor therapies in general, and in the course of the discussion touched on a number of recent relevant presentations given at 

the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 30 to June 3, in Chicago, Illinois. He highlighted the potential of GPC3 as a target for a range of solid tumor types because it is found to be expressed on most squamous tumors. Other antigens he emphasized were potentially important targets included Claudin 6 and Claudin-18.

Creelan also noted the importance of logistics in making cell therapy a more viable option for solid tumors. In particular, he pointed out the potential benefits of allogeneic and in vivo approaches to manufacturing cell therapy for solid tumors. Allogeneic cell therapy could allow for faster time to treatment and in vivo CAR-T therapy could remove the need for aphaeresis and cut down costs.

On the whole, there are myriad methods to making cell therapy a safe and effective treatment modality for a range solid tumors that are currently in the works. Although it may be tempting to debate which upcoming approach is most likely to be a game-changer, or which treating physicians ought to be most optimistic about, the reality may be that a combination of the aforementioned approaches (and potentially yet untested others as well) may end up needing to come together for cell therapy to be viable in cancers beyond hematologic malignancies and a handful of other indications. Indeed, Weber shared his view on this during the course of his discussion with 

“One of the questions we receive typically, when we present our work publicly, is whether the specific manipulations or approaches that we're developing and engineering in our lab are the best ones out there,” Weber said. “Basically, how do you choose what manipulation to use for a given T-cell therapeutic? I think many of us in the field have, for a long time, had a tendency to claim that our approaches are broadly applicable and could be used to enhance CAR T-cells for solid tumors or liquid tumors or to equally enhance TCR-engineered T-cells and CAR T-cells—but much like my previous answer around different T-cell modalities and how they fit into the therapeutic landscape, I think that these manipulations around enhancing T-cell potency will also be context-specific. 

"For example, armoring techniques for chemokines or cytokines may be appropriate for certain solid tumors and not others, just as transcription factor engineering approaches or other synthetic biology approaches may have context-specific use. I hope that as a field, we evolve our preclinical pipelines to tease some of that context-specificity out before the clinical stage.”

REFERENCES
1. Solid tumor research. Thermo Fisher Scientific. Website. Accessed June 30, 2025. https://www.thermofisher.com/us/en/home/life-science/cancer-research/solid-tumor-research.html
2. Common Cancer Types. National Cancer Institute. Website. Accessed June 30, 2025. https://www.cancer.gov/types/common-cancers
3. Xing Y, Liu N, Czeryba N, et al. Functional potency assay predicts CAR-T effectiveness in tumor microenvironment. Presented at: AACR Annual Meeting. April 14-19, 2023; Orlando, FL. Abstract 1782.
4. Weber E. Augmenting CAR T cell fitness through memory reprogramming. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland.
5. Ben Creelan, MD, on the potential of logic-gated tmod CAR-T in lung cancer and other solid tumors. Video. CGTLive. November 15, 2023. Accessed June 30, 2025. https://www.cgtlive.com/view/ben-creelan-potential-logic-gated-tmod-car-t-lung-cancer-other-solid-tumors
6. A2 Bio Presents Oral and Poster Presentations Highlighting BASECAMP-1 and EVEREST-1 Patient Screening at 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting. News release. A2 Biotherapeutics, Inc. November 2, 2023. Accessed June 30, 2025.  https://www.a2bio.com/a2-bio-presents-oral-and-poster-presentations-highlighting-basecamp-1-and-everest-1-patient-screening-at-2023-society-for-immunotherapy-of-cancer-sitc-annual-meeting/
7. Senti Bio announces pipeline prioritization to focus on logic gated cell therapies; updates cash runway guidance. News release. Senti Biosciences, Inc. January 27, 2023. Accessed June 30, 2025.  https://investors.sentibio.com/news-releases/news-release-details/senti-bio-announces-pipeline-prioritization-focus-logic-gated

Several experts weighed in on the various strategies being explored to tackle solid tumors with cell therapy, expressing optimism despite the plethora of obstacles that remain.

Cell Therapy’s Lot in Solid Tumors: Challenges and Opportunities

The FDA is no longer requiring Risk Evaluation and Mitigation Strategies (REMS) for the 6 CD19/BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapies that are approved by the agency.

The 6 products include Bristol Myers Squibb (BMS) and 2seventybio’s idecabtagene vicleucel (ide-cel; marketed as Abecma); BMS’s lisocabtagene maraleucel (liso-cel; marketed as Breyanzi); Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti); Novartis’s tisagenlecleucel (tisa-cel; marketed as Kymriah); Kite Pharma’s brexucabtagene autoleucel (brexu-cel; marketed as Tecartus); and Kite Pharma’s axicabtagene ciloleucel (axi-cel; marketed as Yescarta). The FDA made the move with the view that the REMS are no longer necessary to ensure a favorable risk-benefit-ratio for the products and that dropping the requirement may increase accessibility to these therapies.

“The FDA has taken the bold step to remove the REMS requirement from giving CAR-T therapies,” Vinay Prasad, MD, MPH, the chief medical and scientific officer and the director of the Center for Biologics Evaluation and Research at the FDA, said in a statement.

 “REMS is a useful safety system, but reevaluation over time helps inform whether a REMS is still needed to ensure that the benefits of a product outweigh its risks. Eliminating the REMS that is no longer needed also expedites the delivery of potentially curative treatments to patients and reduces burden on providers.”

With the removal of the REMS requirement, hospitals and clinics that provide these therapies no longer necessitate a specific certification. Additionally, these centers are no longer required to have on-site tocilizumab immediately accessible.

“Physicians and institutions now have greater experience identifying and managing toxicities with the currently approved CAR-T products,” Richard Pazdur, MD, the FDA Oncology Center of Excellence director, added to the statement.

 “This approach will potentially facilitate patient access to these treatments while continuing to prioritize safety.”

Safety monitoring for the affected products will continue in the form of adverse event reporting according to established protocols. The existing requirements for postmarketing observational safety studies assessing secondary malignancy risks and long-term safety follow-up also remain in place.

Alongside removal of the REMS requirement, the FDA also made changes to the labels for liso-cel and ide-cel.

 Notably, BMS released a statement celebrating the FDA’s decision, pointing out that logistical and geographic barriers have likely hindered some patients ability to receive CAR-T that the FDA’s changes to the labels for liso-cel and ide-cel should make the products more accessible. The company noted that historically only about 2 in 10 eligible patients are treated with CAR-T products. BMS highlighted that the FDA’s labeling change reduces the requirement for patients to be located near a healthcare facility for 4 weeks posttreatment down to 2 weeks after treatment with BMS’s CAR-T products.

"Living with blood cancer is challenging, but patients and their loved ones still need to maintain jobs, take care of families, and plan for the future,” Sally Werner, the chief executive officer of Cancer Support Community, said in the BMS press release.

 “Today’s announcement reduces some of the most onerous requirements that may have previously discouraged patients, particularly those who live far from a treatment center, from seeking the potentially transformational effects of cell therapy. We applaud any and all efforts to continue to break down barriers, reducetime burden on patients and caregivers, and increase uptake of this life-saving therapy."

REFERENCES
1. FDA eliminates risk evaluation and mitigation strategies (REMS) for autologous chimeric antigen receptor CAR T cell immunotherapies. News release. FDA. June 27, 2025. July 3, 2025. https://www.fda.gov/news-events/press-announcements/fda-eliminates-risk-evaluation-and-mitigation-strategies-rems-autologous-chimeric-antigen-receptor
2. U.S. Food and drug administration approves streamlined patient monitoring requirements and removal of REMS programs within Bristol Myers Squibb’s cell therapy labels. News release. Bristol Myers Squibb. June 26, 2025. Accessed July 3, 2025. https://news.bms.com/news/corporate-financial/2025/U-S--Food-and-Drug-Administration-Approves-Streamlined-Patient-Monitoring-Requirements-and-Removal-of-REMS-Programs-within-Bristol-Myers-Squibbs-Cell-Therapy-Labels/default.aspx

The FDA made the move with the view that the REMS are no longer necessary to ensure a favorable risk-benefit-ratio for the products and that dropping the requirement may increase accessibility to these therapies.

Florian Eichler, MD

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