In November 2023, the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) granted conditional approval to Casgevy (exagamglogene autotemcel), the world's first CRISPR-based gene-edited therapy. The United States Food and Drug Administration (FDA) followed with its own approval in December 2023. A new era of medicine had begun.

Cell and gene therapies (CGTs) represent a fundamental shift in how we treat disease. Unlike conventional drugs that must be taken repeatedly, CGTs are living drugs—often administered just once, with the potential to provide lifelong benefit. They are not simply medicines; they are biological systems engineered to repair, replace, or reprogram the body's own cellular machinery.

As of July 2025, 36 gene therapies, 36 RNA therapies and 71 non-genetically modified cell therapies have been approved globally. The market is expanding rapidly, and with it, the need for physicians who understand the unique challenges of managing these therapies.

This handbook provides a practical guide for clinicians navigating the complexities of CGTs: the intricate logistics of vein-to-vein delivery, the recognition and management of acute and chronic toxicities, the imperatives of long-term follow-up, and the multidisciplinary frameworks essential for patient success.

The Logistics — From Vein to Vein

The Three Non-Negotiable Chains

The journey of a cell or gene therapy product from patient to manufacturing facility and back to the patient is one of the most complex logistical operations in modern medicine. Unlike conventional pharmaceuticals, CGTs are personalised, living products with strict time and temperature requirements. A single therapy's journey can involve collecting patient materials, transporting them under strict temperature controls, manufacturing the product, and maintaining a tight chain of identity and custody at every step.

At the heart of CGT logistics, there are three non-negotiable chains – identity, condition, and custody:

· Chain of Identity (COI): Ensuring that the product being infused belongs to the correct patient. A failure of identity can be catastrophic.

· Chain of Custody (COC): Every handoff—from apheresis to cell laboratory to bedside—must be documented with full traceability, ensuring accountability across borders, stakeholders, and time zones.

· Chain of Condition: Maintaining the precise temperature and environmental conditions required for the product's viability throughout its journey.

Coordinating the Journey

A single CAR-T therapy journey involves coordinating patient enrollment, apheresis scheduling, cryopreservation, manufacturing, and patient infusion, all while maintaining perfect COI and COC at every touchpoint. Scheduling for apheresis and infusion must be carefully aligned with manufacturing capacity.

The logistics operate across multiple temperature bands, with cryogenic vapor-phase storage required for many products. Premium couriers with active GPS and temperature telemetry are essential, and labels and forms must be carefully aligned with COI and COC requirements.

For physicians, this means that coordination—not just clinical expertise—is a core competency. Treatment centres must juggle multiple digital portals, coordinate manufacturing slots, track logistics, and manage patient journeys simultaneously.

Supply Chain Vulnerabilities

Cell and gene therapies are not off-the-shelf treatments. If the chain of custody or chain of condition is broken, that therapy might not be viable, and for many patients, there's no second chance. The supply chain for CGTs is significantly more complex than traditional pharmaceutical logistics.

Developers struggle with small batch sizes, limited analytical tools, and constrained viral vector supply chains that hinder manufacturing at scale. Strict time windows, often as short as 48 hours, exist for moving fresh apheresis material to a manufacturing facility.

Clinical Implication: Physicians must work closely with logistics coordinators, manufacturers, and couriers to ensure that patient scheduling, product manufacturing, and infusion are seamlessly aligned. Any delay in the chain can render the therapy unusable.

Side Effects — From Acute Toxicity to Chronic Complications

Cytokine Release Syndrome (CRS)

Cytokine release syndrome is the most commonly observed acute toxicity following CAR-T cell therapy. It is a systemic inflammatory reaction triggered by the massive release of cytokines after CAR T cell activation.

CRS can range in severity from low-grade fever to life-threatening multi-organ failure. The management approach is stepwise, using tocilizumab (an IL-6 receptor antagonist) and corticosteroids depending on severity, with recent data supporting the use of anakinra in refractory cases.

Management Algorithm:

· Grade 1: Symptomatic management, antipyretics, hydration

· Grade 2: Tocilizumab (8 mg/kg IV) if symptoms persist or worsen

· Grade 3-4: Tocilizumab plus high-dose corticosteroids (e.g., dexamethasone); ICU support may be required

Centres administering these therapies must have clear, agent-specific protocols in place to ensure timely management of severe reactions. The NCCN and EBMT guidelines provide general guidance for managing CAR T-cell-related CRS. Recent data suggests that early intervention strategies can effectively minimise progression to severe toxicity.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Neurotoxicity, now termed immune effector cell-associated neurotoxicity syndrome (ICANS) , is another common complication of CAR-T therapy. It can manifest as confusion, aphasia, seizures, or cerebral oedema. A consensus grading system for CRS and ICANS has been developed by experts in the field.

ICANS is managed primarily with corticosteroids. Brain oedema, a rare ICANS complication, can be rapidly progressive and fatal within 24 hours.

Less Frequent but Serious Complications

The European Society for Blood and Marrow Transplantation (EBMT) has published best practice recommendations for less frequent complications following CAR T-cell therapies:

· Hemophagocytic lymphohistiocytosis (HLH): A hyperinflammatory syndrome that can be life-threatening

· Graft-versus-host disease (GvHD): Immune attack on recipient tissues

· Thrombotic microangiopathy: Microvascular injury leading to thrombocytopenia and organ damage

· Coagulation disorders: Including disseminated intravascular coagulation

· Secondary malignancies: Due to insertional mutagenesis or immune dysregulation

These complications require early identification, risk mitigation, and therapeutic interventions guided by emerging clinical evidence.

Preconditioning and Immunosuppression

Management strategies to mitigate anticipated toxicity include preconditioning regimens, safer vector design, and immunosuppressive therapies. Prophylactic measures, including levetiracetam and low-dose dexamethasone, have been shown to significantly reduce severe toxicities.

Clinical Implication: Physicians must be vigilant for both common and rare toxicities, maintain low thresholds for intervention, and have clear escalation pathways to ICU-level care when needed.

Long-Term Follow-Up — The 15-Year Horizon

Regulatory Requirements

Cell and gene therapies are not conventional drugs. Their effects may last years or cause delayed adverse events. Major regulatory agencies all require long-term follow-up (LTFU) trials, which can be as long as 15 years, to monitor potential delayed adverse events and the durability of effectiveness.

The FDA has described a range of follow-up periods recommended based on the specific type of gene therapy and its general potential to cause delayed adverse events—ranging from "up to five years" for AAV vectors to fifteen years for integrating vectors. This risk-based approach recommends follow-up durations between 5 and 15 years depending on the therapy's mechanism of action.

The Patient Experience

Long-term follow-up is vital to both patient safety and broader learning, but it often lacks sufficient structural support. Patients face logistical and emotional burdens that can limit follow-up participation, particularly over 10-15 year timelines.

Healthcare providers should set expectations for long-term commitment early. Patients may require follow-up for 5, 10, or even 15 years. This long-term time commitment should be discussed with the patient at the outset.

Best Practices for LTFU

The Multi-Regional Clinical Trials (MRCT) Center has released a Toolkit for Supporting the Design, Conduct, and Reporting of Long-Term Follow-Up Studies for Gene Therapies (Version 2.0). The toolkit provides practical, actionable guidance for best practices across LTFU studies for both investigational and approved gene therapies.

Key Components of Effective LTFU:

· Patient-centred strategies: Including remote tools and streamlined protocols

· Clear communication: Setting expectations for long-term commitment at the outset

· Integration of real-world data: LTFU studies often leverage real-world data (RWD) post-authorisation

· Multidisciplinary coordination: Involving primary care, specialty care, and research teams

Clinical Implication: Physicians must establish LTFU protocols from the moment of treatment initiation, with clear communication about the 5-15 year monitoring horizon. Remote monitoring tools and real-world data integration can reduce patient burden and improve retention.

The Multidisciplinary Team — A Village for Every Patient

The Complexity Demands Collaboration

Because of the complex treatment procedures of CGTs and their specific severe immune-related adverse events, a multidisciplinary integrated case management approach is necessary. The format of the MDT meeting may include an in-hospital system (on-site) and an interhospital system (off-site).

The Core Team

Care teams include a wide range of professionals:

· Physicians: Hematologists, oncologists, transplant physicians, neurologists

· Nurse navigators: Guiding patients through the complex journey

· Advanced practice providers: Supporting clinical management

· Social workers: Addressing psychosocial needs

· Resource specialists: Coordinating logistics and access

· Donor services, apheresis and infusion nurses: Managing the vein-to-vein process

· Financial counsellors: Navigating reimbursement and cost barriers

The Role of Pharmacists

Multidisciplinary collaboration is essential for managing gene therapy complications, with pharmacists playing a critical role in SOPs and adverse event management. Gene therapy requires dynamic SOPs and real-time learning to address unexpected outcomes, emphasising flexibility and innovation.

MDT Before Therapy

A comprehensive MDT discussion should occur before treatment. This should include medical history collection, physical examination, and relevant tests completed before the MDT discussion in the screening period. The MDT should determine eligibility, plan the treatment pathway, and coordinate logistics.

Clinical Implication: Physicians must not work in isolation. CGTs demand a team-based approach with clear roles, responsibilities, and communication pathways.

Site of Care — Where Should Treatment Be Delivered?

The Current Landscape

CAR T-cell treatment requires advanced infrastructure and expertise. It is performed under the supervision of haematologists/medical oncologists in a specialised stem cell therapy unit with round-the-clock critical care support. Most treatments are delivered in FACT-accredited centres.

Outpatient Models

Safe and high-quality outpatient care requires involvement of a multidisciplinary team with clinical pathways for rapid triage and evaluation for CRS and ICANS and their management. Experts recommend flexible monitoring and transfer of care back to primary/community oncology physicians, starting from 2 weeks after infusion to improve access to this potentially curative therapy.

Geographic Barriers

Geography remains one of the biggest barriers to equitable CGT access. Living more than 25 miles from an accredited centre can significantly impact access. Logistical and non-medical requirements—caregiver availability, local housing, and transportation—vary widely across centres.

Clinical Implication: Physicians should consider site-of-care options carefully, balancing patient convenience with the need for specialised expertise and emergency backup.

Reimbursement and Access — The Economic Reality

The Cost Barrier

Treatment costs exceed USD 400,000 per patient, with total costs—including manufacturing, cryogenic logistics, and inpatient management—often surpassing USD 1 million. Reimbursement, infrastructure, and geographic patient access are some of the biggest obstacles to CGT expansion.

Reimbursement Challenges

Despite high payer confidence in safety and efficacy, reimbursement remains fragmented. Traditional reimbursement is often unavailable due to lack of marketing approval, and continued development is financially unsustainable without external support. Payers and providers continue to grapple with the regulatory, manufacturing, and reimbursement challenges posed by these complex and high-cost interventions.

Addressing Access Barriers

The science of cell and gene therapy has outpaced access; regulatory, economic, and awareness barriers remain. Helping patients navigate the reimbursement journey is another key factor. Pay-for-performance and value-based payment models are being explored to align costs with outcomes.

Clinical Implication: Physicians must be prepared to help patients navigate the complex reimbursement landscape, including prior authorisation, appeals, and financial assistance programs.

The Future — Point-of-Care Manufacturing and Decentralisation

The UK's Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025 clarify the licenses and quality standards that hospitals and academic groups need to safely produce CAR-Ts and other personalised treatments on-site. The EASYGEN project aims to bring CAR-T cell therapy directly to the point of care—within hospital settings—making it faster, more affordable, and more accessible to patients across Europe. Decentralised or point-of-care manufacture of CAR-T cells is a potential strategy to improve accessibility and reduce cost and logistic challenges.

For physicians, this means that the role of the treatment centre is evolving. Hospitals may increasingly become manufacturing sites as well as treatment sites, with all the quality, regulatory, and logistical implications that entails.

Conclusion: The New Standard of Care

Cell and gene therapies represent one of the most profound transformations in the history of medicine. These one-time "living drugs" offer the potential for cure where only palliation existed before. But they also demand a new kind of physician—one who understands not just the science, but the logistics, the toxicities, the long-term follow-up, and the multidisciplinary teamwork required for success.

The physician of the CGT era must be:

· A logistician, coordinating the intricate vein-to-vein journey

· A toxicologist, recognising and managing acute and chronic complications

· A long-term planner, ensuring 15-year follow-up for every patient

· A team leader, orchestrating multidisciplinary care

· A patient advocate, navigating reimbursement and access barriers

The therapies are here. The tools are available. The question is whether the medical community will rise to the challenge of delivering them safely, effectively, and equitably to every patient who needs them.

The era of living drugs has arrived. It is time to embrace the responsibility that comes with it.

Cell and gene therapies are not just medicines. They are living drugs — one-time treatments with the power to cure. But they demand a new kind of physician: one who masters logistics, toxicities, and 15-year follow-u

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The Era of Living Drugs

Managing the New Class of Cell and Gene Therapies (CGTs)