Recent advances and the near-term outlook for Advanced Therapy Medicinal Products in cancer treatment

Intoduction

The changing face of ATMP-based cancer innovations

Cancer treatment with biologics has undergone a dramatic change with the advances made first by immunotherapies and, more recently, by ATMPs. A growing number of ATMPs have been granted marketing authorisation (MA) approval, bringing new hope for a cure for many more cancers.

The earlier focus on chimeric antigen receptor T-cell (CAR-T) therapy has expanded significantly, paving the way for new modalities to treat different cancers.

CAR-T therapy

CAR-T therapies have played a transformational role in cancer treatment, particularly for blood cancers such as multiple myeloma.^[1] Researchers are now turning their attention to solid tumours by adopting alternative approaches, with promising results. Approaches include the regional delivery of CAR T-cells, tumour stroma infiltration and the modification of chemokine expression.^[2]

One example is a CAR-T clinical trial that targets paediatric brain tumours, which has resulted in shrinking several patients’ tumours and even a complete response from one patient.^[3]

Nevertheless, CAR-T therapies continue to present safety, efficacy and use limitations. One notable example is the risk of manufacturing failures, with reports showing that these can be as high as 25 percent.^[4] Solid tumours in particular pose unique challenges for CAR-T treatment, most notably tumour-antigen heterogeneity and the immunosuppressive tumour microenvironment,^[5] which has led researchers to assess the next generation of the CAR-T approach with immune cells other than T-cells.

These include macrophages (CAR-MΦ) and natural killer cells (CAR-NK). CAR-MΦ could potentially target and eradicate tumour cells by leveraging the phagocytic and antigen-presenting properties of macrophages and could be administered in combination with other anticancer agents, such as checkpoint inhibitors.^[6] CAR-NK cells are increasingly seen as a promising alternative, given their innate ability to identify and destroy malignant cells without needing prior sensitisation.^[6]

The benefits of using alternative cells for CAR transduction include reduced toxicological risks, off-the-shelf potential, enhanced microenvironment navigation, novel targeting opportunities and reduced graft-versus-host disease.^[7]

CAR-T treatments are also being engineered with gene-editing technologies to enhance the development of next-generation CAR-T therapies. A growing number of clinical trials (CTs) are being conducted to investigate gene-edited CAR-T therapies, demonstrating accelerated advancements in refining this groundbreaking immunotherapeutic approach.^[8]

To date, CAR-T therapies have been generated ex vivo, which presents challenges and limitations, particularly from the point of view of scalability and turnaround time. To overcome these challenges, researchers have been exploring the generation of CAR T-cells directly within the patient’s body, which could potentially simplify manufacturing processes, reduce costs and improve accessibility compared with traditional ex vivo CAR-T therapies.^[9]

Additionally, the short-term nature of in vivo mRNA-modified CAR T-cells allows repeat dosing and real-time dose adjustment which, in turn, increases efficacy and reduces toxicity risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Moreover, the temporary nature of mRNA-based CAR T-cells could prevent the T-cells from becoming exhausted.^[10]

Already, in vivo CAR-T technology is at a clinical stage for several indications across oncology and autoimmune disorders.^[11]

Oncolytic viruses

Studies of oncolytic viruses began in the 1950s based on anecdotal observations of tumour remissions following virus infections.^[12] Despite a large body of research, many CTs, and a scientific guideline from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published in 2008,^[13] only a few oncolytic virus products have been licensed, though many more are in CTs.^[14]

However, with increased understanding of the mechanisms of immuno-oncology, oncolytic viruses are currently undergoing something of a renaissance. Recently, researchers presented findings from a Phase II trial with the oncolytic virus talimogene laherparepvec (T-VEC) to treat patients with difficult-to-resect cutaneous basal cell carcinomas.^[15] The treatment proved to be well-tolerated and successfully achieved resection in half the patients enrolled without the need for reconstructive surgery. Nevertheless, researchers note that further investigation is warranted.

Cancer vaccines

Personalised cancer vaccines (PCVs) have reached a more advanced stage of development, with recent CTs demonstrating potential across multiple cancer types, including kidney, liver and pancreatic malignancies.^[16],^[17],^[18]

PCVs target neoantigens, which are mutated proteins unique to a patient’s tumour. Most personalised cancer vaccines are based on mRNA technology. In the EU, a current review of the legislation revisits the definition of a gene therapy medicinal product.^[19] Depending on the outcome, mRNA-based cancer vaccines may or may not become gene therapies. In July 2023, the UK government signed a major agreement to provide up to 10,000 patients with personalised cancer immunotherapies by 2030 as part of a clinical trial evaluation. The UK government and the NHS leadership view this partnership as an opportunity to provide patients with early access to cutting-edge technology that could transform cancer care.^[20]

Regulators as enablers

For quite some time, regulators have been expanding their role from gatekeeper to enabler of innovation.^[21] They have created regulatory incentives to bring medicines in high-unmet-medical-need situations (which oncology indications typically are) to patients earlier and in safe and measured ways.

One well-established approach is to grant MA earlier but with conditions. This approach is called ‘Accelerated Approval’ in the US,^[22] ‘Conditional Marketing Authorisation’ in the EU,^[23] and ‘Conditional Early Approval System’ (CEAS) in Japan.^[24] In order to maintain MA, the sponsor needs to fulfil agreed commitments with the Agency.

However, this is not a regulatory tool that can be used lightly, as it comes with several issues. Conditional approval is based on less-comprehensive data, suggesting that the data may not be strong enough to support authorisation through conventional pathways.^[25] In this respect, it is important that such data are complemented after such authorisation. However, there are concerns about post-approval evidence gaps. Some regulatory authorities have raised concerns about MA holders not fulfilling their post-authorisation obligations in a timely manner.^[26]

Despite concerns that it may be more difficult for regulators to remove a drug from the market altogether when it is already in use, the withdrawal in 2019 of Zalmoxis, an allogeneic T-cell immunotherapy for high-risk blood cancers post-stem cell transplant, shows the system can work. The drug was withdrawn after Phase III CTs showed that Zalmoxis offered no clinical benefit.^[27]

Regulators have several other approaches at their disposal to advance innovation, which include closer interactions with the regulatory authorities. These include, for example, the US Food and Drug Administration’s (FDA) fast track designation,^[28] breakthrough therapy designation,^[29] and regenerative medicine advanced therapy (RMAT) designation,^[30] the European Medicines Agency’s (EMA) priority medicines (PRIME) designation,^[31] and the UK Medicines and Healthcare products Regulatory Agency’s (MHRA) Innovative Licensing and Access Pathway (ILAP).^[32]

In addition, programmes more specific to oncology have been designed. One noteworthy example is the FDA’s Project Frontrunner,^[33] which allows oncology drugs to be used earlier in the treatment cascade. Standard practice has been to use novel treatments in last-line treatment in heavily pretreated patients, due in part to limited safety data and their novelty. There has been a shift in treatment guidelines that contain evidence that early immunotherapy capitalises on intact immune function and synergises with traditional therapies to improve long-term outcomes.^[34]

In addition, with multiple earlier lines of treatment, safety and efficacy data can be confounded by carryover effects. Programmes such as the FDA’s Project Optimus^[35] may also improve the process for finding an optimal dose. Dose finding is an important cornerstone, especially in oncology because, at the time of approval, regulators will ask two questions:

1. Could a higher dose of the new medicine be more effective and equally safe?

2. Could a lower dose be safer but equally efficacious?

The FDA’s Project Optimus seeks to address dose optimisation to achieve efficacy while improving safety and tolerability, and encourages drug developers to meet with FDA oncology review divisions early in development.

Regulators are also focused on building their own expertise with cutting-edge therapies. Horizon scanning systems (HSS) have proved a useful tool to support policymakers and healthcare professionals in predicting the availability of new medicines and their main impacts. For example, the EU has implemented an Innovative Partnership for Action Against Cancer (iPAAC) and applies HSS for cancer control in Europe.^[36] Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has adopted a horizon scanning method to ensure it has the expertise to review new technologies.^[37]

The new EU Health Technology Assessment Regulation (HTAR) significantly impacts ATMPs and cancer treatments by streamlining their pathway to patient access. Started on 12 January 2025, these products now undergo joint clinical assessments (JCAs) to evaluate their relative clinical effectiveness and safety compared to existing therapies. The HTA Coordination Group (HTACG) estimates that it will conduct 17 JCAs for cancer medicines and eight JCAs for ATMPs in 2025, with cancer-related ATMPs in the cancer category.^[38] Developers can also engage in parallel JCAs from February 2025 onwards, enabling simultaneous regulatory and HTA body feedback to align evidence requirements. This coordination aims to reduce delays, ensuring faster reimbursement decisions while maintaining independent regulatory and HTA evaluations.

Where the patient fits in innovation

Ultimately, the ATMP breakthroughs now being witnessed, combined with efforts by the regulators to spur innovation and improve how and when patients access these products, could revolutionise cancer treatment. At the same time, regulatory and payer caution with the approval process is merited, especially given research that found that many drugs receiving accelerated approval lack proof of added benefit.^[39]

However, earlier patient access is increasingly a goal. Project FrontRunner could enable patients to get access to innovative therapies by encouraging sponsors to consider seeking approval to treat cancer in earlier clinical settings.

In describing Project FrontRunner, the FDA notes that it ‘aims to improve the evidence base for cancer therapies by promoting trial designs and clinical development and regulatory approaches (for example, accelerated approval pathway) that help generate data from gold standard randomised controlled trials to support the safe and effective use of cancer therapies for all patients.’

Although there is currently no equivalent in the EU, there is widespread understanding that the path to regulatory approval can slow the time it takes to get lifesaving medicines to patients in need. Through EU Regulation 1394/2007, exceptions, in particular, hospital exemptions, allow ATMPs without a licence to be administered to certain patients, provided the product meets quality, safety and efficacy standards.^[40]

Additionally, there are requirements that hospital exemption products are administered within a hospital setting, that they are prepared and used in the same Member State, that they are administered by an attending physician, and that manufacturing is based on a medical order and for a specific patient. Nevertheless, a lack of harmonisation across the EU has raised industry concerns about accessibility.^[41]

 Conclusion

As oncology research expands into many new areas of cell and gene therapy, and as researchers finesse their approaches, so too does the potential for transformative treatment options. However, advancing transformative ATMP cancer treatments will require a considered approach by both innovators and regulators.

A progressive yet cautious approach by the regulators, with innovators committed to engaging with the health authorities, is key to transforming cancer care, ensuring that patients benefit from the latest scientific advancements while maintaining rigorous safety and efficacy standards.

 

References

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^[2] Schoenfeld AJ and O’Cearbhaill RE (2021) ‘How Do We Meet the Challenge of Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors?’ Cancer Journal. 01;27(2) pp.134-142. doi: 10.1097/PPO.0000000000000516 (Accessed 29 April 2025).

^[3] Monje M, Mahdi J, Majzner R et al (2025) ’Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas’. Nature. 637, pp. 708-715. doi: 10.1038/s41586-024-08171-9 (Accessed: 29 April 2025).

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^[6] Li J, Chen P and Ma W (2024) ‘The next frontier in immunotherapy: potential and challenges of CAR-macrophages’. Experimental Hematology & Oncology  13, 76 (2024) doi: 10.1186/s40164-024-00549-9

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^[8] Moradi V, Khodabandehloo E, Alidadi M, Omidkhoda A, Ahmadbeigi N (2024) ‘Progress and pitfalls of gene editing technology in CAR-T cell therapy: a state-of-the-art review’. Frontiers in Oncology 14; 2024.  doi: doi.org/10.3389/fonc.2024.1388475  (Accessed: 12 February 2025).

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^[11] Umoja Biopharma (2025) ‘Pioneering in vivo CAR T cell therapies’. (Accessed: 29 April 2025).

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^[13] European Medicines Agency (EMA) (2009) ‘ICH Considerations: Oncolytic Viruses’. (Accessed: 29 April 2025).

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^[16] Braun DA, Moranzoni G, Chea V et al (2025) ‘A neoantigen vaccine generates antitumour immunity in renal cell carcinoma’. Nature. doi: 10.1038/s41586-024-08507-5

^[17] National Institute of Health (NIH) (2023) ‘An mRNA vaccine to treat pancreatic cancer’. (Accessed: 29 April 2025).

^[18] Yarchoan M, Gane EJ, Marron TU et al (2025) ‘Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial’. Nature Medicine   30 pp. 1044-1053 doi: 10.1038/s41591-024-02894-y

^[19] European Commission (EC) (2023) ‘Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC’. (Accessed: 29 April 2025).

^[20] Gov.uk (2023) ‘Major agreement to deliver new cancer vaccine trials’. (Accessed: 29 April 2025).

^[21] Ehmann F, Papaluca Amati M, Salmonson T, Posch M, Vamvakas S, Hemmings R, Eichler HG, Schneider CK (2013) ‘Gatekeepers and enablers: how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude’. Clinical Pharmacology &Therapeutics. 93(5), pp. 425-32. doi: https://doi.org/10.1038/clpt.2013.14  (Accessed: 29April 2025).

^[22] US Food and Drug Administration (FDA) (2024) ‘Accelerated Approval Program’. (Accessed: 29 April 2025).

^[23] European Medicines Agency (EMA) (2025) ‘Conditional marketing authorisation’. (Accessed: 12 February 2025).

^[24] Matsushita S, Tachibana K, Kusakabe T, Hirayama R, Tsutsumi Y, Kondoh M (2021) ‘Overview of the Premarketing and Postmarketing Requirements for Drugs Granted Japanese Conditional Marketing Approval’. Clinical and Translational Science 14(3) pp. 806-811. doi: https://doi.org/10.1111/cts.12898  (Accessed: 29 March 2025).

^[25] Smith JA and Brindley DA (2017) ‘Conditional Approval Pathways: The “Special” Case of Global Regenerative Medicine Regulation’. Rejuvenation Research, 20(1). doi: https://www.liebertpub.com/doi/10.1089/rej.2017.1932  (Accessed: 29 April 2025).

^[26] European Commission (EC) (2014) ‘Relation between pharmaceuticals regulatory framework and timely access of medicines to patients: Reflection on difficulties and opportunities’. (Accessed: 29 April 2025).

^[27] Sharma V (2019) ‘Disappointing End For MolMed’s Zalmoxis Cell Therapy In EU’. (Accessed: 14 February 2025).

^[28] US Food and Drug Administration (FDA) (2024) ‘Fast Track’. (Accessed: 29 April 2025).

^[29] US Food and Drug Administration (FDA) (2024) ‘Breakthrough Therapy’. (Accessed: 29 April 2025).

^[30] US Food and Drug Administration (FDA) (2023) ‘Regenerative Medicine Advanced Therapy Designation’. (Accessed: 12 February 2025).

^[31] European Medicines Agency (EMA) (2025) ‘PRIME: priority medicines’. (Accessed: 12 February 2025).

^[32] Gov.uk (2025) ‘Innovative Licensing and Access Pathway (ILAP)’. (Accessed: 12 February 2025).

^[33] US Food and Drug Administration (FDA) (2024) ‘Project FrontRunner: Advancing Development of Oncology Therapies to the Early Clinical Setting’. (Accessed: 12 February 2025).

^[34] Mittendorf EA, Burgers F, Haanen J and Cascone T (2022) ‘Neoadjuvant Immunotherapy: Leveraging the Immune System to Treat Early-Stage Disease’. American Society of Clinical Oncology Educational Book. doi: https://doi.org/10.1200/EDBK_34941 (Accessed: 29 April 2025).

^[35] US Food and Drug Administration (FDA) (2024) ‘Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology’. (Accessed: 12 February 2025).

^[36] European Commission (EC) (2020) ‘Horizon scanning systems applied for Cancer control in Europe. Innovative Partnership for Action Against Cancer and the Health Programme of the European Union’. (Accessed: 29 April 2025).

^[37]  Shimokawa M, Sato D, Wakao R and Arai H (2021) ‘PMDA’s Vision for Horizon Scanning of Emerging Technologies Potentially Relevant to the Development of New Medical Products: The Regulatory Challenge’. Clinical Pharmacology &Therapeutics  109(2) pp. 295-298. doi: 10.1002/cpt.1986

^[38] European Commission (EC) (2024) ‘Annual Work Programme 2025’. (Accessed: 29 April 2025).

^[39] Utrecht University (2024) ‘Many new oncology drugs approved in the EU lack proof of added benefit’. (Accessed: 29 April 2025).

^[40] Goula A, Gkioka V, Michalopoulos E, Katsimpoulas M, Noutsias M, Sarri EF, Stavropoulos C and Kostakis A (2020) ‘Advanced Therapy Medicinal Products Challenges and Perspectives in Regenerative Medicine’. Journal of Clinical Medicine Research  12(12) pp. 780-786. doi: 10.14740/jocmr3964  (Accessed: 29 April 2025)

^[41] Iribarren M (2024) ‘Commission’s hospital exemption divides health sector’. Euro news (Accessed: 29 April 2025).