Cell Therapy for Solid Tumours: Current Challenges and New Advances
Cell therapy for solid tumours faces unique biological barriers. This analysis unpacks the engineering strategies pharma leaders must understand for R&D success in 2026.
Seven FDA-approved CAR-T therapies now exist for haematological malignancies, but none for solid tumours. The gap in cell therapy coverage for solid tumours is not a coincidence, reflecting a set of biological barriers that have resisted more than a decade of engineering effort and that every oncology R&D team needs to understand.
Why Solid Tumours Are Difficult to Treat
Solid tumours are challenging to treat due to their size, anatomical location, and underlying biological complexity, all of which complicate the identification of effective therapeutic strategies.
Antigen heterogeneity is the first barrier. In blood cancers, targets such as CD19 and B-cell maturation antigen (BCMA), are uniformly expressed across malignant cells. Solid tumours don't offer that consistency.
Within a single tumour mass, antigen expression varies across cell populations. A CAR-T product engineered to target one antigen will eliminate antigen-positive cells while leaving antigen-negative subpopulations intact. The surviving cells drive relapse.
The second barrier, and arguably more formidable, is the tumour microenvironment.
The TME actively suppresses immune function through multiple mechanisms: The physical extracellular matrix (ECM) blocks T cell infiltration; metabolic competition starves infiltrating lymphocytes of glucose and oxygen; and sustained immunosuppressive signalling occurs through cytokines such as TGF-beta, IL-10, and PD-L1 expression on tumour cells.
The combined effect is T cell exhaustion: CAR-T cells that do reach the tumour progressively lose effector function, proliferative capacity, and persistence. In haematological settings, this phenomenon is manageable, while in solid tumours, it is the dominant reason for clinical failure.
A 2025 review in Cell Reports Medicine summarised the core problems as insufficient trafficking, antigen escape, limited persistence, and TME-driven immune suppression.
This represents a four-way challenge that no single engineering modification can resolve.
What the First Solid Tumour Approval Can Tell Us
In August 2024, afami-cel (afamitresgene autoleucel) received FDA approval for synovial sarcoma, a rare but aggressive soft tissue sarcoma in adolescents and young adults, making it the first cell therapy approved for a solid cancer indication. The Phase II SPEARHEAD-1 trial reported a 36% objective response rate and a 71% disease control rate in 45 patients.
The target was MAGE-A4, a cancer-testis antigen. Synovial sarcoma expresses MAGE-A4 with relatively high uniformity, reducing the antigen heterogeneity problem that undermines most solid tumour programmes.
The lesson for R&D strategy: Target selection matters more than engineering sophistication. Uniform antigen expression in a biologically restricted target tissue is the precondition for success.
Engineering Strategies Gaining Ground
Multi-antigen targeting
Programmes addressing antigen escape are increasingly incorporating bivalent or tandem CAR-T architectures.
In glioblastoma, Phase I results for intraventricular delivery of CAR-T cells targeting both EGFRvIII and IL-13Ra2 demonstrated antitumour activity in a disease where single-antigen approaches have repeatedly failed.
The approach does not eliminate antigen escape but reduces its probability by targeting two independent pathways simultaneously.
Synthetic biology and genetic reprogramming
Next-generation CAR-T designs incorporate genetic modifications that directly counteract TME-induced suppression. These include:
- Checkpoint gene knockout: Disruption of PD-1 or TIM-3 expression in the CAR-T product to reduce susceptibility to tumour-derived inhibitory signals.
- Cytokine armoured CARs: Products engineered to secrete pro-inflammatory cytokines such as IL-15 directly at the tumour site. Interleukin-15-armoured GPC3 CAR-T cells demonstrated enhanced persistence and antitumour activity in a 2024 study targeting solid cancers.
- SynNotch receptor systems: A synthetic biology approach that adds a conditional activation layer, allowing CAR-T cells to produce effector molecules only when they detect specific tumour-associated signals, reducing off-tumour toxicity.
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Epigenetic reprogramming: DNMT3A deletion in CAR-T cells has been shown to preserve a stem cell-like phenotype and sustain proliferative capacity in solid tumour models, directly addressing the exhaustion problem.
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Allogeneic cell therapy
Autologous CAR-T production (collecting, modifying, and re-infusing a patient's own T cells) creates logistical and cost challenges that limit access and speed.
Allogeneic (‘off-the-shelf’) approaches using healthy donor T cells are progressing in solid tumour settings, including ongoing trials evaluating NKG2DL-targeting CAR-NK cells across multiple solid tumour types.
Manufacturing standardisation and decentralised production models are increasingly cited as operational priorities by regulatory and commercial teams alike.
Cell Therapy Delivery for Solid Tumours
Systemic intravenous delivery, which works for blood cancers, is poorly suited to solid tumours with dense ECM barriers. Clinical teams are exploring locoregional delivery (administering CAR-T cells directly into or adjacent to the tumour site) to increase infiltration and reduce the volume of product required.
In glioblastoma, intracerebroventricular delivery of B7-H3-targeting CAR-T cells in a Phase I trial showed tumour regression in a disease with almost no durable systemic treatment options.
Locoregional delivery is not universally applicable, but it represents a meaningful strategic shift for tumour types where anatomical access allows it.
The Claudin18.2 Signal in Gastrointestinal Cancers
Claudin18.2 (CLDN18.2) is a tight junction protein aberrantly exposed in gastric and gastrointestinal junction cancers. It has emerged as one of the more tractable solid tumour targets because of its restricted normal tissue expression and consistent overexpression in malignant cells.
Results presented at ASCO 2025 from a Phase II multicentre trial of CLDN18.2-targeted CAR-T cells in advanced pancreatic and previously treated gastric or gastro-oesophageal junction (GEJ) cancer reported objective responses and manageable safety, supporting continued development.
Pancreatic adenocarcinoma is one of the most difficult solid tumour types to treat. It is operationally signficant that responses are visible with CLDN18.2-targeting for programmes in gastric, pancreatic, and GEJ indications.
What R&D Leaders Should Track
R&D leaders should pay attention to three areas within solid tumour treatment programmes:
- Phase III CAR-T data in 2026: Multiple AI-designed and engineered oncology candidates are entering pivotal trials. Phase III readouts will provide the first large-scale evidence of whether next-generation CAR-T architectures produce durable solid tumour responses.
- The FDA's reduced animal testing roadmap: The April 2025 roadmap begins with monoclonal antibodies but signals expanding regulatory acceptance of human-relevant models. Teams designing solid tumour programmes should be preparing for regulatory interactions that include organoid-based efficacy data alongside or instead of animal models.
- Manufacturing access and point-of-care production: Decentralised manufacturing models are becoming a competitive differentiator. Cost and logistics remain the primary barriers to solid tumour cell therapy at scale, and programmes that solve this earlier will have a structural advantage in market access negotiations.
Conclusion: Effectively Designing Cell Therapies for Solid Tumours
No cell therapy has yet achieved regulatory approval for a broad solid tumour indication. The approval of afami-cel for synovial sarcoma is a proof of concept, not a template. The biology of the solid tumour microenvironment (antigen heterogeneity, TME suppression, T-cell exhaustion) demands a coordinated engineering response that no single modification has yet provided.
The programmes most likely to succeed in the next five years are those that combine rational antigen selection, genetic reprogramming to address exhaustion, and delivery strategies suited to the tumour microenvironment.
However, the distance between early Phase I signals and Phase III success has proven consistently wider in solid tumours than in any other oncology setting.
Pharmatica tracks the drug discovery, clinical, and regulatory developments shaping cell and gene therapy across oncology, providing the strategic context pharma leaders need for clinical and market success.
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Frequently Asked Questions
Why has no CAR-T therapy been approved for solid tumours?
No CAR-T therapy has been approved for solid tumours because solid cancers present multiple simultaneous barriers that haematological malignancies do not.
These include inconsistent antigen expression across tumour cells (antigen heterogeneity), an immunosuppressive tumour microenvironment that inactivates infiltrating T cells, poor T cell trafficking through dense extracellular matrix, and rapid T cell exhaustion.
Each barrier independently reduces efficacy; in combination, they have prevented durable clinical responses in most trials to date.
What was the first cell therapy approved for a solid tumour?
Afamitresgene autoleucel (afami-cel) received FDA approval for synovial sarcoma, a rare soft tissue sarcoma in adolescents and young adults, as of April 2025.
In the Phase II SPEARHEAD-1 trial, it achieved a 36% objective response rate and 71% disease control rate in 45 patients with MAGE-A4-expressing tumours. Synovial sarcoma was tractable because it expresses MAGE-A4 with relatively high uniformity; a target selection advantage not available in most common solid tumour types.
What is T cell exhaustion and why does it matter for solid tumour therapy?
T cell exhaustion is a state of progressive functional decline in T cells exposed to persistent antigen stimulation or immunosuppressive signals.
In solid tumours, CAR-T cells that successfully infiltrate the tumour mass encounter chronic stimulation from tumour antigens and suppressive signals from the TME, causing them to lose proliferative capacity and cytotoxic function.
Exhausted CAR-T cells cannot sustain antitumour activity, which is the primary reason solid tumour responses are often short-lived even when initial activity is observed.
What engineering approaches are most promising for overcoming the tumour microenvironment?
The most clinically advanced approaches include checkpoint gene knockout (disrupting PD-1 or TIM-3 expression in the CAR-T product), cytokine-secreting armoured CARs that release pro-inflammatory signals at the tumour site, and epigenetic reprogramming strategies such as DNMT3A deletion to preserve a stem-like T cell phenotype. SynNotch receptor systems provide conditional activation that can reduce off-tumour toxicity. None has individually solved the TME problem; multi-strategy combinations are increasingly the clinical focus.
What is the strategic difference between autologous and allogeneic cell therapy in solid tumours?
Autologous cell therapy uses the patient's own T cells, which avoids immunological rejection but requires individualised manufacturing that is slow and expensive.
Allogeneic cell therapy uses healthy donor T cells manufactured at scale, enabling off-the-shelf availability and faster treatment initiation.
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