Cell therapies: breaking ­barriers in ­solid tumours

Initially approved by the FDA in 2017 for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), Novartis’ Kymriah was groundbreaking in many ways. A chimeric antigen receptor therapy (CAR-T), it can be thought of as a “living drug”, created by harvesting a patient’s own T-cells, genetically modifying them to attack cancer cells, and then injecting them back into a patient. With Kymriah, a special receptor is added to the T-cell that targets the CD-19 antigen commonly found on B cells, but not in healthy tissues.

Results in this very sick group of patients were striking. In the pivotal ELIANA trial, the complete remission rate, including those with incomplete count recovery, was 82%. After five years, 49% of patients in these groups remained relapse-free.

But side effects can be severe. Kymriah carries a boxed warning for cytokine release syndrome (CRS), a potentially life-threatening systemic response to the activation and proliferation of CAR T-cells, causing high fever and flu-like symptoms. Kymriah can also cause life-threatening neurological side effects, meaning patients need close medical attention just to get through the course of treatment.

Despite the ground-breaking approval, there was clearly further work needed to make cancer cell therapies more tolerable. Other drawbacks, such as the costly and slow manufacturing process requiring specialist units, also needed to be addressed.

And the other major hurdle for the first generation of CAR-Ts is that their use is limited only to blood cancers. Tackling solid tumours with cell therapies became the next major challenge for research in the field.

Barriers in solid tumours

The barriers that CAR-T therapies face in solid tumours are the same as those faced by the body’s unmodified immune cells. Solid cancers are able to survive and fend off attacks from the body’s defences because of a series of physical and biological barriers that form in malignant tissue. Known as the tumour microenvironment, this no-man’s land surrounding tumours tests the survival abilities of immune cells. It’s often hypoxic, so immune cells don’t have the oxygen they need to survive. There are physical barriers, such as the cellular matrix surrounding a tumour, and there are immunosuppressive cells enlisted by the tumour to defend against attacks.

Even after creating a therapeutic cell tough enough to get behind enemy lines and into the cancer stronghold, there’s the problem of how to attack the enemy. CAR-T cells have worked effectively in blood cancer because the antigen CD-19 is found almost exclusively on B-cells, meaning the CAR-Ts will tend to ignore healthy tissues. Finding a suitable antigen on solid tumours is much more difficult. There are a handful of validated targets for each tumour type, with a common strategy in next-generation CAR cells being to target two antigens on the tumour cell surface (with targets including, for example, CLDN18.2, Mesothelin, GPC3, B7-H3, GD2, HER2).

Martin Olin, chief executive of London-based cancer cell biotech Swarm Oncology, summarised the ongoing challenges in the field: “Firstly, there is the quality of the surface targets. You have off-target toxicity with CAR-T, which is nasty. Secondly, the tumour microenvironment has been challenging. Manufacturing has been a challenge.”

The laborious manufacturing process translates into high costs, which also means that CAR-T therapies are often not affordable for patients and/or healthcare systems. “The price point for CAR-T is impossible for a broadly applicable therapy,” Olin said.

Where CAR-Ts fear to tread

While research into this next generation of CAR-Ts continues in the clinic, a new cancer cell therapy approach received accelerated FDA approval in 2024 in advanced melanoma. Iovance’s Amtagvi (lifileucel) is based around a Tumour-Infiltrating Lymphocyte (TIL), a white blood cell harvested from a patient’s own tumour. These are enhanced to fight cancer and reintroduced into the patient where the cell recognises special markers found only on the surface of tumours. Neoantigens are found only on the surface of tumours and are caused by the malfunctioning machinery within the cancer cell itself. They vary from patient to patient and thus are hard to target, but nevertheless are a very strong marker that a cell is cancerous and therefore can produce a strong immune response. Amtagvi is not genetically modified; rather, the patient’s cells that can identify neoantigens are encouraged to replicate more than a billion times in the lab, then mixed with the drug IL-2 to stimulate them and encourage them to grow. Patients then receive a dose of chemotherapy to deplete the compromised TILs that are already in the tumour, and they also receive a dose of IL-2 after the infusion to further encourage the new cells to do their job. While clinical results convinced the FDA, regulators in Europe did not take the same view. The overall response rate (ORR) of 31.4% seems solid enough, but only 5.9% of patients produced a complete response, with 25.5% recording a partial response in the treatment arm of 153 patients.

Amtavgi’s US approval is contingent on further confirmatory trial data. Clinical data did not convince regulators from the European Medicines Agency, and Iovance withdrew its marketing authorisation application in Europe in July 2025.

TCRs to the rescue

Another approach is to use T-cell receptor (TCR-T) therapy, where researchers identify receptors that occur naturally on T-cells while they are scanning for malignant cells to attack. T-cells can be modified to express more of the receptors that are trained to attack cancer, making them more effective. One advantage of this kind of therapy is that it can also be used to attack targets within cancer cells and is not limited to those found on the surface.

In August 2025, UK-based Adaptimmune managed its big breakthrough in the TCR field with FDA accelerated approval of Tecelra (afamitresgene autoleucel) for adults with advanced synovial sarcoma. Patients must have received prior chemotherapy, be HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and have tumours expressing the MAGE-A4 antigen. Adaptimmune noted that Tecelra is the first engineered cell therapy for solid tumours to be approved by the FDA.

Tecelra is made by harvesting T-cells and genetically modifying them to target melanoma-associated antigen A4 (MAGE-A4), that can be over-expressed on malignant cells in synovial sarcoma. Approval was based on one 44-patient treatment cohort, showing an overall response rate of 43% with a complete response rate of 4.5%. As with Amtavgi, Adaptimmune must produce confirmatory trial data for the product to remain on the market in the long term.

Natural born killers

There are other alternative cell therapies at various stages of development, which aim to raise the bar in terms of both safety and efficacy. Almost all are based upon modifying various immune cells already found in the body and modifying them so they are more effective at fighting cancer, typically with the added resilience to survive in the hostile tumour microenvironment.

One potential line of attack is CAR-NK cells, modified natural killer cells that have enhanced tumour-killing abilities and added resilience. NK cells, which are part of the innate lymphoid cell family and commonly found in lymph nodes, are of interest because they can recognise and kill cancer cells without prior sensitisation. They produce a different set of cytokine signals when they attack, potentially producing fewer side effects than T-cells and can also be derived from cell lines from healthy donors. This raises the possibility of an “off-the-shelf” allogeneic therapy that is easier to mass produce, with lower production costs than CAR-Ts.

CAR-NKs are in the early stages of clinical development, with more than 40 trials registered according to a review. Progress is furthest in blood cancer, but there are now serious inroads into the clinic in solid tumours. For example, a basket trial in the Second Affiliated Hospital of Guangzhou Medical University is testing several CAR-NK therapies, with receptors targeting Claudin6, GPC3, Mesothelin, or AXL antigens in a range of solid tumours.

Getting engaged

There are a host of other approaches to cell therapy under development – T cell engagers are already approved in several cancers. These agents bind with T-cells and also tumour cells to enhance the body’s own cancer-killing response. Initially restricted to blood cancers, there was a major breakthrough when Amgen’s Imdelltra (tarlatamab) received the FDA nod for small cell lung cancer in May 2024, the first time a T-cell engager had been approved in a solid tumour. Macrophages, the amoeba-like white blood cells that engulf and digest infections and unhealthy tissue, are another cell type that researchers are looking to enlist in the fight against solid tumours. However, translating this modality into the clinic remains challenging. Restricted cell expansion, genetic engineering complexities, and variability in product quality are among the challenges to be overcome.

Macrophages have some key strengths as cancer therapy, as they are adept at infiltrating the tumour microenvironment, as well as eating cancer cells, or calling in a response from the innate immune system by producing signals to enlist T-cells and a wider immune response. Equipping a macrophage with a chimeric antigen receptor to produce a so-called CAR-M cell is a favoured approach. Potential target antigens in solid tumours include HER-2 and GD-2.

Vesicles and other bits of cells

It’s also possible to create delivery mechanisms derived from cells, using components or products to transport a therapeutic payload to targets on cancer cells. Tumor Cell-Derived Extracellular Vesicles (TEVs) from cancer cells, inherit surface proteins such as CD54 that allow high targeting ability towards parent tumor cells and deep tissue penetration.

Immune Cell-Derived EVs derived from macrophage or neutrophil vesicles can target inflamed tumor environments, leveraging their natural chemotactic ability. Mesenchymal stem cells and red blood cells could also be used as delivery systems. Researchers are also looking at ways to improve on the modalities outlined above, in combination with other therapeutic approaches.

A field still in its infancy

TILs and TCR-Ts have now shown that engineered and expanded immune cells can win regulatory approval in solid tumours, but response rates remain modest, patient selection is narrow, and confirmatory trials will determine how durable these first breakthroughs really are. CAR-NKs, CAR-Ms, T-cell engagers and extracellular vesicle-based systems are still finding their clinical footing, but they point to a broader shift: cell therapies are evolving from blunt immune weapons into more sophisticated delivery platforms.

The opportunity is enormous. Solid tumours make up the vast majority of cancer cases, and current treatments still fail too many patients. But the biology is unforgiving, and the next generation of cell therapies will need to solve multiple problems at once: trafficking, persistence, targeting, safety, manufacturability and cost.

CAR-Ts proved that cells can be turned into drugs. The challenge now is to make them work where cancer is hardest to reach. If the field succeeds, cell therapy may move beyond a specialist treatment for rare blood cancers and become a central pillar of solid tumour oncology. ν

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This article was originally published in EBM’s summer edition. Get it here.