Since the first CAR-T cell product was approved by the FDA in 2017, five additional CAR-T cell products have reached the market, all of which target CD19 or BCMA. These products have gathered 14 approvals in different haematological malignancies and some of them have moved to earlier lines of therapy, expanding their target population. Moreover, earlier this year, lifileucel, a non-genetically modified tumour-infiltrating lymphocyte (TIL) therapy, became the first FDA-approved cell therapy product for a solid tumour (metastatic melanoma). Furthermore, an engineered cell therapy product, the T-cell-receptor (TCR)-based therapy afamitresgene autoleucel, may receive approval later this year for the treatment of advanced synovial sarcoma.
However, despite this growth, the cancer cell therapy space faces challenges related to cell persistence, effective targeting of solid tumours and product manufacturing, among others, and intense research is needed to overcome these. Here, we provide an updated analysis of the cell therapy landscape in oncology, including clinical research and real-world data on the use and implementation of this modality.
Cell therapy clinical trial landscape
As of March 2024 and since records began in 1986, there are 5,639 interventional cancer cell therapy clinical trials registered in the CRI’s Immuno-oncology (IO) Intelligence database (Supplementary Fig. 1). Of these, 1,791 trials have already been completed and 2,306 are ongoing (Fig. 1a). Almost 2,700 unique cell therapy products are included in these trials. The number of unique assets tested per year increased to 433 in 2021 and decreased to 409 in 2023 (Supplementary Fig. 2). Of the 2,306 ongoing trials, 96 are testing already approved CAR-T or TIL products (Supplementary Fig. 3).
The number of new cell therapy trials has decreased in the past two years. Our analysis of changes in the cell therapy landscape over the past five years shows that the number of new trials peaked in 2021 and has since decreased by 3.9% in 2022 (led by a 10.5% reduction in phase II trials) and by 4.3% in 2023 (led by a 24.3% decrease in phase I studies). Despite this overall reduction, phase III trials have grown by 33.3% and 43.8% in both years, respectively, and the total number of new trials in 2022–2023 still exceeds the number in 2019–2020 (Fig. 1b). Notably, the reduction in overall trials is tied to trials sponsored by institution or government rather than company-sponsored trials (Supplementary Fig. 4).
To better understand the observed changes, we broke down trial data by indications, cell therapy modalities and targets. These analyses show that cell therapy clinical research has decreased the most in haematological malignancies and gastrointestinal cancers (–9.1% and –4.1% in 2023 compared to 2022, respectively), whereas their use has gone up in central nervous system (CNS) tumours (25.0%), respiratory cancer (90.0%) and mixed solid tumours (3.5%) trials (Supplementary Fig. 5). A broader classification of indications into solid and haematological malignancies shows that cell therapies for solid tumours have continuously grown since 2020, and in 2023 they comprised 53.4% of all new cell therapy trials (Supplementary Fig. 5).
Trends in cell therapy modalities and targeted proteins. Further analysis of this data reveals that in 2023, cell-based cancer vaccines, CAR-NK cells and bacteria-based therapeutics grew relative to 2022 (50.0%, 17.4% and 4.9%, respectively), whereas CAR-T cells and other T-cell products reduced their share in the space (–15.1% and –19.3%, respectively) (Fig. 1c). This is the first time we observe a decrease in new CAR-T cell therapy trials, across both solid and haematological malignancies (Supplementary Fig. 6), even though this is still the dominant cell therapy modality in the IO space. Despite this general reduction, the number of CAR-T cell and other T cell trials has gone up in CNS tumours (27.3% and 50%, respectively) (Supplementary Fig. 7). A closer look at the other subtypes of T cell-based therapeutics shows a sharp growth of gamma-delta TCR-T cells (100% over the prior year), although the fraction of studies using this cell type is still relatively small (Fig. 1d).
When classifying cell therapies by source, our analysis shows that allogeneic products lost ground in 2023, with a 14.7% overall reduction relative to 2022, versus a 1.5% growth in autologous therapies over the same timeframe. Reduction in allogeneic CAR-T cell therapies is more dramatic, with a 42.1% drop in trials in the past year. Notably, 2023 saw the first in vivo CAR-T cell therapy entering the clinic (Supplementary Fig. 8).
Regarding targets, the most common proteins are still CD19, BCMA and CD22, but their use has decreased in the past year (–15.4%, –3.7% and –60.0%, respectively). By contrast, other targets have increased their presence, such as CD7 (33.3%), HER2 (14.3%) and NKG2D (233.3%) (Supplementary Fig. 9). The diversity of targets in the space has also changed over time, growing from 87 to 94 unique targets from 2022 to 2023 (Supplementary Fig. 10). Supplementary Fig. 11 shows a breakdown of targets by cell therapy modality.
Real-world use of CAR-T cell therapies
CAR-T cell therapies have the potential to revolutionize cancer treatment, but our last landscape update reported in 2022 identified several barriers that dampen the real-world use of this modality, such as cost, slot availability and manufacturing complications. To evaluate the evolution of CAR-T cell therapy implementation in the clinic over the past years, we leveraged IQVIA’s CAR-T Cell Center Insights survey data, exploring current barriers that prevent patients referred to CAR-T cell therapy centres receiving treatment. We also compared the new results with those presented in our 2022 publication (Nat. Rev. Drug Disc. 21, 631–632; 2022).
According to IQVIA, on average, 38% of referred patients do not receive CAR-T cell therapy. Oncologists at CAR-T cell therapy centres in the USA (N = 51, one responder per centre) were surveyed between 1 October and 31 December 2023, and asked for the reasons behind this. The results of this survey indicate that the primary reasons why referred patients did not receive CAR-T cell therapies were disease progression (45%), patient choice (43%) and patient eligibility (41%), although less oncologists identified these as decisive factors than in the Q4 2021 survey (54%, 54% and 63%, respectively). Also, product cost has gone from being an important factor for 65% of surveyed oncologists in 2021 to only 37% of them in 2023. Notably 39% of surveyed oncologists highlighted the current availability of bispecific antibodies against the same targets and indications as a reason to not proceed with a CAR-T cell treatment (Supplementary Fig. 12).
Importantly, slot availability (25%) and manufacturing issues (16%) have become less of a barrier for patient treatment in comparison to the 2021 survey (31% and 27%, respectively) indicating an improvement on logistics constraints over the past two years. Only 12% of surveyed oncologists identified availability of treatment beds at CAR-T cell treatment centres as a barrier to treatment (Supplementary Fig. 12). Indeed, we observed that the number of CAR-T cell treatment centres in the USA has continuously increased over the past five years, from 88 in 2018 to 198 in 2023. Of all referrals in IQVIA’s dataset from Q4 2023, most oncologists sent patients to a CAR-T cell therapy centre located as far as 31 miles away from their clinical practice. This means that, on average, patients travel around 2.5 hours to receive treatment (Supplementary Fig. 13).
Conclusions and future directions
Our analysis of cell therapy trials in oncology shows that clinical research in this field has decelerated in 2022 and 2023, with fewer new trials than in 2021 but still above pre-2021 numbers. Although CAR-T cells and other T-cell products are still the largest categories in the space, they have experienced the sharpest decline, whereas NK cells and bacteria-based therapies have grown both in 2022 and 2023. This may indicate a diversification of the field in terms of treatment modalities. We observe a similar effect on targets, where the total pool keeps growing whereas the research on CD19, BCMA and CD22 decreases. These may be healthy signs of continued discovery linked to a reduction of duplicative efforts in the space.
New cell therapy trials have decreased in the past two years, but this may not be due to field-specific factors but rather to the general downturn in the biopharma industry in recent years. In fact, a January 2024 IQVIA Pharma Deals analysis shows that despite the observed shrinkage, cell therapy oncology deals represent a larger share of all life sciences deals in 2023 than in any other year in the past decade (Supplementary Fig. 14).
Another factor that may be contributing is the growing interest in cell therapies in non-oncology indications such as autoimmune, cardiac and infectious diseases, with gene-modified cell therapy trials in autoimmune disorders increasing by almost fourfold between 2021 and 2023 (Supplementary Fig. 15). Although the number of trials in non-oncology indications is still relatively low, this data may suggest a potential interplay, with trials across different indications competing for shared manufacturing and treatment site resources. Even so, the barriers to receive CAR-T cell therapies have experienced a considerable reduction since 2021. It will be interesting to see how the CAR-T cell therapy space adapts to a growing landscape of addressable indications and to a rising number of approvals in earlier lines of haematological indications. Continued monitoring of the cell therapy landscape, from clinical research to real-world usage, will be vital to understand the evolving trends in the space and optimize efforts to make these therapies easily available to all patients in need.
