The CAR-T cells for solid tumors They are once again at the center of scientific debate following a series of preclinical studies led by Columbia University that point to a paradigm shift. A set of studies published in Science describe a ultrasensitive version of these cell therapies capable of locating and destroying kidney, pancreatic and ovarian tumors in experimental models, something that until now was considered practically unattainable.
At a time when CAR-T therapies are already part of clinical practice for several hematological cancers In Spain and the rest of Europe, these results reopen the discussion on how to apply this strategy to solid organ cancerswhich account for the vast majority of cancer diagnoses. Experts welcome the progress, but caution that these are preclinical studies and urge prudence: questions remain unanswered about toxicity, regulation, costs, and patient selection.
Why CAR-T therapies had failed in solid tumors
CAR-T cell therapies originated as a “living medicine”T lymphocytes are extracted from the patient's own body, modified in the laboratory to recognize a specific cancer protein, and then reinfused to locate and destroy the tumor. This strategy has changed the course of various leukemias and lymphomas, achieving prolonged remissions even in people who had exhausted other treatment options.
However, the jump from the blood to the solid organs It has been a problem for over a decade. Unlike hematological cancers, where almost all tumor cells uniformly display the same surface target (such as CD19), solid tumors exhibit a great heterogeneitySome cells express a lot of the target antigen, others very little, and still others appear not to express it at all. This kind of "mosaic" makes it easier for part of the tumor to remain outside the reach of the therapy and eventually recur.
Furthermore, the tumor microenvironment itself functions as a “castle” difficult to stormPhysical barriers hinder the entry of T cells, immunosuppressive signals deplete them, and an inflammatory context limits their survival. In this scenario, the first trials with CAR-T cells targeting solid tumors have yielded modest and, in many cases, disappointing results.
One of the proteins that had been proposed as a possible target was CD70, whose presence had been detected in multiple carcinomas, especially in kidney, ovary, brain tumors and pancreasThe problem is that traditional studies suggested that only a percentage of the cells within each tumor expressed CD70, which limited its usefulness as a single therapeutic target. Clinical trials with anti-CD70 CAR-T cells in metastatic renal cell carcinoma, for example, had resulted in low objective response rates, between 6% and 21%.
CD70, from “irregular” target to pan-tumoral objective
The team led by the immunologist Michel SadelainA historical figure in the development of CAR-T therapies, decided to thoroughly review the role of CD70. The researcher Sophie Hanina It started from a simple but disruptive hypothesis: perhaps many of the cells considered “CD70-negative” did have the protein, but at such low levels that they escaped the usual detection techniques and the recognition of conventional CAR-T cells.
Through advanced microscopy and fluorescence analysis in patient-derived models (xenografts), the group found that the situation was not as binary as previously thought. CD70 expression formed a continuous spectrumFrom very high levels to almost imperceptible, but present, amounts. Even cells that appeared negative showed more CD70 than those in which the gene had been completely eliminated in the laboratory.
The study also delves into the mechanism behind this very low expression. The authors link the phenomenon to a EZH2-mediated epigenetic silencing and the histone marker H3K27me3, associated with gene repression. In cells with very reduced CD70, an enrichment of these repressive signals was observed in the gene promoter. When EZH2 was inhibited, CD70 expression increased, reinforcing the idea that the tumor partially “switches off” the target to evade the immune system.
Based on this data, the research proposes a reinterpretation of the classic tumor “heterogeneity”: instead of tumors with cells that are fully positive or negative for CD70, there would be an epigenetically regulated gradationThis allows us to recover the concept of CD70 as pan-cancer target provided that receptors capable of detecting even those residual levels are available.
HIT: the new generation of ultra-precise receivers
The key to the advance lies precisely in this new type of receiver. The Columbia group has developed the so-called HIT cells (HLA-Independent T cell receptor), an evolution of conventional CAR-T cells that much better mimics the natural way in which T cells recognize antigens.
Unlike traditional CARs, which need a relatively high density of the target antigen To activate, HIT receptors are designed to react to quantities CD70's "ultra-low"The authors describe these cells as a kind of "high-precision sensor" capable of detecting a "whisper" where previously only "shouts" were heard.
To further enhance their performance, the researchers combined the HIT receptors with costimulatory molecules such as CD80 and 4-1BBLThis dual signaling reinforces T cell activation and improves their resistance to the hostile tumor environment, reducing the risk of early exhaustion. Sadelain summarizes this concept by emphasizing that CAR-T cells and their derivatives are “live drugs” that can expand inside the patient, unlike traditional chemical treatments, which the body eliminates relatively quickly.
The result is modified lymphocytes that combine hypersensitivity to locate “hidden” antigens with a better capacity to survive and continue functioning inside the tumor "castle." In the words of several experts, this would be the next generation of CAR-T cells, specifically aimed at overcoming the barriers of solid tumors.
Preclinical results: tumor eradication in mouse models
Once CD70 expression was characterized and HIT cells were developed, the team tested the strategy in patient-derived models with kidney, ovarian and pancreatic cancerThese xenograft models quite faithfully reproduce the complexity and heterogeneity of human tumors, and are therefore considered a demanding tool when evaluating experimental therapies.
In these tests, the conventional CAR-T targets CD70 They were able to effectively eliminate cells with high antigen expression, but left behind subpopulations with very low or seemingly nonexistent levels. This residual fraction was enough for the tumor to continue growing or reappear over time, consistent with the modest results seen in previous clinical trials.
When they were used instead anti-CD70 HIT cellsThe behavior changed markedly. In mice with kidney, pancreatic, and ovarian tumors, the researchers describe a “complete and lasting eradication” of cancerHIT cells also detected and eliminated cells with ultralow CD70 expression, thus preventing classic tumor escape.
The data suggests that CD70 is particularly overexpressed in metastatic lesionssuch as lung metastases from kidney cancer. In some of these models, a single administration of HIT cells was sufficient to achieve tumor disappearance, something the authors highlight as one of the most promising findings of the work.
Preclinical safety studies are equally relevant. The analysis of more than 30 types of healthy tissue This indicates that CD70 is barely expressed outside the tumor context, except in some immune system cells when they are activated. In mice, No increased toxicity was observed than that described for already approved CAR-T cells. Even so, immunologists such as Ignacio Melero (University of Navarra Clinic) indicate that the elimination of certain immune cells could have clinical consequences that will need to be carefully monitored.
A conceptual shift in CAR-T therapy for solid tumors
Several experts consulted agree that the interest of the study is not limited to the CD70 target itself, but that it introduces a conceptual nuance with broad impact in the design of immunotherapies for solid tumors. As summarized Luis Álvarez-VallinaThe work, led by head of immunotherapy at the CNIO-HMarBCN, suggests that The problem is not so much the absence of the target antigenbut the lack of sensitivity of current receptors.
This reinterpretation opens the door to reviewing other antigens that had been discarded due to a apparent excessive heterogeneityIf there is indeed a widespread residual expression, the key could lie in developing increasingly sensitive receptors, combined with epigenetic strategies that prevent the tumor from "lowering the volume" of its targets.
The authors go so far as to suggest that CD70 is a pan-tumoral target potential, given that it has been detected heterogeneously in more than twenty solid tumors, including glioblastoma and pancreatic adenocarcinomaThe approach would also serve as a methodological model for identifying other “hidden objectives” that until now went unnoticed.
Álvarez-Vallina points out that the study “fits well with previous evidence” and that its conclusions are supported by solid data, although he insists that we are talking about preclinical studies with inherent limitationsLooking to the “real world,” it anticipates an expansion of the catalog of potential targets in solid tumors, changes in patient selection criteria, and a greater regulatory complexity, along with the risk of toxicity if sensitivity is taken to the extreme.
Other experts point out that the article by Science maintains a good methodological level and that the associated press release reasonably accurately reflects the central message, although it may tend to oversimplify the "pan-cancer" nature of CD70 and the "ultrasensitive" label applied to the receptors, which is actually compared to a conventional CAR design reinforced with CD80/4-1BBL co-stimulation.
Implications for Spain and Europe: access, cost and regulation
The potential impact of effective CAR-T therapies against solid tumors is especially relevant in healthcare systems such as Spanish and Europeanwhere these therapies are already integrated, although with indications restricted to hematological cancers. In Spain, for example, there are five commercial CAR-T therapies financed by the National Health System against leukemias, lymphomas and myelomas, in addition to two academic therapies developed at the Hospital Clínic of Barcelona.
These treatments have a very high cost per patientThis cost can reach or exceed €300.000 for industrial options, and be around €90.000 for some academic projects. The potential extension of the model to solid tumors, which are much more common, would require a rethinking of the approach. financing strategies, manufacturing capacity and prioritization criteria within public systems.
In parallel, the development of HIT receptor-based therapies poses additional regulatory challenges. increased sensitivity This involves demonstrating in detail that they do not increase the risk of serious toxicities outside the tumor. European and national agencies will likely require this. long-term monitoring programs and very careful test designs to minimize risks in the early stages.
Researchers involved in the field, such as the immunologist Manel Juan At the Hospital Clínic in Barcelona, they value this new strategy as a solid proof of concept which could be combined with other approaches (antibodies, conventional immunotherapy, epigenetic drugs) to improve responses in solid tumors. But they insist that more data is still needed on possible adverse effects on healthy tissues and about how these cells will behave in the complexity of a human organism.
If its effectiveness is confirmed, Europe would also have to address issues such as decentralized vs. centralized production These cell therapies include training for hospital centers, coordination between countries, and price negotiations with industry, as well as the potential development of public academic platforms similar to those already implemented in Catalonia and other regions.
From the lab to the clinic: the next step
Currently, work with anti-CD70 HIT cells is in the early stages. strictly preclinicalSadelain himself acknowledges that the main immediate challenge is to achieve the necessary financing to start clinical trials in humans and consolidate a large-scale manufacturing infrastructure that meets quality requirements.
The first human studies are planned, according to the Columbia team, in patients with glioblastoma, acute myeloid leukemia, ovarian cancer, and pancreatic cancerAlthough it is expected that it will begin by focusing on one or two indications. In any case, these would be trials of early phase (I/II), focused primarily on evaluating safety and dosage, rather than demonstrating definitive efficacy.
In parallel, the researchers are working on refine detection methods of CD70 in patient samples, since the decision of who might benefit from the therapy will depend on accurately assessing that “spectrum” of expression. The incorporation of advanced imaging techniques and genomic analyses could be key to selecting people with higher probability of response.
The authors and independent experts agree that, although the results are “very encouraging”, it is too early to make predictions about its real-world translation to the clinicMany cancer treatments that showed spectacular efficacy in mouse models have subsequently fallen by the wayside due to the complexity of the human organism and regulatory requirements.
Nevertheless, the work has rekindled the interest of the scientific community and the biomedical sector in the CAR-T cells for solid tumorsIf human trials confirm a significant portion of these preclinical results, oncology could gain a new tool to address cancers with a very poor prognosis, such as pancreatic adenocarcinoma, certain kidney tumors, or glioblastomaareas where current options remain very limited.
Taken together, the research on anti-CD70 HIT cells reinforces the idea that the future of Cellular immunotherapies in solid tumors It involves increasing receptor sensitivity, better understanding the biology of the targets, and combining these strategies with other treatments, always with rigorous clinical evaluation to distinguish reasonable enthusiasm from promises yet to be proven.