Transforming TGF-β suppression into IL-15 stimulation: Advancing engineered CAR-T therapy for solid tumors

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Chimeric antigen receptor (CAR)-T cell therapy has led to a paradigm shift in the treatment of blood cancers.¹ However, solid tumor-targeting CAR-T therapies are relatively less effective. T cell exhaustion, tumor antigen escape, and the immunosuppressive tumor microenvironment (TME) are known to be major barriers for solid tumor target therapies. Among the many factors, transforming growth factor β (TGF-β) in TME stands out as a major obstacle. TGF-β is known to actively suppress T cell activation and growth, making it more difficult for CAR-T therapies to work effectively in solid tumors.^2,3 To overcome TGF-β in TME, a variety of strategies have been devised to target the suppressive effects of TGF-β, including the use of CRISPR to knock out TGF-β receptors and the armoring of CAR-T cells with dominant-negative TGF-β receptors to impede its signaling.^4,5

These approaches primarily focus on blocking the suppressive effects of TGF-β without leveraging its signaling potential. To address this, Zheng and colleagues have proposed a novel strategy in a recent study involving the development of CAR-T cells with an inverted cytokine receptor (ICR) that effectively converts the TGF-β inhibitory signal into an interleukin-15 (IL-15) stimulatory signal (Figure 1).⁶ This coactive design has the potential to both antagonize the TGF-β-mediated suppression and improve the efficacy of CAR-T cells, which represents a significant advancement in the development of CAR-T cell therapy for solid tumors.

Figure 1.

Engineered TGF-β receptors to enhance T cell function

Differences between the wild-type TGF-β receptor II (WT TGF-βRII), the dominant-negative TGF-β receptor II (dn TGF-βRII), and the TB15-modified TGF-β receptor II (TB15 TGF-βRII). The WT TGF-βRII transduces suppressive signals upon TGF-β binding, inhibiting CAR-T cell proliferation, cytotoxicity, and survival. The dn TGF-βRII blocks this suppressive signaling by deleting the intracellular domain, preventing signal transduction. The TB15 TGF-βRII goes further by repurposing TGF-β signaling into a stimulatory signal; it replaces the intracellular domain with the cytoplasmic domain of IL-15Rα, enabling TGF-β binding to activate IL-15 signaling, thereby enhancing CAR-T cell proliferation, cytotoxicity, and survival.

They achieved this by cleverly redesigning the TGF-β receptor itself. By fusing the extracellular domain of TGF-β receptor II (TGF-βRII) with the cytoplasmic domain of IL-15 receptor α (IL-15Rα), they create a receptor that effectively “flips” the TGF-β signal from inhibitory to stimulatory. Basically, rather than merely neutralizing TGF-β, the researchers have transformed it into a signal that enhances the functionality of CAR-T cells. What was once a suppressive signal now acts as a boost for CAR-T cells. They call this ICR design TB15 (Figure 1). This, in turn, enhanced CAR-T cell proliferation and function in the TME.⁶ This innovative approach not only addresses immunosuppression but also exploits it to benefit CAR-T therapy. This TB15-modified CAR-T cell signifies a substantial advancement in addressing the challenges posed by the TME in solid tumors. These cells exhibited enhanced cytotoxic activity, effectively targeting and eradicating TGF-β-rich tumor cells, even under suppressive conditions that typically hinder conventional CAR-T therapies. Moreover, the TB15 modification facilitated sustained proliferation and reduced exhaustion, enabling the cells to maintain their functionality and persistence within the hostile TME. In preclinical mouse models, these modifications demonstrated remarkable in vivo efficacy, with TB15-modified CAR-T cells achieving significant tumor suppression, increased intra-tumoral infiltration, and prolonged survival.⁶ These findings underscore the potential of these cells as a next-generation CAR-T therapy for solid tumors.

Currently approved CAR-T cell therapies are second-generation designs that incorporate a single-chain variable fragment for antigen recognition, a co-stimulatory domain, and a CD3 signaling domain.⁷ While these are effective for treating hematological malignancies, they face significant limitations in overcoming the challenges posed by the TME in solid tumors. To address these challenges, ongoing research is focused on developing next-generation CAR-T cells. These include approaches to equip CAR-T cells with the ability to secrete additional cytokines or to enhance their functionality by modulating transcription factors and epigenetic pathways, aiming to improve their efficacy against solid tumors.⁸ However, approaches involving multiple genetic modifications or equipping CAR-T cells with several layers of “armor” can significantly complicate the development process, making it challenging to translate these therapies into clinical applications. In contrast, the strategy presented in this study offers a streamlined and innovative solution. By designing a single construct that simultaneously blocks TGF-β signaling and enhances IL-15 signaling, the authors have effectively addressed two major obstacles in one step. This dual-function approach represents a simplified yet highly effective method, paving the way for more practical and efficient CAR-T cell therapies for solid tumors.

In consideration of toxicity and safety, TB-15 ICR technology exhibits additional benefits compared to other armored CAR-T technologies. Other armored CAR-T therapies, designed to treat solid tumors by secreting inflammatory cytokines like IL-15 or through their direct systemic administration, often carry significant risks.⁹ These include off-target activation of normal tissues, which can lead to severe side effects such as cytokine storms. In contrast, the TB15-modified CAR-T cells developed in this study offer a more controlled and targeted approach. By engineering IL-15 signaling to be specifically triggered within CAR-T cells in response to TGF-β in the TME, this strategy minimizes systemic exposure to IL-15.⁶ As a result, it has the potential to not only enhance the therapeutic efficacy of CAR-T cells but also reduce the likelihood of cytokine-related toxicities, making it a safer and more refined approach for solid tumor therapy.

While the TB15 ICR represents an exciting advance in CAR-T engineering, its exact mechanism of action raises some intriguing questions. Unlike natural IL-15 signaling, which relies on trans-presentation involving IL-15Rα on dendritic cells and IL-15Rβ and gamma chain (γc) on T cells,¹⁰ the TB15 ICR uses the cytoplasmic domain of IL-15Rα within T cells to directly activate the JAK/STAT pathway. This bypasses the traditional intercellular interaction required for IL-15 signaling and simplifies cytokine activation. However, whether this engineered signaling pathway fully replicates the robustness and specificity of natural IL-15 signaling remains to be determined. Additionally, it is unclear whether the absence of IL-15Rβ/γc involvement might limit the strength or persistence of T cell activation in the TME. One potential consideration is whether using the cytoplasmic domains of IL-15Rβ or γc, which are naturally expressed on T cells and play crucial roles in IL-15 signal transduction, might have provided a more physiologically relevant and effective signaling mechanism. These questions highlight the need for further research to validate the functional equivalence of TB15 ICR signaling, explore alternative receptor designs, and assess their long-term impact on CAR-T cell efficacy and safety.

Despite these challenges, this work provides a clear roadmap for tackling some of the most formidable barriers to CAR-T therapy in solid tumors. By transforming an immunosuppressive signal into a stimulatory one, Zheng et al. have developed a compelling strategy that not only addresses current limitations but also has the potential to reshape the future of CAR-T therapy. As the field moves toward clinical translation, further refinement of the TB15 ICR strategy and validation through clinical trials will be crucial in unlocking its full potential for solid tumor treatment.

Acknowledgments

This work was supported by National Research Foundation of Korea grants (RS-2023-00242443, RS-2023-00210035, and RS-2023-00282907) funded by the Korean government. Figure 1 was created with Biorender.com.

Declaration of interests

The author declares no competing interests.