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Gli effetti dello zucchero sulla salute pubblica: diabete, malattia cardiache ed ora anche renali

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Cancer immunotherapy on every possible change toward the route 66: to uproot the enemy once for all

Modern immunotherapies boost the body’s own defenses against cancer. They activate killer T cells of the immune system that can specifically recognize and destroy cancer cells. In many patients, however, cancer cells adapt and become invisible to killer T cells so that the treatment is no longer effective. Partners in the international consortium CAR T-REX announce the awarding of a highly competitive grant, following the positive evaluation of their project entitled ‘CAR T Cells Rewired to Prevent EXhaustion in the Tumour Microenvironment’, with a total funding of 2.7 million euros. CAR T-REX was recognized for its radical and ambitious vision to improve the efficacy and safety of CAR T-based solid tumor-targeted cell therapies. THe consortium brings together a multidisciplinary team with unique expertise and capabilities in genome editing, non-viral gene delivery, immunology and T cell therapy. The project will start in June 2023 and run for 4 years.

By combining innovative methods of genome editing and non-viral gene delivery, CAR T-REX will explore the engineering of transcriptional networks in Chimeric Antigen Receptor (CAR) modified T lymphocytes, to selectively circumvent T-cell exhaustion upon activation in the tumour microenvironment. The consortium aims to (1) build novel auto-regulated genetic circuits controlled by microRNAs (miRNAs) in immune cells, (2) employ a novel high-performance non-viral gene delivery platform for delivery of the synthetic miRNA constructs, (3) select and benchmark the best-performing construct(s) in preclinical settings, and (4) execute the manufacturing run(s) for the final CAR T product. Cell and gene therapies are at the forefront of healthcare innovation, with the potential to transform the current therapy toolbox. Indeed, highly personalized CAR T cell therapies have dramatically changed the treatment landscape patients with blood cancers.

However, while CAR T cell therapies have shown remarkable efficacy for the treatment of specific hematological malignancies, broad clinical use is limited by manufacturing costs and side effects. Moreover, treatment of patients with solid tumors has thus far failed to demonstrate clinical benefit, with antigen heterogeneity, limited infiltration into tumor tissue and (especially) T cell exhaustion/loss of function, negatively impacting clinical outcomes. In this regard, CAR T-REX aims to explore a novel paradigm for the generation of improved CAR T cells. By combining non-viral gene delivery with precise genome editing of T cell autoregulatory pathways, CAR T-REX proposes a strategy to overcome the mechanisms by which solid tumors (and the immunosuppressive TME) “switch off” the anti-tumoural immune response, potentially extending the utility and safety of current CAR T technologies.

An interdisciplinary team of researchers from Magdeburg has now discovered a new mechanism that enables the immune system to also eliminate invisible cancer cells. These findings open up new possibilities for the development of improved cancer immuno-therapies. The results have now been published in the renowned journal Nature. Using an experimental cancer model, the researchers observed that a small number of helper T cells can eradicate advanced cancers as effectively as a much larger number of killer T cells. The helper T cells were also able to eliminate cancer cells that had become invisible to killer T cells. Studying immune cells in living cancer tissue revealed that helper T cells behave fundamentally differently from killer T cells. Furtherly, helper T cells secrete chemical mediators that attract scavenger cells of the immune system and induce them to support the destruction of cancer cells on their behalf.

Together, these two cell types can effectively fight bacterial and viral infections. Their cooperation can also be exploited to mobilize the full arsenal of immune defense against cancer cells. In search for the underlying mechanisms of action, the researchers found that the interaction between helper T cells and scavenger cells enhances their ability to release inflammatory mediators which act remotely to drive cancer cell death, as if they were infected by a pathogen. Exactly how this happens is still not completely understood, and the significance of this mechanism for cancer immunotherapies will have to be elucidated. Based on these findings, the researchers in Magdeburg are developing new strategies for cancer immunotherapy that are also effective in patients with cancers that have become invisible to killer T cells.

Another team shed light on the interaction between the immunotherapy and their regulation by steroid therapy. Not all patients respond well to immunotherapy. Why? Scientists aren’t always sure. Sometimes, immunotherapy patients experience side effects that glucocorticoids (GCs) can treat. Their new research indicates glucocorticoids may indirectly lead to some immunotherapy treatment failures by driving the production of a protein called Cystatin C (CyC). The scientists found that patients who were more likely to produce CyC in response to GCs had a worse overall survival rate. These patients were also less likely to benefit from treatment. This suggests CyC production within a tumor may contribute to the failure of cancer immunotherapy. To confirm CyC connection with cancer, the researchers turned to good old-fashioned lab work.

In mice, they deleted the CyC-encoding gene so it was not expressed in cancer cells. They found that tumors without CyC grew slower, meaning that higher levels of CyC are linked to poorer outcomes of this type of therapy. This meand that dosing CyC in oncological patients undergoing immunotherapy could be a reliable biomarker to predict the immunotherpay outcome itself. Finally, scientists at the UCLA Jonsson Comprehensive Cancer Center identified another biomarker that could allow to predict if a patient with melanoma would be responsive to immunotherapy. The researchers found when T cells are activated, they release a chemokine called CXCL13, which helps attract more B cells and T cells to the tumor site. The B cells then show the T cells specific parts of the tumor, which leads to increased activation of the T cells and their ability to fight the cancer.

Data indicated that there is a support role for antigen presentation by B cells to T cells in the tumor microenvironment. This cooperation between T cells and B lymphocytes was associated with improved survival in patients diagnosed with metastatic melanoma who were treated with immunotherapy, but not for those who received targeted therapy (MEK inhibitors like trametinib and cobimetinib). This study suggests that CXCL13 may play an important role in bringing together T and B cells in the tumor microenvironment in patients who respond to checkpoint immunotherapy, and that this cooperation may be key to effective anti-tumor responses. The team now plans to further explore these mechanisms in preclinical cancer models and test whether antigen presenting B cell and CXCL13 manipulation can improve anti-tumor immune responses in non-responders.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Barden M et al. Front Immunol. 2023 Jun; 14:1110482.

Ding L et al. Front Immunol. 2023 Jun; 14:1176994.

Kruse B, Buzzai AC et al. Nature. 2023 Jun 14 in press.

Balasko AL et al. Sci Rep. 2023 Jun 21; 13(1):10082.

Kleeman S et al. Cell Genomics 2023 Jun; 100374.

Hirayama AV et al. Blood Adv. 2023; 7(11):2479-2493.

Csaplár M et al. Cancers (Basel). 2021; 13(17):4301.

Curti BD, Faries MB. New Engl J Med 2021: 384:2229.

Tóth G, Szöllősi J et al. Int J Mol Sci. 2020; 21(3):1039.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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