Synthetic IL-9 receptor enhances T-cell therapy to cure solid tumors without chemoradiotherapy
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The latest paper by the father of CAR-T: Synthetic IL-9 receptor enhances T-cell therapy to cure solid tumors without chemoradiotherapy.
Immunotherapy is currently a hot topic in the field of tumor treatment, and has shown excellent therapeutic effects in tumor treatment. Among them, adoptive T cell therapy is undoubtedly the most anticipated.
Unfortunately, although this therapy has significant antitumor activity in patients with hematological cancers, its efficacy in patients with solid tumors is very limited.
The main limiting factor for this outcome is the poor proliferative capacity and persistence of adoptively transferred T cells in vivo, which requires patients to typically undergo invasive therapy prior to adoptive T cell therapy (CAR-T, TCR-T, TIL ) .
High-dose chemotherapy or radiotherapy is used for myeloablation to remove immune-suppressing cells from the body, but the side effects of high-dose chemotherapy or radiotherapy are also very obvious, including nausea, extreme fatigue, and hair loss.
This also prevents some patients from receiving such treatments.
On June 8, 2022, Christopher Garcia of Stanford University, Carl H. June of the University of Pennsylvania , Antoni Ribas of the University of California, Los Angeles , Anusha Kalbasi and others published a research paper in Nature entitled: Potentiating adoptive cell therapy using synthetic IL-9 receptors .
This study shows that a synthetic interleukin-9 (IL-9) receptor can enable adoptive T-cell therapy (CAR-T, TCR-T, TIL) to play a role in cancer treatment without the need for prior chemotherapy or radiotherapy . What’s more, the research team demonstrated the powerful anti-tumor ability of this new therapy in a mouse model of solid tumors, with the highest cure rate exceeding 50%.
CAR-T cells are the natural anti-infection and anti-cancer immune cells T cells from the blood of cancer patients are genetically reprogrammed in vitro to express receptor proteins that can recognize specific antigens on cancer cells in the patient, which is the so-called chimeric antigen receptor (CAR ) .
These genetically engineered CAR-T cells are then expanded using cell culture techniques and reinjected into patients to attack cancer cells.
Since 2017, the US FDA has successively approved five CAR-T cell therapies for the treatment of leukemia, lymphoma and myeloma.
Carl June estimates that tens of thousands of people around the world have now received CAR-T cell therapy.
Professor Carl June
Dr. Anusha Kalbasi , lead author of the latest paper , said some cancer patients struggle with chemotherapy with side effects just to clear the body’s immune system so that the infused T cells can fight the cancer cells.
But with this latest technology, T-cell therapy can be done directly without having to eliminate the autoimmune system.
As early as 2018, Christopher Garcia , the corresponding author of the study, published a paper in Science , focusing on the concept of orthogonal cytokines and their receptors.
Orthogonal cytokine receptors are mutated forms of normal receptors that selectively bind mutated cytokines but not normal cytokines.
This Science paper demonstrates that the concept is feasible, and that a synthetic orthogonal IL-2 receptor (o2R) can selectively bind orthogonal IL-2 (oIL-2) , but not wild-type IL -2. 2.
At the same time, oIL-2 does not bind to the wild-type IL-2 receptor.
That is, orthogonal IL-2 cytokines and their receptors can selectively modulate the activity of adoptive T cells in mice without pretreatment with chemotherapy or radiotherapy.
In this latest Nature paper, the research team made a new attempt by designing a new chimeric receptor with an orthogonal IL-2 receptor extracellular domain (ECD) fused to a The receptor intracellular domain (ICD) , thereby enabling orthogonal IL-2 cytokines to trigger the corresponding γc cytokine signals, such as IL-4, IL-7, IL-9 and IL-21.
Schematic diagram of wild-type IL-2Rβ, orthogonal IL-2Rβ or γc family chimeric orthogonal receptor complexes
Of these γc cytokines, IL-9 is the more interesting one to study—unlike other γc cytokines, IL-9 signaling is not active in naturally occurring T cells.
Therefore, a synthetic chimeric orthogonal IL-9 receptor (o9R) will make adoptive T cells more powerful in fighting tumors.
o9R T cells activate STAT1, STAT3 and STAT5
Further investigation revealed that T cells signaling through o9R were distinguished by concomitant activation of STAT1, STAT3, and STAT5, and displayed a unique mix of stem and killer cells.
Compared with previous o2R T cells, o9R T cells have better anti-tumor effects in two refractory melanoma and pancreatic cancer mouse solid tumor models, with the highest cure rate exceeding 50%!
o9R T cells present a unique mix of stem and killer cells
The therapy was effective whether the cytokines were delivered systemically to mice or injected directly into tumors, says first author Anusha Kalbasi .
In all cases, T cells engineered with the synthetic, orthogonal IL-9 receptor outperformed and cured some refractory solid tumors.
o9R-engineered T cells have powerful antitumor efficacy
Collectively, this study demonstrates that adoptive T cells can be activated to acquire new functions without the need for chemotherapy or radiotherapy to deplete the immune system through synthetic, orthogonal IL-9 and its receptor IL-9R. , enhanced antitumor activity against refractory solid tumors.
These discoveries will open a new door for humans to conquer cancer, and in the future, adoptive T cell therapy may become as simple and rapid as blood transfusion.
Paper link :
https://www.nature.com/articles/s41586-022-04801-2
https://www.science.org/doi/10.1126/science.aar3246
Synthetic IL-9 receptor enhances T-cell therapy to cure solid tumors without chemoradiotherapy
(source:internet, reference only)
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