Immunotherapy is currently a hot topic in the field of tumor treatment, and has shown excellent therapeutic effects in clinic. Among all kinds, adoptive T cell therapy is undoubtedly the most anticipated. However, 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 be firstly treated with high-dose chemotherapy or radiotherapy for myeloablation to remove immune-suppressing cells from the body, and then treated with adoptive T cell therapy (CAR-T, TCR-T, TIL). The side effects of high-dose chemotherapy or radiotherapy are obvious, including nausea, extreme fatigue, and hair loss. This makes such treatments impossible for some patients.
On June 8, 2022, Christopher Garcia of Stanford University, Carl H. June of the University of Pennsylvania, together with Antoni Ribas and Anusha Kalbasi of the University of California, Los Angeles, published their new research in Nature entitled “Potentiating adoptive cell therapy using synthetic IL-9 receptors”.
This study shows that a synthetic interleukin-9 (IL-9) receptor allows 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 mouse models of solid tumors, with the highest cure rate exceeding 50%.
Since 2017, the United States Food and Drug Administration (FDA) has successively approved five CAR-T cell therapies for the treatment of leukemia, lymphoma, and myeloma. Dr. Carl June, the CAR-T pioneer, estimates that tens of thousands of people around the world have now received CAR-T cell therapy.
Dr. Anusha Kalbasi, the lead author of the 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 the elimination of the autoimmune system.
Back in 2018, Christopher Garcia, the corresponding author of this 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 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. 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 adoptive T cell activity in mice without pretreatment with chemotherapy or radiotherapy.
In this latest paper published in Nature, the research team made a new attempt by designing a new chimeric receptor with an orthogonal IL-2 receptor extracellular domain (ECD) fused to an intracellular domain (ICD), thereby enabling orthogonal IL-2 cytokines to elicit the corresponding γc cytokine signals, such as IL-4, IL-7, IL-9, and IL-21.
Of these γc cytokines, IL-9 is an interesting one to further 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) would make adoptive T cells more powerful in fighting tumors.
Further investigation revealed that T cells signaling through o9R were distinguished by concomitant activation of STAT1, STAT3, and STAT5, and displayed a unique mixture of stem and killer cells. Compared with o2R T cells, o9R T cells have better antitumor effects in two refractory melanoma and pancreatic cancer mouse models, with the highest cure rate exceeding 50%!
The therapy was effective whether the cytokines were delivered systemically to mice or injected directly into tumors. In all cases, T cells engineered with synthetic, orthogonal IL-9 receptors outperformed and cured some refractory solid tumors, claimed Anusha Kalbasi.
Generally, this study demonstrates that adoptive T cells can be activated without the need for chemotherapy or radiotherapy to deplete the immune system through synthetic, orthogonal IL-9 and its receptor IL-9R, which enhances the adoptive T cells’ antitumor activity against refractory solid tumors. These findings 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.
References
1. Kalbasi, Anusha, et al. “Potentiating adoptive cell therapy using synthetic IL-9 receptors.” Nature 607.7918 (2022): 360-365.
2. Sockolosky, Jonathan T., et al. “Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes.” Science 359.6379 (2018): 1037-1042.