The right angle on IL-2 therapy

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Science Immunology  06 Apr 2018:
Vol. 3, Issue 22, eaat6418
DOI: 10.1126/sciimmunol.aat6418


Engineered cytokines are able to improve immunotherapy in mouse tumor models.

The adoptive transfer of tumor-specific T cells is sometimes effective in cancer, but transferred T cells typically survive for short periods in vivo and rapidly lose function. One approach to extend the lifespan and function of these introduced T cells is to administer interleukin-2 (IL-2) to recipients of adoptive T cell therapy. However, IL-2 can induce toxicity at high doses and can also expand regulatory T cells in vivo, thus complicating the efficacy of adoptive T cell therapies. Although high dose IL-2 was described as an effective treatment for metastatic renal cell carcinoma, its use never gained wide acceptance partly because of treatment-related toxicities. This experience impeded more widespread adoption of cytokines as therapeutics for cancer.

Sockolosky and colleagues engineered murine T cells to express an altered IL-2 receptor β subunit that could only respond to an orthogonal mutant IL-2 that was separately created. The ortho IL-2 was incapable of triggering the wild-type IL-2 receptor, and normal IL-2 could not bind to the ortho IL-2 receptor. These investigators demonstrated that this elegant ligand-receptor pair induced similar STAT5 activation and interferon γ production when compared with wild-type IL-2 and the wild-type IL-2 receptor. Ortho IL-2, unlike IL-2, did not induce large amounts of inflammatory cytokines presumably because bystander effector T cells were not activated by ortho IL-2. In addition, the ortho IL-2 likely generated less dysfunctional T cells than conventional IL-2 as gauged by the lower levels of TIM-3 induced on T cells in the orthogonal system.

Tumor-specific ortho IL-2Rβ T cells were infused in a murine melanoma model followed by ortho IL-2 infusion, and these cells were as effective in reversing tumor growth as tumor-specific T cells that were not engineered and that were administered with wild-type IL-2.

This work is a remarkable accomplishment in immune engineering with wide-ranging translational potential. When linked to adoptive T cell therapies for cancer involving either engineered T cell receptors or chimeric antigen receptors, such an approach would facilitate anti-tumor T cell persistence and function while eliminating bystander effector T cell activation and its attendant toxicities. It would also preclude the unwanted activation by IL-2 of regulatory T cells.

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