Synthetic IL9 Receptors Improve Adoptive T-cell Therapies

Adoptive cell therapy (ACT) using T cells has had limited success in solid tumors and requires toxic lymphodepleting conditioning chemotherapy that diminishes feasibility. Use of synthetic cytokine receptor signaling has been suggested to overcome these hurdles; therefore, Kalbasi, Siurala, Su, and colleagues designed chimeric receptors that are composed of the IL2 receptor extracellular domain fused with the intracellular domain of receptors for other common gamma chain cytokines, IL4, IL7, IL9, or IL21, which then elicit the corresponding cytokine signal. Stimulation of these chimeric receptors using orthogonal IL2 (oIL2) showed that orthogonal signaling specifically through the IL9 receptor (o9R) resulted in potent STAT1, 3, and 5 phosphorylation that was unique among these chimeric orthogonal receptors and is consistent with native IL9 receptor signaling, which is not commonly active in T cells. Investigation into the effects of o9R signaling using the transgenic pmel mouse model, which expresses an endogenous T-cell receptor for an antigen overexpressed in melanoma, showed this same STAT signaling profile as well as acquisition of qualities of both stem cell memory and effector T cells with superior cytolytic capacity. Despite weaker in vitro proliferation, o9R T cells expanded in vivo and showed increased tumor infiltration. Moreover, in the absence of lymphodepletion, o9R T cells resulted in consistent antitumor effects and prolonged survival. Furthermore, o9R signaling in the context of chimeric antigen receptor (CAR)–based ACT in a model of pancreatic cancer exhibited similar results with tumor-restricted rather than systemic delivery of oIL2. Complete tumor regression was observed in nonlymphodepleted mice after a combination of CAR-o9R T cells and intratumorally delivered adenoviral vector encoding oIL2, with the superior antitumor efficacy of CAR-o9R cells being attributed to their improved potency. Experiments conducted in human T cells displayed comparable results even in a model of continuous antigen exposure. Overall, this study illustrates that the use of an orthogonal IL2 cytokine receptor platform improves antitumor activity in solid tumor models even without conditioning lymphodepletion and suggests its potential use in hard-to-treat solid tumors.

Kalbasi A, Siurala M, Su LL, Tariveranmoshabad M, Picton LK, Ravikumar P, et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature 2022 Jun 8 [Epub ahead of print].

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