Selective stimulation of T cells in solid tumors using oncolytic viral delivery of orthogonal IL-2

Inventors

Siurala, Mikko • June, Carl H. • Posey, Avery • Ribas, Antoni • KALBASI, Anusha

Assignees

University of Pennsylvania Penn • University of California San Diego UCSD

Abstract

The present disclosure provides orthogonal chimeric cytokine receptor/orthogonal cytokine pairs and compositions and methods for modified immune cells or precursors thereof (e.g., modified T cells) comprising an orthogonal chimeric cytokine receptor (e.g., an oIL2R-IL9R chimeric receptor) and a chimeric antigen receptor (CAR) or a T cell receptor (TCR). The present disclosure further provides an oncolytic adenoviral vector comprising a nucleic acid sequence encoding an orthogonal cytokine (e.g., oIL2), as well as methods of using the modified cells and the vector for treating cancer in a subject in need thereof.

Core Innovation

The disclosure describes an orthogonal IL2 cytokine/orthogonal chimeric IL-2 receptor signaling platform in which an orthogonal chimeric cytokine receptor includes an orthogonal IL2 receptor (oIL2R) extracellular domain and an intracellular signaling domain from a cytokine receptor that is not IL2R. In described embodiments, the orthogonal IL2 receptor extracellular domain is an orthogonal IL2 receptor beta (oIL2Rb), and the intracellular signaling domain includes IL9R or IL-9Rb1 signaling.

The platform is used in modified immune cells that comprise the orthogonal chimeric cytokine receptor and at least one chimeric antigen receptor (CAR) or at least one T cell receptor (TCR). The CAR or TCR targets a tumor antigen, including mesothelin, pmel-1, and NY-ESO-1, and the oncolytic adenoviral vector comprises a nucleic acid sequence encoding an orthogonal IL2 cytokine.

The disclosure further describes administering modified immune cells or precursors expressing the orthogonal chimeric cytokine receptor together with CAR and/or TCR, combined with administering the oncolytic adenoviral vector encoding orthogonal IL2. The disclosed treatment context is treating cancer in a subject, including pancreatic cancer and melanoma, and administration can include intratumoral injection.

Claims Coverage

The consolidated claim coverage includes four independent claims directed to selective receptor activation systems and corresponding methods of treating cancer. Across the independent claims, the inventive architecture is an orthogonal chimeric cytokine receptor with an oIL2R extracellular domain and a non-IL2R intracellular signaling domain, used with an oncolytic adenoviral vector encoding orthogonal IL2 cytokine, in CAR-based and TCR-based embodiments.

The independent claims cover selective activation using modified immune cells with an orthogonal chimeric cytokine receptor and orthogonal IL2 expression from an oncolytic adenoviral vector, applied in CAR or TCR systems. The claim set also includes corresponding methods of treating cancer in a subject.

Stated Advantages

Documented Applications