IP Library › Granted Patent US 12,661,401
Granted Patent B2
US 12,661,401 · App. 18/549,503 · Granted Jun 23, 2026

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

Inventors: Mikko Siurala (Philadelphia, PA); Carl H. June (Merion Station, PA); Avery Posey (Philadelphia, PA); Antoni Ribas (Los Angeles, CA); Anusha Kalbasi (Beverly Hills, CA)
Assignees: The Trustees of the University of Pennsylvania; The Regents of the University of California
A61K40/4255A61K35/761A61K40/11A61K40/30A61K40/31A61K40/32A61K40/4217A61K40/4269A61K40/4276A61K48/0075A61P35/00C07K14/55C07K14/7155C12N5/0636C12N15/86A61K2239/31A61K2239/38A61K2239/57C07K2319/03C07K2319/75C12N2510/00C12N2710/10032C12N2710/10043
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Quick Facts
Patent No.
US 12,661,401
App. No.
18/549,503
Filed
Sep 7, 2023
Granted
Jun 23, 2026
Kind
B2
Examiner
YU, MISOOK
Art Unit
1641
USPC
424/93.21
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.

Claims (60)

1 . A system for selective activation of a receptor in a cell, the system comprising:

(a) a modified immune cell comprising

(i) an orthogonal chimeric cytokine receptor, and

(ii) at least one chimeric antigen receptor (CAR), and

(b) an oncolytic adenoviral vector comprising a nucleic acid sequence encoding an orthogonal IL2 cytokine,

wherein the orthogonal chimeric cytokine receptor comprises an extracellular domain of an orthogonal IL2 receptor (oIL2R) and an intracellular signaling domain of a cytokine receptor that is not IL2R;

further wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular domain, optionally wherein the antigen binding domain targets a tumor antigen.

2 . The system of claim 1 , wherein:

(a) the extracellular domain of an oIL2R is an extracellular domain of an orthogonal IL2 receptor beta (oIL2Rb); and/or

(b) the intracellular signaling domain of the orthogonal chimeric cytokine receptor comprises an IL9R intracellular signaling domain, optionally wherein the IL9R intracellular signaling domain is an IL9R-alpha (IL9Ra) intracellular signaling domain.

3 . The system of claim 1 , wherein:

(a) the orthogonal chimeric cytokine receptor comprises an extracellular domain of an oIL2Rb and an intracellular signaling domain of an IL9Ra, and

(b) the CAR comprises an anti-mesothelin antigen binding domain.

4 . A method of treating cancer in a subject in need thereof, the method comprising:

(a) administering to the subject an effective amount of a modified immune cell or precursor thereof (a population of modified immune cells) comprising:

(i) an orthogonal chimeric cytokine receptor, and

(ii) at least one chimeric antigen receptor (CAR), and

(b) administering to the subject an oncolytic adenoviral vector comprising a nucleic acid sequence encoding an orthogonal IL2 cytokine;

wherein the orthogonal chimeric cytokine receptor comprises an extracellular domain of an orthogonal IL2 receptor (oIL2R) and an intracellular signaling domain of a cytokine receptor that is not IL2R;

further wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular domain, optionally wherein the antigen binding domain targets a tumor antigen.

5 . The method of claim 4 , wherein:

(a) the extracellular domain of an oIL2R is an extracellular domain of an orthogonal IL2 receptor beta (oIL2Rb); and/or

(b) the intracellular signaling domain of the orthogonal chimeric cytokine receptor comprises an IL9R intracellular signaling domain, optionally wherein the IL9R intracellular signaling domain is an IL9R-alpha (IL9Ra) intracellular signaling domain.

6 . The method of claim 4 , wherein:

(a) the orthogonal chimeric cytokine receptor comprises an extracellular domain of an oIL2Rb and an intracellular signaling domain of an IL9Ra, and

(b) the CAR comprises an anti-mesothelin antigen binding domain.

7 . The method of claim 4 , wherein the population of modified immune cells assume stem cell memory (Tscm) features with improved trafficking and effector function, thereby treating the cancer.

8 . The method of claim 4 , wherein administering the vector comprises intratumoral injection.

9 . The method of claim 4 , wherein the cancer is selected from the group consisting of pancreatic cancer and melanoma.

10 . The method of claim 9 , wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

11 . A system for selective activation of a receptor in a cell, the system comprising:

(a) a modified immune cell engineered to express:

(i) an orthogonal chimeric cytokine receptor, and

(ii) at least one T cell receptor (TCR), and

(b) an oncolytic adenoviral vector comprising a nucleic acid sequence encoding an orthogonal IL2 cytokine,

wherein the orthogonal chimeric cytokine receptor comprises an extracellular domain of an orthogonal IL2 receptor (oIL2R) and an intracellular signaling domain of a cytokine receptor that is not IL2R;

optionally wherein the TCR targets a tumor antigen.

12 . The system of claim 11 , wherein:

(a) the extracellular domain of an oIL2R is an extracellular domain of an orthogonal IL2 receptor beta (oIL2Rb); and/or

(b) the intracellular signaling domain of the orthogonal chimeric cytokine receptor comprises an IL9R intracellular signaling domain, optionally wherein the IL9R intracellular signaling domain is an IL9R-alpha (IL9Ra) intracellular signaling domain.

13 . The system of claim 11 , wherein:

(a) the orthogonal chimeric cytokine receptor comprises an extracellular domain of an oIL2Rb and an intracellular signaling domain of an IL9Ra, and

(b) the TCR is a pmel-1 TCR or an NYESO1-specific TCR.

14 . A method of treating cancer in a subject in need thereof, the method comprising:

(a) administering to the subject an effective amount of a modified immune cell or precursor thereof (a population of modified immune cells) modified to express:

(i) an orthogonal chimeric cytokine receptor, and

(ii) at least one T cell receptor (TCR), and

(b) administering to the subject an oncolytic adenoviral vector comprising a nucleic acid sequence encoding an orthogonal IL2 cytokine;

wherein the orthogonal chimeric cytokine receptor comprises an extracellular domain of an orthogonal IL2 receptor (oIL2R) and an intracellular signaling domain of a cytokine receptor that is not IL2R;

optionally wherein the TCR targets a tumor antigen.

15 . The method of claim 14 , wherein:

(a) the extracellular domain of an oIL2R is an extracellular domain of an orthogonal IL2 receptor beta (oIL2Rb); and/or

(b) the intracellular signaling domain of the orthogonal chimeric cytokine receptor comprises an IL9R intracellular signaling domain, optionally wherein the IL9R intracellular signaling domain is an IL9R-alpha (IL9Ra) intracellular signaling domain.

16 . The method of claim 14 , wherein:

(a) the orthogonal chimeric cytokine receptor comprises an extracellular domain of an oIL2Rb and an intracellular signaling domain of an IL9Ra, and

(b) the TCR is a pmel-1 TCR or an NYESO1-specific TCR.

17 . The method of claim 14 , wherein the population of modified immune cells assume stem cell memory (Tscm) features with improved trafficking and effector function, thereby treating the cancer.

18 . The method of claim 14 , wherein administering the vector comprises intratumoral injection.

19 . The method of claim 14 , wherein the cancer is selected from the group consisting of pancreatic cancer and melanoma.

20 . The method of claim 19 , wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

Continuity (2)
Provisional Application 63158671 · Mar 9, 2021
Related Publication 20240299541A1 · Sep 12, 2024
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