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