US 12,227,555 B2
Use of gene editing to generate universal TCR re-directed t cells for adoptive immunotherapy
Yangbing Zhao, Lumberton, NJ (US); Xiaojun Liu, Wallingford, PA (US); and Wei Pan, Philadelphia, PA (US)
Assigned to The Trustees of the University of Pennsylvania, Philadelphia, PA (US)
Filed by THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA (US)
Filed on Jan. 13, 2021, as Appl. No. 17/147,521.
Application 17/147,521 is a division of application No. 15/951,904, filed on Apr. 12, 2018, granted, now 10,934,336.
Claims priority of provisional application 62/485,166, filed on Apr. 13, 2017.
Prior Publication US 2021/0155667 A1, May 27, 2021
Int. Cl. C07K 14/705 (2006.01); A61K 31/65 (2006.01); A61K 38/17 (2006.01); A61K 39/00 (2006.01); A61P 35/00 (2006.01); C07K 14/725 (2006.01); C07K 16/28 (2006.01); C07K 19/00 (2006.01)
CPC C07K 14/7051 (2013.01) [A61K 31/65 (2013.01); A61K 38/177 (2013.01); A61K 39/4611 (2023.05); A61K 39/4632 (2023.05); A61K 39/464488 (2023.05); A61P 35/00 (2018.01); C07K 14/705 (2013.01); C07K 19/00 (2013.01); A61K 2239/31 (2023.05); A61K 2239/38 (2023.05); C07K 2319/03 (2013.01); C07K 2319/30 (2013.01)] 17 Claims
 
1. A method of generating a genetically modified immune cell that is resistant to immune-cell exhaustion, the method comprising:
(i) introducing into the immune cell a nucleic acid comprising an exogenous nucleic acid encoding an exogenous receptor under the control of an inducible expression system,
wherein the inducible expression system comprises:
(a) a first nucleic acid comprising a constitutive promoter operably linked to a nucleic acid sequence encoding a transactivator protein; and
(b) a second nucleic acid comprising an inducible promoter operably linked to a nucleic acid sequence encoding an exogenous receptor which selectively binds to a tumor antigen expressed on a tumor;
wherein the first nucleic acid and the second nucleic acid are on the same expression construct; and
(ii) contacting the modified immune cell periodically with an induction agent,
wherein the induction agent periodically induces the expression of the gene expression system and the exogenous receptor is periodically expressed on the surface of the immune cell, thereby counteracting the immune-cell exhaustion.