Pharmaceuticaly Modified T cells for Adoptive Cell Therapy Against Cancer

Description:

Inventors have found that treatment of tumor-reactive human T cells with drugs that co-modulate β-catenin and PI3Kδ enhances their antitumor capacity, especially their ability to exert a long-term immune response against cancer. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while β-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and β-catenin inhibitors. Moreover, these cells regained β-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. These pharmaceutically enhanced T cells are transcriptionally distinct from donor matched T cells grown in current preparation protocols and represent an effectively different therapeutic product. Overall, ICOS signaling endows Th17 cells with a superior ability to regress tumors. ICOS-stimulated Th17 cells persist in vivo, self-renew, and mediate recall responses against tumor rechallenge.

Overview: Recent breakthroughs in adoptive cell transfer (ACT) therapies have generated excitement for Th17 cells as effective agents for clearing tumors. Th17 cells are defined as a CD4 helper T cell subset that secretes IL-17A.

 

Applications: This dug combination could be combined with cellular product as well as checkpoint modulators, vaccines, or cytokines that modulate the immune system, as these drugs enhance the durability of T cells and other immune cells.

Advantages:  Superior ability to regress tumors

Key Words: Th17 cells, adoptive cell transfer, ACT, tumor, CD4, melanoma, lymph node, lung, spleen, ICOS, CD28, IL-21, IL-17A, tumor, cancer

 

Publication: Majchrzak, Kinga, et al. "β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity." JCI insight 2.8 (2017).

 

Inventors: Chrystal Paulos, Kinga Majchrzak, Jacob Bowers

Patent Status:        Provisional Patent Application Filed 01/25/2017              

MUSC-FRD Technology ID: P1685

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Chrystal Paulos
Kinga Majchrzak
Jacob Bowers
Keywords:
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