Chimeric Antigen Receptor T Cells and Methods of Use Thereof

Description:

The current state of the art

With four FDA-approved therapies (Axicabtagene ciloleucel, Brexucabtagene autoleucel, lisocabtagene maraleucel, and Tisagenlecleucel), the adoptive T cell (ACT) therapies’ market is attracting more investment. Although ACT has shown some successful clinical application, it has not been effective in treating most solid tumors. Moreover, some patients failed to respond to treatment or succumbed to late relapse after the initial response.  

The problems with the current art

Studies have shown co-presence of CD4+ and CD8+ T cells are correlated with favorable patient outcomes. CD4+ T cells can produce multiple inflammatory cytokines to improve CD8+ T cell activation and antitumor effects of ACT in mice and cancer patients. However, CD4+ are susceptible to tumor-induced dysfunction and exhaustion, in turn, causing CD8+ T cell dysfunction. Therefore, it is important to develop exhaustion-resistant CD4+ T cells to improve the efficiency of ACT.

The advantages of our invention:

Scientists at AU have developed novel tumor-specific CD4+ T cells that constitutively express murine STAT5A, which enables these CD4+ T cells to concurrently express two or three cytokines, characteristics of different T helper cell lineages and a unique polyfunctional phenotype. STAT5A systematic activation in CD4+ cells upregulated the levels of Fos and Jun but repressed the expression of Tox, Pdcd1, Ctla4, Haver2 (Tim3), Lag3, Tigit, and Slamf6, enabling T cells to acquire resistance to tumor-induced exhaustion. In B-cell lymphoma mouse model, systemic activation of STAT5 of CD4+ T cells and CD19 CAR T cells eradicated tumors 20 days after injection (Fig 1 and Fig 2). One safety concern of systematic activation of STAT5, leukemia development, was not observed in mice cured long after (3 months) receiving CASTAT5 transduced CD19CAR T cells. Therefore, persistent activation of STAT5 in CD4+ T cells represents a promising strategy to potentiate the efficacy of ACT including CAR T cell therapy.

 

AURI-2020-023

Lead Inventor: Gang Zhou, PhD https://www.augusta.edu/cancer/research/labs/gang-zhou.php

Patent Status: US 63/061339 (Filing date: 08/02/2020)

Reference: https://immunology.sciencemag.org/content/5/52/eaba5962

 

Patent Information:
Category(s):
Therapeutics
For Information, Contact:
Lei Wan
Technology Transfer Associate
Augusta University
lewan@augusta.edu
Inventors:
Gang Zhou
Keywords:
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