Method of Enhanced Adoptive Cellular Therapy without Lymphodepletion

Description:

The invention involves a method to overcome the need to provide lymphodepleting chemotherapy to patients receiving adoptive cellular therapy (Figure 1).  Thus, endowing donor T cells with elevated levels of cytokine receptors allows them to outcompete host cells for exogenously provided cytokine.  With this approach, donor T cells can persist and mediate effective anti-tumor immunity without the need for lymphodepletion. In work published in Science Translational Medicine, the inventors have developed a method to achieve effective donor T cell engraftment and anti-tumor immunity in the absence of lymphodepletion.  Briefly, one aspect of the invention involves the transfer of the cytokine receptor subunit, IL-2Rα, gene into T cells prior to adoptive transfer.  Donor T cells expressing elevated IL-2Rα can then outcompete host cells for limited amounts of recombinant IL-2. This technology could be applied in multiple ways.  One possibility would be to design a CAR or TCR retroviral construct linked to an IL-2Rα gene (Figure 2). Adoptively transferred CAR-IL-2Rα or TCR-IL-2Ra-modifed T cells could then outcompete host cells for exogenously administered IL-2 and mediate anti-tumor immunity in the absence of lymphodepletion. A secondary advantage of cells expressing elevated IL-2Rα is that patients may respond to lower doses of recombinant IL-2. Thus, this invention provides for a powerful method to achieve effective anti-tumor immune responses in patients in the absence of lymphodepletion and/or high dose IL-2. (Please see representative data in Figure 3 at the end of this document.)

Overview: A major limitation to the wide spread application of adoptive cellular therapy (ACT) is the need to provide lymphodepleting chemotherapy (usually cyclosphosphamide and fludarabine) to patients prior the transfer of tumor-reactive T cells. Despite the significant toxicities and costs, lymphodepletion is thought to be necessary to eliminate host cells that would otherwise compete with donor T cells for limited resources. Our invention provides a method to overcome this significant clinical barrier.

Applications: Enhancing adoptive cellular therapy strategies for cancer and infectious disease by avoiding the need for lymphodepleting chemotherapy and high-dose IL-2.

 

Advantages: 

1) Patients may not require lymphodepletion chemotherapy such as cyclophosphamide and fludarabine.

2) Patients may respond to low-dose IL-2 and not require high dose IL-2.

3) This invention was initially conceived with IL-2.  However, the overall principle could be applied to other cytokines or ligands.

 

Key Words: T cell, immunotherapy, cytokine, cancer, interleukin, immune, lymphocytes, lymphodepletion, adoptive cellular therapy (ACT), chemotherapy

Publications: Su, Ee W., et al. "IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy." Science Translational Medicine 7.311 (2015): 311ra170-311ra170.

 

Inventors: Mark P. Rubinstein, David J. Cole

Patent Status: PCT Application Filed 1/22/2016

MUSC-FRD Technology ID: P1322

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Mark Rubinstein
David Cole
Keywords:
© 2017. All Rights Reserved. Powered by Inteum