Method of Enhanced Adoptive Cellular Therapy without Lymphodepletion

Description:

Technology: MUSC researchers have found a method to overcome the need to provide lymphodepleting chemotherapy to patients receiving Adoptive Cellular Therapy (ACT) by endowing donor T cells with elevated levels of cytokine receptors to outcompete host cells for exogenously provided cytokines (Figure 1).  One aspect of the invention involves the transfer of the cytokine receptor subunit IL-2Rα gene into T cells prior to ACT. For example, this could be done with CAR or TCR retroviral constructs linked to an IL-2Rα gene. Donor T cells expressing elevated IL-2Rα can then outcompete host cells for limited amounts of exogenously administered recombinant IL-2, and mediate anti-tumor immunity in the absence of lymphodepletion. Another advantage of cells expressing elevated IL-2Rα is patients may respond to lower doses of recombinant IL-2.

Proof-of-concept for this technology has been demonstrated by the significant reduction in tumor burden when ACT IL-2Rαhi donor T cell ACT is combined with IL-2 therapy (Figure 2). Overall, this invention provides a powerful method to achieve effective anti-tumor immune responses in patients in the absence of lymphodepletion and/or high dose IL-2.

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: 1. Wrangle JM., et al. “IL-2 and Beyond in Cancer Immunotherapy.” J Interferon Cytokine Res. 2018 Feb;38(2):45-68.

2. 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/US2016/014516 , US20180057794A1 and EP 16740831.9

MUSC-FRD Technology ID: P1322

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Shan Panneer Selvam
MUSC Foundation for Research Development
panneers@musc.edu
Inventors:
Mark Rubinstein
David Cole
Keywords:
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