Method of Enhanced Adoptive Cellular Therapy without Lymphodepletion

Description:

Technology:

Lymphodepleting chemotherapy is a significant hurdle to the use of adoptive cellular therapy. 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.  One aspect of the invention involves the transfer of the cytokine receptor subunit IL-2R 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 (Figure 1). 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: US10377988B2 and EP3247368A1

MUSC-FRD Technology ID: P1322

Figure 1.  Modification of donor T cells with cytokine receptors will facilitate engraftment without lymphodepleting chemotherapy.  (A) Donor T cells transferred without lymphodepleting chemotherapy fail to engraft.  (B) Donor T cells transferred into mice lymphodepleted engraft but host lymphocytes are destroyed.  (C) Donor T cells modified to express cytokine receptor genes engraft efficiently in the presence of administered recombinant cytokine.

Figure 2.  T cells expressing high levels of a cytokine receptor can mediate potent anti-tumor immunity in the absence of lymphodepletion.  (A) Schematic showing treatment of mice. B16-tumor bearing mice were adoptively transferred with cytokine-receptor high-expressing (IL-2R) T cells approximately 1 week after tumor injection. Systemic cytokine was subsequently administered.  (B) In this lymphodepletion-dependent model, effective anti-tumor immunity was achieved in the absence of lymphodepletion using T cells with high levels of cytokine receptor and administration of cognate cytokine (IL-2) or as control (IL-15).

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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