Processes for Generating Superior Anti-tumor T Cell Effector and Memory Cells

Description:

Inventors have identified a redox-based strategy to generate, expand, and enable redirection of memory T cells. This strategy promotes higher levels of thiols to generate a therapeutic population of T cells for adoptive T cell therapy. These T cells are not only engineered and ex vivo programmed using a unique cell culture conditions that render them with high anti-oxidant property, but also results in low glycolytic and low mitochondrial membrane potential phenotype, which correlates with a superior ability to control established large tumors. This strategy also shows that tumor epitope reactive T cells persist longer in vivo, and also contribute to the generation of antitumor memory response in order to render long-term control of tumor growth (Figure 1). Thus, the thesis to use antioxidant capacity as biomarker for identifying T cells that will not only persist longer in vivo, but also ‘help’ in generation of anti-tumor memory response to render long-term control of tumor growth will be of immediate translational significance.

Overview: Adoptive T cell therapy (ACT) is a promising approach for treating patients with advanced malignancies. However, ACT is only able to cure a small proportion of the patients treated, leaving a substantial room for improvement. Additionally, ACT immunotherapy studies predominantly comprise of terminally differentiated T cells with effector memory (Tem) phenotype, which have a limited life span. A rapid expansion step is usually employed to obtain a large number of T cells (1-1,000x108 cells for ACT). The majority of T cells subjected to rapid expansion have a Tem phenotype with increased susceptibility to undergo activation induced cell death (AICD). Therefore, the recent strategies have focused on altering the T cell expansion protocols to generate central memory (Tcm) phenotype cells that persist longer and exhibit better tumor control. Among the approaches used to program the expanding T cells towards a Tcm phenotype is to block the mTOR, the Akt, or the glycolytic pathways. Another approach designed to increase the therapeutic efficacy of T cells for ACT is to reprogram the expanding T cells towards a ‘memory stem cells’ (Tscm) phenotype. Tscm cells are reported to have increased persistence and far improved tumor control due to their pluripotent or "stem-cell like" properties. Therefore, any T cell expansion process that programs the T cells towards a Tcm or a Tscm phenotype has a real potential to improve the effectiveness of ACT

Applications: Adoptive T cell therapy for solid tumor cancers

Advantages: Longer in vivo life and generation of anti-tumor memory response that renders long-terms control of tumor growth

Key Words: Cancer, solid tumor, melanoma, adoptive T cell therapy, antioxidant, thiol

Related Publications: Kesarwani, Pravin, et al. "Anti-oxidant capacity and anti-tumor T cell function: A direct correlation." OncoImmunology 4.1 (2015): e985942.

Kesarwani, Pravin, et al. "Promoting thiol expression increases the durability of antitumor T-cell functions." Cancer research 74.21 (2014): 6036-6047.

Inventors: Shikhar Mehrota, Michael Nishimura, Pravin Kesarwani, Shilpak Chatterjee
Patent Status: PCT Application Filed 04/28/2017
MUSC-FRD Technology ID: P1569

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Shikhar Mehrotra
Michael Nishimura
Pravin Kesarwani
Shilpak Chatterjee
Keywords:
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