Pharmaceuticaly Modified T cells for Adoptive Cell Therapy Against Cancer


Technology: Inventors from MUSC have identified that inhibiting PI3Kδ and β-catenin pathway enhances anti-tumor functions of Th17 cells in adoptive T cell therapy (ACT). The inventors have discovered that expansion of Th17 cells in vitro with CAL-101 and indomethacin inhibitors generated T cells with augmented memory phenotype (enhanced CD62L expression) and reduced regulatory properties in vivo (less FoxP3 expression). Precursor Th17 cells upon antigen recall overexpressed genes and proteins of the PI3K/Wnt/β-catenin pathway (β-catenin and Tcf7). Th17 cells primed only with CAL-101 mediated tumor regression as potently as cells primed with both inhibitors. Mice treated with Indomethacin plus CAL-101 primed Th17 cells increased survival over 64 days and was effective in tumor regression. These pharmaceutically enhanced T cells are transcriptionally distinct from donor matched T cells grown in current preparation protocols and represent an effectively different therapeutic product. Overall, our discovery underscores that PI3Kδ and β-catenin inhibitors, including FDA approved small molecule inhibitors, can be used to boost anti-tumor functions of long lived memory T cells, which could be applied to enhance various forms of cancer immunotherapy.


Figure: β-Catenin and p110δ (PI3K) inhibition augments antitumor Th17 immunity.

(A and B) Treating ICOS-activated Th17 cells with indomethacin (Indo) plus CAL-101 improves their capacity to regress tumors. (A) Average tumor growth curve. (B) Survival after transfer of 0.75 × 106 TRP-1 CD4+ T cells polarized toward a Th17 phenotype were expanded with TRP-1 peptide and ICOS agonist and/or primed in vitro with CAL-101 or Indo. Percentage survival of mice; n = 6–9 mice/group. Mantel-Cox curves compared by log-rank test; *P < 0.05, ***P < 0.001. (C) Average tumor growth curve. (D) Survival after transfer of 0.75 × 106 TRP-1 Th17 cells stimulated with TRP-1 peptide and ICOS agonist and expanded in vitro with Ly294002 and/or Indo. Percentage survival by Mantel-Cox curves, compared by log-rank test; ***P < 0.001.


Overview: Th17 cells are CD4+ T helper cells that secrete IL-17A and have recently shown great promise in adoptive cell therapy (ACT) in clearing established tumors. Th17 cells express high levels of Tcf7 and Lef1, downstream target genes of the Wnt/β-catenin pathway, which is associated with self-renewal potential of hematopoetic stem cells (HSCs). Th17 cells require TCR signaling and co-stimulation for activation. The inventors at MUSC have found that inducible costimulatory signaling (ICOS) is crucial for Th17 generation and enhancement of anti-tumor activity. Th17 cells expanded with ICOS agonist induced Wnt/β-catenin and phosphoinositide-3-kinase (PI3K)/p110δ (PI3Kδ) pathways. Interestingly, co-inhibition of PI3K and β-catenin reduces 1l-17A secretion and ablates RORγt in Th17 cells in vitro. C57BL/6 mice inoculated with melanoma B16F10 cancer cells upon ACT with ICOS-stimulated TRP-1 Th17 cells mediated superior tumor regression when expanded in vitro in the presence of CAL-101 or CAL-101 plus Indomethacin.


Applications: Inhibition of PI3K alone or a combination of PI3K plus β-catenin inhibition using CAL-101 and indomethacin respectively can effectively enhance T cell durability and function in adoptive T cell therapy (ACT).


Advantages:  Pharmaceutically modulating T cells ex vivo with FDA approved drugs could be a potent strategy to enhance ACT.


Key Words: Th17 cells, adoptive cell therapy, ACT, CAL-101, indomethacin, tumor, CD4+ T cells, melanoma, ICOS, IL-17A, anti-tumor, cancer immunotherapy.


Publication: Majchrzak, Kinga, et al. "β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity." JCI insight 2.8 (2017).


Dwyer, Connor J et al. “Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8+ T cells.” European journal of immunology vol. 50,9 (2020).


Inventors: Chrystal Paulos, Kinga Majchrzak, Jacob Bowers

Patent Status:   US publication 20200283728 A1     

MUSC-FRD Technology ID: P1685


Patent Information:
For Information, Contact:
Scott Davis
Associate Director, Licensing
MUSC Foundation for Research Development
Chrystal Paulos
Kinga Majchrzak
Jacob Bowers
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