Immunosuppressant resistance in anti-viral T cell products

Reference Number TO 32-00083

Keywords

Keywords: CRISPR-Cas, immunotherapy, tacrolimus, T cells, FKBP12, solid organ transplantation, GMP manufacturing, TReAT, Cell Therapy

Invention Novelty

The present invention provides an innovative approach for the treatment of life-threatening immunopathology caused by virus
reactivation, such as CMV, induced by immunosuppressants, and viral infections like SARS-CoV-2. This approach utilizes specific
anti-viral T cells that are resistant to calcineurin inhibitors, e.g. Tacrolimus. These virus-specific T cells maintain their critical anti-viral
functions while restoring sensitivity to other calcineurin inhibitors, such as Cyclosporine A, as a safety measure.

Value Proposition

T cell responses are crucial in both protecting against and causing immunopathology from viral infections. In immunosuppressed
patients, such as those undergoing transplants or suffering from autoimmune conditions, reduced virus control by T cells disrupts
the immune balance and induces tissue-damaging inflammation. Treating viral infections in these patients typically requires anti-viral
drugs, which often have toxic side effects. This new technology addresses this issue by using GMP-compliant manufactured antiviral
T cell products, thereby eliminating the need for toxic and less effective anti-viral drug treatments.

Fig 1. Testing of CRISPR-Cas9-Edited Tacrolimus-Resistant Antiviral T Cells for ATT in human based lung organoids (modified after Amini et al., 2021)

Technology Description

Using CRISPR-Cas9 technology, the coding sequence of FKBP12, the adaptor protein for the calcineurin inhibitor Tacrolimus, is
knocked out, resulting in the production of GMP-compliant, Tacrolimus-resistant T cells with various viral specificities. These highly
pure, virus-specific T cells are produced in small, semi-enclosed bioreactors using GMP-compliant media and supplements, allowing
for rapid cell expansion and efficient translation to patient care.
As part of TReAT (https://treat-project.com), funded by the Federal Ministry of Education and Research (BMBF), these anti-viral T
cell products will be tested for safety and efficacy in human-based organoid/organ-on-a-chip systems.

Commercial Opportunity

In-licensing or collaboration for further development.
Investments for clinical trials.

Development Status

T cell products specific to CMV and SARS-CoV-2 were manufactured using a GMP-compatible process and extensively characterized using
CITE-seq, proteomics, epigenomics, and off-target sequencing.Those with FKBP12 knockout (FKBP12-KO) remained functional after
Tacrolimus treatment, as shown by the production of inflammatory cytokines such as TNF-α, IFN-γ, CCL3, and CCL4, and a decrease in
the exhaustion marker LAG3. GMP-compatible manufacturing of T cell products specific to EBV and IAV is planned for the near future.
In addition, a phase I/IIa clinical trial with CMV-specific Tacrolimusresistant anti-viral T cell products in lung transplant recipients is in preparation.

Patent Situation

Priority filed in 2020, International application published in 2022 (WO2022034233A1). EP EP4196572A1 published in 2023, national applications pending in US, CN, CA.