On May 11, 2021 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in cell therapy to treat cancer, reported preclinical data from its HiT targeting mesothelin, being co-developed with Astellas, during a poster presentation at the American Society for Cell and Gene Therapy (ASGCT) (Free ASGCT Whitepaper) meeting today (Press release, Adaptimmune, MAY 11, 2021, View Source [SID1234579688]).

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"These data are very exciting because our HLA-independent TCR targeting mesothelin induced complete regression in a mouse tumor xenograft model and also outperformed a TRuC construct that we developed in-house," said Karen Miller, SVP, Pipeline Research. "The natural signaling machinery of the TCR, as well as our proprietary TCR engineering and affinity optimization expertise, offer distinct advantages over cell therapies that rely on antibody moieties to engage antigen. We are evaluating further HiT targets, as we deliver against our 2-2-5-2 strategic plan to bring new cell therapy products forward for clinical development and launch."

Adaptimmune has developed a T-cell receptor (TCR) that can directly bind to the cell surface protein mesothelin, independent of HLA, using the Company’s proprietary naïve phage display libraries and affinity optimization techniques. The HLA-independent TCR or HiT platform enables the Company to target extracellular proteins, such as those utilized by CAR or TRuC T-cell therapies. Data from the ASGCT (Free ASGCT Whitepaper) presentation are summarized below.

Adaptimmune’s HiTs are CD8 and HLA-independent and kill mesothelin expressing human tumor cells

Human T-cells expressing the mesothelin-targeted HiT kill human tumor cell lines and primary human lung tumor cells expressing mesothelin
Data demonstrate that the mesothelin HiT is not dependent on CD8 to kill target cells, and CD4 cells expressing the HiT are cytotoxic towards tumor cells
A TRuC construct was developed by Adaptimmune as a comparator for these experiments, which also killed mesothelin target cells independently of CD8
Adaptimmune’s HiTs are not neutralized by free mesothelin, but the TRuC construct is

Data from additional in vitro experiments clearly show that Adaptimmune’s HiT is not neutralized by soluble mesothelin, unlike the TRuC construct
It has been described that CAR-T and similar therapies, which rely on high affinity antibody moieties to engage antigen, can be neutralized by soluble target protein, inhibiting their function1
This is particularly important for many tumor targets that are both cell-surface bound and secreted, as is the case with mesothelin
Adaptimmune’s HiT T-cells targeting mesothelin induce complete tumor regression in a mouse xenograft tumor model and outperform a comparator TRuC construct

Immunodeficient mice were implanted with human pancreatic Capan-2 mesothelin-expressing tumor cells
Mice with pre-established tumors received HiT T-cells or TRuC comparator T-cells by a single IV injection
Data showed a strong, dose-dependent, and persistent tumor regression with HiT T-cells
TRuC T-cells only inhibited tumor growth at comparative doses to those used with the HiT T-cells