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Precision T-Cell Solid Tumor Therapy Trial Underway

T lymphocyte

Colorized scanning electron micrograph of a T lymphocyte. (NIAID)

30 May 2023. A clinical trial has begun testing a treatment for solid tumor cancers using engineered T-cells with proteins to attack specific tumor cells, but also avoid healthy cells. The study is conducted by A2 Biotherapeutics Inc. in Agoura Hills, California, assessing the safety of its experimental therapy code-named A2B530 in patients with colorectal, pancreatic, and non-small cell lung cancers.

A2 Biotherapeutics is a five year-old company that says its biotechnology process is designed to overcome a shortcoming in many of today’s cancer immunotherapies, namely imprecise targeting of cancer cells. While these cancer treatments use altered T-cells from the immune system to seek out tumor cells expressing characteristic antigen molecules, says the company, those same antigens are also found on some healthy cells. As a result, many of today’s immunotherapies can cause off-target toxic effects.

To meet this problem, A2 Bio says its technology, called Tmod, modifies a cancer patient’s T-cells with chimeric antigen receptor proteins, or CAR T-cells like other immunotherapies, but takes the process further. Its cancer treatments include activator protein molecules targeting precise antigens of the patient’s tumor, but also a blocker protein that stops the activator from attacking healthy cells. The blocker looks for expression of a certain human leukocyte antigen or HLA protein on the cell surface indicating a healthy state, from a characteristic genomic pattern called heterozygosity.

Patients first screened in associated trial

A2 Bio says A2B530, the therapy candidate tested in the clinical trial, uses CAR T-cells with an activator protein that seeks out tumor cells expressing the characteristic carcinoembryonic antigen, and the blocker protein looking for HLA-A*02 proteins on cells indicating a healthy state. Thus A2B530 attacks only cells displaying the carcinoembryonic antigen, but also without an HLA-A*02 protein, indicating tumor cells, and sparing healthy cells.

The early- and mid-stage clinical trial is enrolling 160 participants in the U.S. with colorectal, pancreatic and non-small cell lung cancers considered non-treatable with surgery, locally advanced, or metastatic, and expressing the carcinoembryonic antigen. Participants are first screened in an associated clinical trial for loss of HLA proteins on tumor cells, with T-cells harvested from those patients meeting those criteria, and personalized A2B530 treatments manufactured for each patient. A2 Bio collaborated with Tempus Labs in Chicago that uses artificial intelligence algorithms to develop companion diagnostics for this screening system.

Trial participants are preconditioned with chemotherapy to remove their existing T-cells, followed by infusion of the treatments, and the company says the first A2B530 dose in the trial was administered. The study team is looking initially for adverse effects, such as overreaction by the immune system called cytokine release syndrome or toxicity to nerve cells at different A2B530 dosage levels. Participants are also tracked for two years on their response rates to the treatments. In addition, the study team is testing participants for the persistence of A2B530 as well as cytokine levels in blood samples over two years.

“Tmod CAR T,” notes A2 Bio’s chief medical officer William Go in a company statement, “is designed to address the fundamental challenge of selectivity in solid tumor targeted therapy: to avoid on-target, off-tumor dose-limiting toxicity.” Company CEO Scott Foraker adds, “This is the first medicine of an innovative pipeline that leverages the selectivity provided by the blocker to provide potentially safer and more efficacious therapeutics for cancer patients.”

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