The SCIENCE

Filtering out disease-causing leukocytes

The TLA platform leverages one of the most fundamental inflammatory processes – leukocyte tissue infiltration. By identifying and characterizing key chemokine mediators in patient groups with various types of inflammatory disease, this process may be exploited to reduce inflammatory burden in these patients – in the context of a TLA column device.

The inflammatory process

The inflammatory process is characterized by an influx of immune cells from the circulation to the site of inflammation. This migration is carefully orchestrated through interactions between families of inflammatory mediators, produced in the tissue, and their responding receptors on the surface of immune cells. One such family is chemokines, that serve to direct the immune cells from the circulation to the inflammatory site in the tissue.

In the TLA column device, synthetically produced chemokine is immobilized onto a solid matrix. During treatment, blood is perfused through the device whereby immune cells expressing the corresponding chemokine receptor binds to the immobilized chemokine and are retained. Untouched cells pass freely through the device and are returned to the patient.

Chronic inflammatory disorders

Chronic inflammatory disorders are often complex and multi-factorial. Some have a strong genetic component, whereas others are acquired and elicited by environmental triggers.

A feature they do have in common is the aberrant immune responses that result in tissue injury as a result from the dysregulated inflammation.

The goal of TLA therapy is to disrupt the ongoing inflammation by physical removal of its main mediator, the inflammatory cell.

Limitations of other treatments

Anti-inflammatory drugs commonly used to treat chronic inflammatory disorders include corticosteroids, aminosalicylates (5-ASA) and biological therapies. Corticosteroids and 5-ASA have been on the market since the mid-20th century and function by systemically suppressing the immune system.

Biological agents, such as anti-TNF-alpha, have been available since the late 1990s and exert their function by specifically blocking key mediators of the inflammatory response. Even though the therapeutic landscape available to treat severe inflammation is constantly developing, side-effects resulting from overall immune suppression continues to be a vast problem. This especially applies to long-term use that is associated with treatment of patients with chronic inflammatory disorders. Also, long-term treatment with biological therapies may result in therapy resistance, rendering these alternatives useless in a sub-group of patients.

During TLA therapy, where a fraction of well-defined immune cells is removed from the blood stream, no pharmacological agent is introduced to the body. TLA therapy is therefore easier to dose and less likely to elicit systemic side effects than conventional anti-inflammatory treatments.

Unmet need in IBD treatment

In the western world, IBD has been increasing over the last decade, with an average prevalence of around 1% of the population. The clinical manifestations of IBD often start during adolescence, with peak age of onset ranging from the second to fourth decades of life. Standard management of IBD currently requires an escalating set of drug treatments (biologics and steroids), many times culminating in surgery (proctocolectomy). Only 50-60% of patients achieve long-term remission with present treatments. Thus, there is a great unmet need and a place for a novel intervention using the TLA column to remove inflammatory cells in patients with IBD.

Research and Clinical trials

In its first-in-man clinical trial in patients with ulcerative colitis, TLA has demonstrated proof of its concept of relieving inflammatory burden through physical removal of activated immune cells from the blood stream. TLA is constantly developing its R&D pipeline to encompass further clinical indications through in-depth characterization of chemokine receptor expression profiles in various inflammatory disorders.

The pre-clinical research is mainly carried out in research facilities at Karolinska, where affinities are evaluated and potential patient groups identified. TLA’s close proximity to the clinical facilities of the Karolinska Hospital enable target screening and early validation in patient samples of various inflammatory disorders, as well as access to clinical sites for patient trials.