Laurance Johnston, Ph.D.

ACTIVATED MACROPHAGES (ACUTE INJURY)

Dr. Michal Schwartz and colleagues (Rehovot, Israel) founded Proneuron, a SCI-focused biotechnology company whose mission is to develop immunological approaches that minimize post-injury neurological damage. Inspired by Hippocrates’ ancient wisdom that “natural forces within us are the true healers of disease,” Schwartz uses the body’s inherent healing mechanisms to develop therapeutic approaches that proactively augment naturally occurring autoimmune processes.

Specifically, the investigators use activated macrophages (a white blood cell) isolated from patient’s blood to reduce neurological damage after acute SCI. Although healing immune cells are scarce in the “immune-privileged” central nervous system, Schwartz and her colleagues haves circumvented this limitation by incubating the patient’s macrophage-containing blood with skin tissue. The isolated macrophages are then surgically implanted into the spinal cord within 14 days of injury. By mediating protective immune responses, these activated macrophages theoretically promote functional recovery.

In 2005, Dr. Nachshon Knoller and Proneuron colleagues reported the results of a preliminary phase I clinical trial in which eight individuals with acute SCI were treated with such skin-activated macrophages. Age ranged from 18 to 65 years (mean 27 years), seven of the eight subjects were men, and five had been injured from traffic accidents. All had sustained ASIA-A-complete injuries ranging from the C5 to T11 level within two weeks of treatment.  

To prepare the activated macrophages, 200 milliliters of blood was collected, and a 10x3-centimeter strip of skin was excised from the patient’s arm. Macrophages isolated from the blood were incubated for one day with the skin tissue and then harvested. After surgically exposing the injured cord through a laminectomy and opening of protective membranes, four-million cells were injected into the area right below (i.e., caudal) the injury-site lesion.

Functional improvement was measured over the course of a year using ASIA assessment standards and various electrophysiological measurements. Of the eight patients treated, three improved from ASIA A to C (complete injury to partial motor and sensory recovery). Electrophysiological measurements indicated restoration of some nerve conductivity in most subjects during the follow-up period. Although adverse events were observed during the study period, none were attributed to the therapeutic intervention per se.

Proneuron initiated a much larger phase-II clinical trial intending to recruit 61 patients at several treatment sites in Israel and the USA. In 2006, Proneuron suspended the trial, stressing that this action was not due to any safety or clinical issues.

In 2009, Dr. Daniel Lammertse (USA), one of the trial’s study directors, reported the results obtained in subjects recruited and evaluated before the study was stopped. Of the 50 subjects recruited, efficacy data had been collected on 40. Approximately, 29% of the macrophage-treated subjects improved from ASIA-A complete injuries to ASIA-B incomplete injuries. In contrast, about 62% of the untreated control subject made the same transition. In other words, the controls did better. The investigators concluded: “The results do not support the clinical use of autologous incubated macrophage therapy for complete SCI.”  

In a 2012 publication, Dr. Lammertse and investigative-team colleagues confirmed these results. This article reported that efficacy data now had been collected on 43 participants. Seven treatment and 10 of control participants had improved from ASIA-A to ASIA-B injuries. In addition, two treatment and two control participants converted from ASIA-A to ASIA-C. The investigators concluded: “Although these results do not support treatment of complete SCI with autologous incubated macrophage therapy as specified in this protocol, it is hoped that ongoing preclinical research will yield improved methods of producing a therapeutic cell phenotype and less invasive cell delivery.”