Recent update: regulatory T cell add-back therapy
by Adam Burrack, PhD
Regular readers of this series will be aware that insulin-producing beta cells in the pancreas are destroyed by T cells of the immune system preceding a diagnosis of type 1 diabetes (T1D). Clinical treatment of T1D focuses on the replacement of insulin because virtually all insulin-producing beta cells are destroyed. One of the “big names” in research into the pathology of T1D is Dr. Jeff Bluestone at the University of California-San Francisco. Dr. Bluestone’s work focuses on T cell biology and activation in context of autoimmunity. Dr. Bluestone has long been interested in developing methods to inhibit the “autoreactive” T cells that destroy beta cells.
A recent report from Dr. Bluestone and collaborators at the University of San Francisco’s Diabetes Center, including Qizhi Tang describes results of a phase I clinical trial they have been working on for several years. In our previous post about Dr. Bluestone we described the rationale for this approach. Briefly, adding in more down-regulatory T cells at the time of a diagnosis of T1D has the potential to inhibit autoreactive T cells. Inhibiting beta cell destruction by blocking these T cells could either decrease insulin requirements (by keeping more beta cell mass functional) or facilitate beta cell regeneration (if beta cells retain the ability to proliferate).
In theory, since people with T1D appear to have quantifiable beta cell mass as much as 50 years post-diagnosis, inhibiting autoreactive T cells at any point in disease may prove useful. This report from Dr. Bluestone’s group in the journal Science Translational Medicine describes 1-year follow-up results, tracking the safety profile of people with new-onset T1D, whose regulatory T cells were harvested, expanded in test tubes (in vitro) in the lab, and then re-infused into the patients.
The goal with this approach is to halt beta cell destruction. An even more ambitious goal is to re-educate autoreactive T cells. As we have previously described, a phase I clinical trial is intended to study safety, not efficacy. Encouragingly, the 14 subjects in this study at UCSF had zero severe adverse reactions to the infusion of their own regulatory T cells, even to cell transfers of as many as 2 billion cells. Encouragingly, researchers did not observe re-activation of any latent viruses nor the development of any new cancers, both of which were safety concerns prior to this study. In addition, the purity of the regulatory T cell populations transferred back into the subjects was very high (generally >95%) and the researchers could find some of the transferred T cells months later. However, it does appear that there is a rate of decay of transferred cells – only small fractions could be detected up to 1 year after transfer. In this report investigators demonstrated that the regulatory T cells maintained their phenotype as regulatory T cells, which from a safety perspective is critical because studies in mouse models of T1D had suggested that inflammation and other signals from the immune system might ‘skew’ these transferred T cells to an ‘effector’ phenotype rather than a ‘down-regulatory’ phenotype.
Overall, these are encouraging results, and we look forward to the next steps in this research. The major hurdle of general safety seems to have been met for transfer of “autologous” (self-derived) regulatory T cells. The next step, which will be helped out by a recent large monetary donation from Napster founder Sean Parker directly to Dr. Bluestone’s laboratory, will be to test whether any number of these down-regulatory T cells can positively influence beta cell survival in vivo – in the patients.