Human Immune Monitoring and Cellular Therapy
Author: Dr. med. Michael Neuenhahn
An ever increasing number of immunocompromised patients (mainly due to secondary immune defects caused by the HIV pandemic, organ transplantation and intensified immunosuppressive treatment strategies for cancer and autoimmune diseases) remind clinicians every day that strategies to reconstitute the human immune system are highly warranted.
Even though immunologists have used mouse models successfully during the last decades to describe the cellular texture of the immune system and its failures in disease, the translation of this knowledge into human cellular therapy still lacks behind. One reason for this gap lies in the difficulties to extrapolate findings from experimental mice to human patients, which is probably best explained by the evolutionary distance of 65 million years (Davis, Immunity 2008).
Therefore, sophisticated human immune monitoring strategies have to be envisioned and realized to close this gap of knowledge and gain all the missing information about human immune cells required for the intelligent design of cellular therapies.
In this context, our group´s goal is to monitor in depth human T cells in order to identify relevant features (e.g. memory T cell subsets, cytokine patterns, T cell avidity) for successful T cell therapy. In doing so, our main technological focus lies on flow cytometry and the refined usage of MHC Multimers. Complementary mouse models are established and used whenever appropriate.
Being part of a multi-institutional immune monitoring platform ( www.helmholtz-muenchen.de/immunmonitoring;(link is external) Coordination “Adoptive T cell therapy” ) we are well integrated into a strong network and actively take part in immune monitoring harmonization efforts (e.g. proficiency panels MHC multimers).
However, even with a promising cell therapy at hand, several hurdles have to be addressed and overcome before a cellular product can be clinically tested to get final approval for use in human beings. Major critical issues are the availability of donor cells, the establishment of gentle isolation techniques under GMP conditions, the approval by an ethics committee and the subsequent authorization by the responsible authorities.
Our group is currently involved in an authorized phase I/II adoptive T cell transfer study. In this trial, highly immunocompromised patients after allogeneic hematopoietic stem cell transplantation are treated by ex vivo isolated CMV-specific CD8+ T cells using reversible MHC I Streptamers. Virus-specific T cells are thoroughly monitored before, during and after T cell transfer using multicolor flow cytometry analyses and molecular biological T cell tracking techniques.
In the future, we want to use the above-mentioned experiences to install a GLP-grade Flow Cytometry and GMP Cell Processing environment for clinical cell therapy. Reversibly binding reagents, recently developed for the gentle isolation of human blood cell subsets, will be clinically tested within this platform. The resulting cell products might eventually become a corner stone for a broad range of novel immune reconstitution therapies.