Introduction 

T-cell depletion is a strategy to remove T-cells from bone marrow or peripheral stem cells taken from a donor before they are given to a patient. T-cell depletion (TCD) has been around for quite some time, at least since the early 1980s. TCD decreases the risk of graft-versus-host disease (GVHD) and, in particular, deaths from GVHD. The goal is to also have similar survival to non-T-cell depleted transplants (sometimes referred to T-cell replete or T replete). This would be a significant advance. Removing only the naïve T-cells from the graft looks like a promising approach to achieve these goals. The recent article Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease reports on a trial looking at the use of naïve T-cell depletion and comparing the results to historical controls.  

What are Naïve T-cells? 

I had not heard of naïve T-Cells before. According to an article from the National Cancer Institute (NCI) Can Chronic Graft-Versus-Host Disease Be Prevented? 

T cells are among the many types of immune cells that can attack cancer cells. But there are several subsets of T cells. Naive T cells have never encountered an antigen—a protein or other molecule that can provoke an immune response. For reasons that are not yet fully understood, they are more likely to react to healthy cells in the transplant recipient. 

I don’t know how naïve T-cells can be distinguished from other T-cells, but apparently this is possible. 

Problems with T-Cell Depletion 

TCD does significantly reduce the risk of GVHD and deaths from GVHD, however it is not without drawbacks.    There have been many attempts at T-cell depletion over the years, first removing all T-cells and more recently selectively removing some of the T-cells. However, most of the problems listed below have persisted to some degree: 

1. Graft failure is generally higher in TCD transplants than in non TCD transplants  
2. Epstein-Barr virus–associated lymphoproliferative disorders (LPD). This is a rare side effect of T-replete transplants, but is much more common in TCD transplants (as well as solid organ transplants) Generally, the decrease in deaths acute GVHD are about equivalent in the increase in deaths LPD  
3. There is a much higher rate of disease recurrence after TCD transplants. It is well established that patients who experience GVHD have a lower rate of relapse (this was known at the time of my transplant, almost 30 years ago). This is because of what is known as a graft-versus-leukemia (GVL) effect (or more generally as a graft-versus-tumor, GVT effect). The T-cells are causing GVHD by attacking the host cells in the patients.  Since any residual cancer cells are also recognized as foreign by the T-cells, they are destroyed as well.

Current Study 

For the most part the current study did not show the problems listed above. There were 138 patients with acute leukemia treated in this trial. There were 2 patients who experienced graft failure (< 2%). The incidence of Epstein-Barr virus (EBV) reactivation was rare, only 3 patients (2.3%) experiences this.  Only 1 required treatment with rituximab (Rituxan, which is one of the more effective therapies for EBV related LPD).  The overall incidence of relapse was 23%, which is in line with the expected relapse rate from T-replete transplants. The incidence of acute GVHD was low and most patients who experienced acute GVHD were treated successfully with steroids.  Only 7% of patients developed chronic GVHD (much lower than T-replete transplants), which also largely responded to steroids. 

Future Reading 

1. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease, the full article from the Journal of Clinical Oncology, from April 2022 (registration may be required). 
2. A blog article from the National Cancer Institute (NCI) Can Chronic Graft-Versus-Host Disease Be Prevented? This is quite interesting and not nearly as technical as the journal articles. 
3. An older abstract (2020) from the same author, Marie Bleakley: Naive T-cell depletion in stem cell transplantation  
4. Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults with Blood Cancers Undergoing Donor Stem Cell Transplant, the clinical trial description from the National Cancer Institute 
5. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation  from the journal Blood.  A technical and older (2001) article but may be interesting to some. 
6. Does GVHD Ever Resolve in Acute Myeloid Leukemia Patients?

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References

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease Marie Bleakley, Alison Sehgal, Stuart Seropian, Melinda A. Biernacki, Elizabeth F. Krakow, Ann Dahlberg, Heather Persinger, Barbara Hilzinger, Paul J. Martin, Paul A. Carpenter, Mary E. Flowers, Jenna Voutsinas, Theodore A. Gooley, Keith Loeb, Brent L. Wood, Shelly Heimfeld, Stanley R. Riddell, and Warren D. ShlomchikJournal of Clinical Oncology 2022 40:11, 1174-1185