Thwarting relapse in patients with acute myeloid leukemia

From the Hill Lab, Clinical Research Division

For patients with acute myeloid leukemia who are in a stage of complete remission and undergo stem cell transplantation, long-term survival outcomes are excellent. However, for those patients who do not achieve complete remission, risk of relapse after transplant is high causing this population to be generally considered ineligible for transplant. Successful anticancer outcome of transplantation hinges on a phenomenon known as the graft-versus-leukemia (GVL) effect. This is a mechanism whereby immune cells from the transplant donor destroy cancer cells present in the bone marrow. Conversely, graft-versus-host disease (GVHD) develops when donor T-cells attack non-leukemic tissues in the transplant recipient, a leading cause of transplant failure. Expanding on their previous research with anti-inflammatory glucocorticoids in patients who have not reached complete remission, members of Dr Geoffrey Hill’s Laboratory in the Fred Hutch Clinical Research Division focused on two spatially distinct regions, the gastrointestinal tract and the bone marrow. Their work in pre-clinical models, recently published in JCI Insights, reveals that treatment with glucocorticoids during the peri-transplant window simultaneously improved GVL while decreasing the impact of GVHD.

As a key first step, the authors sought to replicate the effects of stem cell transplant using mouse models. The mice were treated with glucocorticoids for several days before and after transplant and compared to control mice to determine effects on GVL and GVHD. Encouragingly, reduced incidence of GVHD was observed in treated mice, alongside signs that the effects of GVL were not abrogated during treatment. To understand the mechanism by which glucocorticoid treatment could interfere with GVHD, the authors utilized additional mouse models and noted that glucocorticoid treatment inhibited the spread of T-cells in the gastrointestinal tract and gut-draining lymph nodes. Building on this finding, they next assessed the impact of glucocorticoids on T-cell signaling by transplanting glucocorticoid receptor-deficient or unmodified T-cells into their mouse models. Glucocorticoid treatment altered T-cell expansion in the gastrointestinal tract and downregulated gut-homing α4β7 expression on the surface of these cells, irrespective of glucocorticoid receptor deficiency.  

Glucocorticoid treatment can ameliorate effects of graft-versus-host disease and promote graft-versus-leukemia effects in pre-clinical models.
Glucocorticoid treatment can ameliorate effects of graft-versus-host disease and promote graft-versus-leukemia effects in pre-clinical models. Image provided by Dr Geoffrey Hill.

The authors next compared treatment with post-transplant cyclophosphamide (PT-Cy), a routine clinical treatment, to glucocorticoid treatment to determine the impact on GVL. The mice treated with glucocorticoids experienced lower relapse rates and lower presence of leukemic cells in the blood, compared to PT-Cy treatment which greatly reduced GVL effects. Shifting their focus to the bone marrow to better understand this improved GVL effect with glucocorticoid treatment, the authors observed high levels of donor CD8 and CD4 T-cell migration to this site. By labelling T-cells in vivo, the authors were able to identify circulatory and resident T-cell populations and observed the presence of higher numbers of circulating CD8 T-cells in the bone marrow after glucocorticoid treatment. Initial population counts of resident donor CD8 T-cells were modest shortly after treatment, but they greatly expanded over time. Isolation of these cells and subsequent RNA-sequencing analysis provided insights into expression profiles that facilitated their migration patterns, including increased expression of CXCR4 which is involved in T-cell homing to the bone marrow.

Finally, to better understand outcomes in a patient setting, the authors examined data from patients treated with PT-Cy versus patients treated with glucocorticoids. Focusing first on GVHD, PT-Cy treatment performed better at preventing acute GVHD than glucocorticoids, however chronic levels of GVHD were similar. Interestingly, patients treated with glucocorticoids exhibited lower relapse rates and had better overall survival outcomes. Taking all these finding together, this encouraging research has demonstrated how “early steroid treatment in haploidentical transplantation inhibits antigen presentation and GVHD in the gut but enhances donor T cell trafficking to the bone marrow and improves GVL effects”, described Dr Hill.

The results from this study have raised important questions that the Hill lab and collaborators hope to address including whether “early steroid therapy can improve the anti-tumor effect of T cell therapies,” according to Dr Hill.  Elaborating on next steps, Dr Hill further explained, “We are currently looking at these effects in other stem cell transplantation platforms and T cell therapies. A prospective clinical trial is being planned in Japan by the first author of the study.”

This work was funded by grants from the National Institutes of Health, ORIP, the Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, MEXT-Supported Program for the Strategic Research Foundation at Private Universities from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

UW/Fred Hutch Cancer Consortium members Geoffrey Hill and Scott Furlan contributed to this work.

Inoue T, Koyama M, Kaida K, Ikegame K, Ensbey KS, Samson L, Takahashi S, Zhang P, Minnie SA, Maruyama S, Ishii S, Daimon T, Fukuda T, Nakamae H, Ara T, Maruyama Y, Ishiyama K, Ichinohe T, Atsuta Y, Blazar BR, Furlan SN, Ogawa H, Hill GR. Peri-transplant glucocorticoids redistribute donor T-cells to the bone marrow and prevent relapse after haploidentical SCT. JCI Insight. 2021 Oct 12:e153551. doi: 10.1172/jci.insight.153551. Epub ahead of print. PMID: 34637399.