Reversal of T Cell Exhaustion in Pre-Treatment Marrow T Cells Is Associated with Effective Graft-Versus-Leukemia Responses to Donor Lymphocyte Infusion

• Published in: Blood 2012-11, Vol.120 (21), p.1903-1903
• Main Authors: Bachireddy, Pavan, Hainz, Ursula, Rooney, Michael, Pozdnyakova, Olga, Aldridge, Julie, Haining, W. Nicholas, Goldstein, Natalie R., Canning, Christine M, Soiffer, Robert J., Ritz, Jerome, Hacohen, Nir, Kim, Haesook T, Alyea, Edwin P, Wu, Catherine J
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.1903.1903

Abstract 1903 Donor lymphocyte infusion (DLI) can provide curative treatment for relapsed hematologic malignancies following allogeneic hematopoietic stem cell transplant (HSCT). However, the precise mechanism by which DLI eliminates leukemia cells in vivo has not been established. We hypothesized that marrow-infiltrating immune populations play a critical role in DLI responses since marrow is the primary site of disease and a reservoir of high-avidity antigen-specific memory T cells that can recognize tumor antigens, therefore potentially mediating graft-versus-leukemia (GvL) responses. We performed immunohistochemical staining of immune cells in serial marrow biopsies collected before and after DLI from 29 patients with relapsed CML. Twenty-two patients achieved cytogenetic remission within twelve months (‘responders') while 7 patients demonstrated persistent disease (‘non-responders'). While no significant changes in the numbers of circulating T cells were seen between patient groups following DLI, the median number of marrow-infiltrating CD8+ T cells increased 2-fold in responders but remained unchanged in non-responders (P=0.02), demonstrating that clinical response to DLI is associated with T cell responses at the site of disease that may not be apparent in the peripheral blood. To investigate whether immune cell infiltration of the marrow could predict DLI response, we compared pre-treatment samples from both patient groups. Responders exhibited significantly higher proportions of CD8+ T cells in pre-DLI marrow compared to non-responders (5% vs 2.5%; P=0.01). Because disease burden is a known risk factor for ineffectual DLI response, we evaluated the interaction between disease burden and pre-existing CD8+ T cell infiltrate through the clinical course of 8 patients with high (≥70%) pre-treatment marrow cellularity. Three of 8 had ≥5% CD8+ T cell marrow infiltrates, and all 3 subsequently achieved cytogenetic remission. In contrast, 5 of 8 patients had