Antiviral Responses following L-Leucyl-L-Leucine Methyl Esther (LLME)-Treated Lymphocyte Infusions: Graft-versus-Infection without Graft-versus-Host Disease

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Antiviral Responses following L-Leucyl-L-Leucine Methyl Esther (LLME)-Treated Lymphocyte Infusions: Graft-versus-Infection without Graft-versus-Host Disease Joanne Filicko-O'Hara, Dolores Grosso, Phyllis R. Flomenberg, Thea M. Friedman, Janet Brunner, William Drobyski, Andres Ferber, Irina Kakhniashvili, Carolyn Keever-Taylor, Bijoyesh Mookerjee, Julie-An Talano, John I. Wagner, Robert Korngold, Neal Flomenberg Biology of Blood and Marrow Transplantation Volume 15, Issue 12, Pages 1609-1619 (December 2009) DOI: 10.1016/j.bbmt.2009.08.020 Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 LLME depletion. Flow cytometry of product prior to LLME treatment shows the presence of NK (CD56 or 16+/CD3−) cells, and CD3+/CD8+ cells, and CD3+/CD4+ cells. However, following LLME treatment, cells that contain perforin, namely, the NK cells and a portion of CD8+ cells, are markedly depleted. The CD4 cell population is only minimally depleted in contrast (A). Following treatment with LLME, products showed adequate depletions of NK and CD8+ cells with a median 95.2% (range: 79.9-100) depletion of NK cells, 76.1% (range: 35.1-92.8) of CD3+/CD8+ cells, but only 31.0% (0-88.8) of CD3+/CD4+ cells (B). Biology of Blood and Marrow Transplantation 2009 15, 1609-1619DOI: (10.1016/j.bbmt.2009.08.020) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Reconstitution of perforin-positive cells. Following LLME DLI, a product containing perforin-negative cells, patients were able to reconstitute both perforin-negative and then perforin-positive cells. For the sample patient seen here, recovery of CD3+/CD4+ cells was apparent by day 37 after LLME DLI (A). Earlier time points were measured (B) showing recovery of the same populations of cells but at lower numbers. The recovery of NK cells heralded (third dot plot and third column) preceded the recovery of CD8 cells. Reconstitution of CD8 cells included both perforin-positive and perforin-negative cells and preceded the recovery of CD4-positive cells. Biology of Blood and Marrow Transplantation 2009 15, 1609-1619DOI: (10.1016/j.bbmt.2009.08.020) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Immune reconstitution following LLME DLI. Patients developed rapid and sustained reconstitution of lymphocyte subsets following LLME DLI. As shown in this sample patient, this included CD3+/CD4+, CD3+/CD8+, and CD3−/CD56 or 16+ cells (A) as well as both memory and naïve CD4 cells (B). In 1 patient who had not converted to 100% donor cells at the time he received LLME DLI, the recovery of memory CD4 cells was more prominent (C). Biology of Blood and Marrow Transplantation 2009 15, 1609-1619DOI: (10.1016/j.bbmt.2009.08.020) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Antiviral responses. Sample data are shown for 2 patients. In panels A and B, one sees the data from a patient who developed adenovirus hepatitis. Shortly after receiving the LLME DLI, he began to clear the adenovirus with a 10-fold drop in PCR titers by 11 days s/p DLI (113 days s/p HPCT), and complete resolution by 42 days s/p DLI (144 days s/p HPCT). This was associated with an adenovirus specific CD4 IFN-γ response that was evident at 147 and 175 days post-DLI. Sample from a second patient, who had developed CMV infection, is shown in panels C and D. Once again, the patient had rapid resolution of CMV PCR titers with a significant drop within 6 days and complete resolution by 20 days s/p DLI (68 days s/p HPCT). He was also found to have developed both a CMV-specific CD8 response (anti-A2 peptide) and CD4 response (CMV ag), but no response to adenovirus. Biology of Blood and Marrow Transplantation 2009 15, 1609-1619DOI: (10.1016/j.bbmt.2009.08.020) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Vβ spectratyping. Representative histograms of Vβ spectratype analysis of the CD4+ T cells enriched from the peripheral blood of 1 of the patients/pairs. The repertoire complexity of the donor sample before LLME treatment (A), after LLME treatment (B), and reconstituting in the patient post-LLME DLI (C) exhibit similar levels of complexity. Biology of Blood and Marrow Transplantation 2009 15, 1609-1619DOI: (10.1016/j.bbmt.2009.08.020) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions