From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
7. Hod EA, Brittenham GM, Billote GB, et al. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood. 2011; 118(25):6675-6682. 8. Chaplin H Jr, Beutler E, Collins JA, Giblett ER, Polesky HF. Current status of red-cell preservation and availability in relation to the developing national blood policy. N Engl J Med. 1974;291(2):68-74.
9. Steiner ME, Assmann SF, Levy JH, et al. Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7). Transfus Apheresis Sci. 2010;43(1):107-116. 10. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381(9880): 1845-1854. © 2014 by The American Society of Hematology
l l l TRANSPLANTATION
Comment on Bachireddy et al, page 1412
Reversing CD81 T-cell exhaustion with DLI ----------------------------------------------------------------------------------------------------Paul J. Martin1
1
FRED HUTCHINSON CANCER RESEARCH CENTER
In this issue of Blood, Bachireddy et al explain why infusion of donor CD4 T cells induces remission in some patients with persistent chronic myeloid leukemia (CML) after allogeneic hematopoietic cell transplantation (HCT), but not in others.1
The extent of T-cell infiltration of the marrow and a gene expression profile indicating “exhaustion” in T cells are associated with response after DLI in patients with persistent CML after allogeneic hematopoietic cell transplantation. The number of donor CD8 cells that have previously infiltrated the marrow is higher in responders (A) than in nonresponders (B), and a gene expression profile indicating exhaustion is observed only in responders. See Figure 6 in the article by Bachireddy et al that begins on page 1412.
BLOOD, 27 FEBRUARY 2014 x VOLUME 123, NUMBER 9
n a landmark report, Kolb et al2 described 3 patients with recurrent CML after bone marrow transplantation who were treated with interferon-a and buffy coat cells from the marrow donor. All 3 patients had a durable complete hematologic and cytogenetic remission. A subsequent study showed that donor lymphocyte infusion (DLI) induced durable complete remission in ;75% of patients with persistent or recurrent chronic-phase CML after allogeneic HCT.3 In this study, however, ;40% of the patients developed graftversus-host disease (GVHD), and in another study, 76% of the patients developed acute or chronic GVHD.4 In 1995, Giralt et al5 reported preliminary results suggesting that treatment with lower numbers of donor cells and depletion of CD8positive T cells from DLI might decrease the risk of GVHD, without loss of anti-leukemic efficacy. Subsequent studies at the DanaFarber Cancer Institute supported this hypothesis. In a study by Alyea et al,6 15 of the 19 patients with cytogenetic or hematologic persistence of CML after allogeneic HCT had a complete cytogenetic response after CD8depleted DLI, and only 32% of patients in the trial developed acute or chronic GVHD. These results demonstrated that donor CD4 T cells can induce an anti-leukemic response in patients with CML, but they raised 2 related questions. First, if hematopoietic stem cells and their malignant CML counterparts do not express major histocompatibility complex class II molecules that present antigens to CD4 T cells, how do donor CD4 T cells eliminate these cells in the recipient? Second, why is CD8-depleted DLI effective in some patients with CML, but not others? Bachireddy et al1 compared the characteristics of cells from 29 patients categorized according to their response to DLI and report 3 main findings. (1) Before DLI, the numbers of CD8 T cells in the marrow were higher in responders than in nonresponders, while overall marrow cellularity was higher in nonresponders than in responders. The combination of both characteristics had 100% sensitivity and specificity for predicting response in this cohort. (2) After DLI, the numbers of CD8 cells in the marrow increased over time only in responders, while the numbers CD4 T cells and B cells in the marrow did not show statistically significant changes in either group. (3) Gene transcription profiles
I
1289
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
showed evidence of “exhaustion” in T cells from the marrow before DLI only in responders, and response after DLI was associated with downregulated expression of these genes. Exhaustion of CD8 T cells results from chronic antigen stimulation, as can occur with persistent viral infections and certain malignancies.7 Exhaustion is characterized by a distinctive gene expression profile,8 with sustained expression of inhibitory receptors that cause poor effector function, including lack of interleukin-2 production, poor proliferative capacity, loss of cytotoxic killing, and inability to produce tumor necrosis factor and interferon-g. Loss of help from CD4 T cells exacerbates exhaustion of CD8 T cells. Functions of exhausted CD8 T cells are inhibited by signaling through programmed cell death protein-1 (PD-1) and a variety of other coexpressed receptors.9 The results of Bachireddy et al1 suggest that the infused donor CD4 T cells eliminate recipient CML cells by reversing exhaustion in donor CD8 T cells that have previously infiltrated the marrow (see figure). From a translational perspective, the authors suggest that testing for the presence of exhausted CD8 T cells could help to identify candidates who are most likely to benefit from the use of DLI to treat persistent CML after
1290
allogeneic HCT. The authors further suggest the intriguing possibility that these patients might alternatively benefit from treatment with new agents that inhibit signaling through PD-1 or other inhibitory receptors expressed by exhausted CD8 T cells, although inhibition of this pathway could exacerbate GVHD.10 The findings of Bachireddy et al1 raise provocative questions regarding the causes of exhaustion in donor CD8 T cells after allogeneic HCT and the extent to which exhaustion might affect responses to DLI in patients with other diseases. Is exhaustion caused primarily by chronic antigen stimulation of donor CD8 T cells, or by lack of help from donor CD4 T cells, or do both factors contribute? As demonstrated previously,3,4 response rates after DLI are much lower in patients with acute leukemia and other diseases as compared with those with CML. Studies of gene transcription profiles in marrow T cells obtained before and after DLI from patients with acute leukemia and other diseases could help to determine whether exhaustion contributes to the lower response rate. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Bachireddy P, Hainz U, Rooney M, et al. Reversal of in situ T-cell exhaustion during effective human anti-
leukemia responses to donor lymphocyte infusion. Blood. 2014;123(9):1412-1421. 2. Kolb HJ, Mittermu¨ ller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76(12):2462-2465. 3. Kolb HJ, Schattenberg A, Goldman JM, et al; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86(5):2041-2050. 4. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15(2):433-444. 5. Giralt S, Hester J, Huh Y, et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood. 1995;86(11):4337-4343. 6. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and efficacy of defined doses of CD4(1) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood. 1998;91(10):3671-3680. 7. Wherry EJ. T cell exhaustion. Nat Immunol. 2011; 12(6):492-499. 8. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. Network analysis reveals centrally connected genes and pathways involved in CD81 T cell exhaustion versus memory. Immunity. 2012;37(6): 1130-1144. 9. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD81 T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37. 10. Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062-3073.
© 2014 by The American Society of Hematology
BLOOD, 27 FEBRUARY 2014 x VOLUME 123, NUMBER 9
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 1289-1290 doi:10.1182/blood-2014-01-547000
Reversing CD8+ T-cell exhaustion with DLI Paul J. Martin
Updated information and services can be found at: http://www.bloodjournal.org/content/123/9/1289.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
7. Hod EA, Brittenham GM, Billote GB, et al. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood. 2011; 118(25):6675-6682. 8. Chaplin H Jr, Beutler E, Collins JA, Giblett ER, Polesky HF. Current status of red-cell preservation and availability in relation to the developing national blood policy. N Engl J Med. 1974;291(2):68-74.
9. Steiner ME, Assmann SF, Levy JH, et al. Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7). Transfus Apheresis Sci. 2010;43(1):107-116. 10. Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381(9880): 1845-1854. © 2014 by The American Society of Hematology
l l l TRANSPLANTATION
Comment on Bachireddy et al, page 1412
Reversing CD81 T-cell exhaustion with DLI ----------------------------------------------------------------------------------------------------Paul J. Martin1
1
FRED HUTCHINSON CANCER RESEARCH CENTER
In this issue of Blood, Bachireddy et al explain why infusion of donor CD4 T cells induces remission in some patients with persistent chronic myeloid leukemia (CML) after allogeneic hematopoietic cell transplantation (HCT), but not in others.1
The extent of T-cell infiltration of the marrow and a gene expression profile indicating “exhaustion” in T cells are associated with response after DLI in patients with persistent CML after allogeneic hematopoietic cell transplantation. The number of donor CD8 cells that have previously infiltrated the marrow is higher in responders (A) than in nonresponders (B), and a gene expression profile indicating exhaustion is observed only in responders. See Figure 6 in the article by Bachireddy et al that begins on page 1412.
BLOOD, 27 FEBRUARY 2014 x VOLUME 123, NUMBER 9
n a landmark report, Kolb et al2 described 3 patients with recurrent CML after bone marrow transplantation who were treated with interferon-a and buffy coat cells from the marrow donor. All 3 patients had a durable complete hematologic and cytogenetic remission. A subsequent study showed that donor lymphocyte infusion (DLI) induced durable complete remission in ;75% of patients with persistent or recurrent chronic-phase CML after allogeneic HCT.3 In this study, however, ;40% of the patients developed graftversus-host disease (GVHD), and in another study, 76% of the patients developed acute or chronic GVHD.4 In 1995, Giralt et al5 reported preliminary results suggesting that treatment with lower numbers of donor cells and depletion of CD8positive T cells from DLI might decrease the risk of GVHD, without loss of anti-leukemic efficacy. Subsequent studies at the DanaFarber Cancer Institute supported this hypothesis. In a study by Alyea et al,6 15 of the 19 patients with cytogenetic or hematologic persistence of CML after allogeneic HCT had a complete cytogenetic response after CD8depleted DLI, and only 32% of patients in the trial developed acute or chronic GVHD. These results demonstrated that donor CD4 T cells can induce an anti-leukemic response in patients with CML, but they raised 2 related questions. First, if hematopoietic stem cells and their malignant CML counterparts do not express major histocompatibility complex class II molecules that present antigens to CD4 T cells, how do donor CD4 T cells eliminate these cells in the recipient? Second, why is CD8-depleted DLI effective in some patients with CML, but not others? Bachireddy et al1 compared the characteristics of cells from 29 patients categorized according to their response to DLI and report 3 main findings. (1) Before DLI, the numbers of CD8 T cells in the marrow were higher in responders than in nonresponders, while overall marrow cellularity was higher in nonresponders than in responders. The combination of both characteristics had 100% sensitivity and specificity for predicting response in this cohort. (2) After DLI, the numbers of CD8 cells in the marrow increased over time only in responders, while the numbers CD4 T cells and B cells in the marrow did not show statistically significant changes in either group. (3) Gene transcription profiles
I
1289
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
showed evidence of “exhaustion” in T cells from the marrow before DLI only in responders, and response after DLI was associated with downregulated expression of these genes. Exhaustion of CD8 T cells results from chronic antigen stimulation, as can occur with persistent viral infections and certain malignancies.7 Exhaustion is characterized by a distinctive gene expression profile,8 with sustained expression of inhibitory receptors that cause poor effector function, including lack of interleukin-2 production, poor proliferative capacity, loss of cytotoxic killing, and inability to produce tumor necrosis factor and interferon-g. Loss of help from CD4 T cells exacerbates exhaustion of CD8 T cells. Functions of exhausted CD8 T cells are inhibited by signaling through programmed cell death protein-1 (PD-1) and a variety of other coexpressed receptors.9 The results of Bachireddy et al1 suggest that the infused donor CD4 T cells eliminate recipient CML cells by reversing exhaustion in donor CD8 T cells that have previously infiltrated the marrow (see figure). From a translational perspective, the authors suggest that testing for the presence of exhausted CD8 T cells could help to identify candidates who are most likely to benefit from the use of DLI to treat persistent CML after
1290
allogeneic HCT. The authors further suggest the intriguing possibility that these patients might alternatively benefit from treatment with new agents that inhibit signaling through PD-1 or other inhibitory receptors expressed by exhausted CD8 T cells, although inhibition of this pathway could exacerbate GVHD.10 The findings of Bachireddy et al1 raise provocative questions regarding the causes of exhaustion in donor CD8 T cells after allogeneic HCT and the extent to which exhaustion might affect responses to DLI in patients with other diseases. Is exhaustion caused primarily by chronic antigen stimulation of donor CD8 T cells, or by lack of help from donor CD4 T cells, or do both factors contribute? As demonstrated previously,3,4 response rates after DLI are much lower in patients with acute leukemia and other diseases as compared with those with CML. Studies of gene transcription profiles in marrow T cells obtained before and after DLI from patients with acute leukemia and other diseases could help to determine whether exhaustion contributes to the lower response rate. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Bachireddy P, Hainz U, Rooney M, et al. Reversal of in situ T-cell exhaustion during effective human anti-
leukemia responses to donor lymphocyte infusion. Blood. 2014;123(9):1412-1421. 2. Kolb HJ, Mittermu¨ ller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76(12):2462-2465. 3. Kolb HJ, Schattenberg A, Goldman JM, et al; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86(5):2041-2050. 4. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15(2):433-444. 5. Giralt S, Hester J, Huh Y, et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood. 1995;86(11):4337-4343. 6. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and efficacy of defined doses of CD4(1) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood. 1998;91(10):3671-3680. 7. Wherry EJ. T cell exhaustion. Nat Immunol. 2011; 12(6):492-499. 8. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. Network analysis reveals centrally connected genes and pathways involved in CD81 T cell exhaustion versus memory. Immunity. 2012;37(6): 1130-1144. 9. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD81 T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37. 10. Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062-3073.
© 2014 by The American Society of Hematology
BLOOD, 27 FEBRUARY 2014 x VOLUME 123, NUMBER 9
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 123: 1289-1290 doi:10.1182/blood-2014-01-547000
Reversing CD8+ T-cell exhaustion with DLI Paul J. Martin
Updated information and services can be found at: http://www.bloodjournal.org/content/123/9/1289.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
