1) CML: The advent of TkI has transformed CML treatment, but while targeted treatment is highly effective at reducing disease burden to minimal levels, it is not a reliable curative approach. Continuing investigations explore potential of using leukemia vaccines to eradicate residual disease and eliminate the need for continued TkI treatment. Resistance of CML stem cells to the GVL effect: Late relapse occurring in the second decade after SCT is a particular problem for patients with CML. Recurrence after a long period of disease quiescence suggests that in CML disease is never eradicated but is mostly effectively suppressed by a continuing long-lived GVL effect. To better define clinical and biological parameters determining post-relapse outcome, we studied 59 patients with CML relapsing after HLA-identical sibling allo-SCT between 1993 and 2008. Eighteen (30.5%) were transplanted in advanced phase and 41(69.5%) in chronic phase. At a median follow up from relapse of 7.9 years, 5-year post-relapse survival (PRS) was 62%. Multivariate analysis found disease status at transplant, time to diagnosis of relapse from transplant, and pre- transplant TKI use as significant factors associated with PRS. Analysis of BCR-ABL transcript expression in the hematopoietic progenitor compartment was performed in 36 patients (22 relapsed, 8 non-relapsed, and 6 TKI alone controls). Patients with BCR-ABL expression in their early hematopoietic stem cell compartment (HSC: Lineage-CD34+CD38-CD90+) had worse survival irrespective of the disease status. These findings demonstrate that disease status remains the strongest clinical prognostic factor for PRS in CML following allo-SCT. The persistence of BCR-ABL expression in the progenitor cell compartment in some patients after SCT emphasizes the need to develop new immune strategies to target CML-leukemia stem cells. 2) Acute Myeloblastic Leukemia: Both NK cells and T lymphocytes are cytotoxic to AML cells. Clinical evidence for immune control of AML comes from the observation of a strong GVL effect of allogeneic SCT, and several observations linking rapid lymphocyte recovery after chemotherapy-induced remission with relapse free survival. The inability of chemotherapy to maintain remission, once achieved, has stimulated investigators to apply immunotherapeutic approaches to patients in remission. Many immunotherapeutic strategies are currently being explored, including antileukemic antibodies, leukemia specific vaccines, growth factors, cell therapy with NK cells and immunomodulatory agents such as lenalidomide, and 5-AZA. However many questions need need to be answered before rational immunotherapy can be applied to AML. NK cells in myeloid malignancies: Dr Kate Stringaris has completed studies of natural killer (NK) cell immune function in acute myelogenous leukemia: In 32 AML patients undergoing remission induction chemotherapy patients were found to have reduced NK activatory receptors, increased NK inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors. These abnormalities corresponded with failure to achieve remission and could be induced in normal NK incubated with AML blasts. These results indicate that KIR genetics have a limited influence on AML development and outcome but that AML can impair NK function, reducing the chance of achieving remission. These findings have implications for NK based immunotherapy for AML. Immune profiling in AML: To explore T cell function in AML we established A collaboration with Dr Stephen Strickland, (Vanderbilt University Hospital, Nashville TN) to study immune profile of patients with AML at presentation, after remission induction, and at relapse. We hypothesize that immune function is compromised by the leukemia through one or more mechanisms that suppress T cell responses. We have analyzed 30 patients. We found an increase in T reg cells at presentation and remission and the occurrence of AML blasts with myeloid-derived suppressor cell function suggesting that immune responses to AML may be blunted by a negative immune milieu. Levels of IL-27 are strongly elevated in AML and patients failing to enter remission had the highest and most persistent elevations in IL-27. These findings suggest that AML blunts the T cell response by an IL27 mediated induction of regulatory T cells and a concomittent exhaustion of effector T cells. We also analyzed the potential of patients with AML in remission to generate LAA specific T cells. In comparison with their HLA identical stem cell transplant donors patients possess a comparable but different repertoire of cytotoxic T cells recognizing a panel of LAA. These findings support the development of LAA-specific T cell in the autologous setting to maintain remission in AML patients. Ultimately these studies should identify protective immune mechanisms in AML that inform rational immunotherapy with cytokine treatment or adoptive NK or T cell therapy. 3) MDS: The interaction of T cells with MDS cells remains a model for studying the immune response to a myeloid malignancy. We have shown in prior reports that patients with low grade MDS can respond to immunosuppressive treatment with monoclonal anti T cell antibodies. We have now addressed the problem of MDS patients with more advanced disease in transformation to AML who do not respond to immunosuppression. These patients have a poor prognosis. A clinical trial (12-H-0146) Clofarabine Followed by Lenalidomide for Treatment of High Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia is ongoing and has accrued five patients. 4) Large granular lymphoproliferative disease (LGL): is a bone marrow failure disorder caused by an expanded large granular lymphocyte CD8 T cell clone or clones. Patients may have erythrocytopenia, granulocytopenia or both. Initial clinical trials at NHLBI showed that patients with LGL can recover from neutropenia or anemia using treatment with CSA. We showed that the LGL clone was distributed across central memory, effector-memory and a CD57+ effector cell suggesting that the true progenitor is a central memory T cell. To explore whether more intensive immunosuppression would be more effective at restoring hematopoiesis, we initiated a phase II non-randomized trial of the immunosuppressive monoclonal antibody alemtuzemab (anti CD52) in LGL (www.clinicaltrials.gov - NCT00345345). Twenty consecutive subjects with T-LGL were enrolled. After a 1 mg test dose, alemtuzumab was administered at 10 mg/dose/day intravenously for 10 days. At 3 months 11/20 subjects had a hematological response. Treatment with alemtuzumab produced sustained reduction of both CD57+ and CD57- T-cytotoxic lymphocytes, but the abnormal clone persisted in responders. When compared with healthy volunteers T-LGL subjects had a distinct plasma cytokine signature as well as JAK-STAT pathway activation prior to treatment but neither was correlated to clinical responses to alemtuzumab, likely due to the diversity of prior treatments. This is the largest and only prospective cohort of T-LGL subjects treated with alemtuzumab reported. Treatment was well tolerated with minimal side effects. The 55% overall response rate (73% in typical T-LGL) represents an effective and safe treatment for this condition. Clonal LGL samples are being screened against a combinatorial peptide library to identify the cognate peptides and attempt to identify the target protein of the LGL clone (collaboration with Dr M Wooldridge, Cardiff, UK). Understanding how the LGL T cell suppresses myelopoiesis and erythropoiesis may shed light on the mechanism of suppression of both normal and leukemic cells by cytotoxic T cell populations.

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Barrett, Austin John (2017) Transplant biomarkers ready for the clinic? Blood 129:137-139
Barrett, A John (2017) Antibody darts on target for acute myelogenous leukemia. Ann Transl Med 5:80
Jain, Prachi; Klotz, Jeffrey; Dunavin, Neil et al. (2017) Cellular immune profiling after sequential clofarabine and lenalidomide for high risk myelodysplastic syndromes and acute myeloid leukemia. Leuk Res Rep 7:40-44
Ishii, Kazusa; Barrett, Austin J (2016) Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic). Ther Adv Hematol 7:17-39
Whitehill, Greg D; Amarnath, Shoba; Muranski, Pawel et al. (2016) Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia. Mol Ther :
Zhao, Xin; Tian, Xin; Kajigaya, Sachiko et al. (2016) Epigenetic landscape of the TERT promoter: a potential biomarker for high risk AML/MDS. Br J Haematol 175:427-439
Hourigan, Christopher S; Goswami, Meghali; Battiwalla, Minoo et al. (2016) When the Minimal Becomes Measurable. J Clin Oncol 34:2557-8
Barrett, Austin J (2015) Tailoring steroid-sensitive virus-specific T cells with TALEN. Blood 126:2767-8
Barrett, Gene R; Thibodeaux, Kasey E; Replogle, William H et al. (2015) Body Mass Index as an Indicator of Associated Intra-articular Injuries in Patients With Anterior Cruciate Ligament Tears. J Surg Orthop Adv 24:159-63
Barrett, Austin John; Bollard, Catherine M (2015) The coming of age of adoptive T-cell therapy for viral infection after stem cell transplantation. Ann Transl Med 3:62

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