Decreased Type 1 cytokine production has been observed in T cells of patients with untreated chronic myeloid leukemia (CML). The important role of T cells and T-cell cytokines in the long-term control of CML is well established, for example in allogeneic stem-cell graft recipients. This study examined whether or not molecularly targeted therapy with imatinib, an inhibitor of the BCR-ABL tyrosine kinase, improved endogenous T-cell function in patients resistant to or intolerant of previous IFN-alpha therapy. Intracellular cytokine staining and detection by flow cytometry was used to analyze the expression of the T1 cytokine IFN-gamma in T cells. To secure independence from changes in white blood cell counts during treatment, a constant number of T cells was purified from the peripheral blood before analysis of the proportion of IFN-gamma synthesizing T cells. Twenty-nine patients with CML were tested before and after a median follow-up of 3 month on imatinib. In addition, late follow-up (past the median time to best cytogenetic response) of 15 patients were obtained Twenty-nine age- and gender-matched individuals were used as healthy controls. The frequency of IFN-gamma producing T cells in CML patients resistant to or intolerant to previous IFN-alpha therapy was lower than in healthy individuals (p=0.0181, Mann-Whitney test). Imatinib therapy led to a significant increase over pre-treatment values (p<0.0001, Mann-Whitney test). Late follow-up indicated that the increase was sustained in patients not in major cytogenetic response. In contrast, in major responders levels returned towards values comparable to healthy individuals. In conclusion, treatment with imatinib achieves a significant increase in Type 1 (IFN-gamma) cytokine-producing T cells in patients with CML. This is consistent with the view that enhanced T-cell function is achievable in patients with CML, even in the absence of allo-mechanisms.
Background: gd T cells are a rare component of the circulating innate immune system capable of exerting anti-neoplastic activity. This population may be suitable for the adoptive immunotherapy of acute myeloid leukemia (AML). Little is known however, about the frequency and function of circulating gd T cells in AML. The aim of the study was to enumerate peripheral blood gd T cells in patients with AML and explore the feasibility of their use clinically.Methods: We compared the absolute circulating gd T cell levels in 33 AML patients before and after treatment versus 20 healthy volunteers using flow cytometry. The function of gd T cells was assessed by detection of intracelluar interferon-g (IFN-g) and cytotoxicity against leukemic blasts.Results: AML patients with high blast counts prior to induction chemotherapy had marginally decreased gd T cell levels compared with healthy controls: median 38/mL versus 83/mL; P = 0.051. Sequential gd T cell enumeration after induction showed significantly decreased counts in patients with a persistently high blast burden compared to patients with reduced but detectable residual disease (molecular maker or borderline bone marrow infiltration): median 7/mL versus 105/mL; P = 0.008. Patients with residual disease had significantly higher gd T cell counts compared to those retested after they had achieved complete remission (CR); P = 0.0025. In CR, gd T cell counts remained lower than those of healthy individuals: median 33/mL versus 83/mL, P = 0.030. We detected a sharp increase (on average, four-fold higher than values in CR) of gd T cells in patients in very early morphologic or molecular relapse. We also tested the functional properties of gd T cells from patients with AML in CR. Flow cytometric assessment of IFN-g revealed similar numbers of gd T cells expressing the T1 cytokine compared with healthy controls. We also showed that gd T cells were able to kill leukemic target cells in vitro.Conclusion: Flow cytometric assessment of gd T cells in patients with AML revealed quantitative shifts with respect to disease status. Our data suggest that gd T cells warrant further investigation as potential therapeutic agents. q
Prolonging event-free survival of AML with autologous activated immune cells is a promising concept. GD-T cells are a rare circulating lymphocyte population (1%) and a component of the innate immune system capable of exerting anti-neoplastic activity. Their role as potential anti-cancer immune effector cells deserves further exploration. It is noteworthy that GD-T cells are over-represented in reactive regions surrounding melanoma lesions. While patients with an accumulation of GD-T cells showed a survival benefit over those who did not, such increases were not present in patients with metastatic disease and high tumor cell burden (Bachelez, J. Invest. Dermatol.98:369,1992). Little is known about the role of GD-T cells as immuno-effectors, their absolute numbers in peripheral blood or the feasibility of purifying functional GD-T cells from patients with AML. We are interested in testing the clinical feasibility of using GD-T cells freshly purified from PB against minimal residual disease in AML. As a first step towards achieving this goal, we compared circulating GD-T cell levels sequentially in 33 AML patients with 20 healthy adult volunteers. We used ultra-low volume multi-color flow-cytometry and microbeads to measure absolute numbers of GD-T cells in PB. Functional studies were done by the chromium release assay and single-cell intra-cellular interferon-gamma detection. We observed that AML patients with a high leukemic blast cell burden (e.g. prior to chemotherapy) had marginally decreased GD-T cell levels compared with healthy controls: median 38/μl, Q1-Q3, 27–86/μl, versus median 83/μl, Q1-Q3, 45–122/μl, respectively, p= 0.051. We re-examined the AML patients at several time points after induction therapy and observed significantly increased numbers of GD-T cells in patients with lower but detectable residual disease (either molecular maker positive or borderline bone marrow blast infiltration by morphology) compared to patients with persistently high blast cell burden: median 105/μl, Q1-Q3, 105–133/μl versus median, 7/μl, Q1-Q3, 6–15/μl; p=0.008. Patients with residual disease also showed significantly higher numbers of absolute GD-T cells per microliter blood compared to those retested after they had achieved complete remission (CR); p=0.0025. In CR, GD-T cell counts remained lower than those of healthy individuals: median 33/μl, Q1-Q3, 22–35/μl versus median 83/μl, Q1-Q3, 45–122/μl; p=0.030. Interestingly, we found a sharp increase (on average, 4.9-fold higher than values obtained in CR) in GD-T levels at the time of very early morphologic (n=3) or molecular relapse (n=2). Hence, we were interested in studying the functional properties of the GD-T cells from AML patients. We were able to isolate functional GD-T cells from the PB of patients with AML in CR-1 in sufficient numbers and purity to assay for interferon-gamma and found that similar numbers of GD-T cells expressed the Th1 cytokine compared with healthy controls: 84% versus 93% of all GD-T cells, respectively. We also showed that GD-T cells were able to kill leukemic target cells (AML-OCI2) in vitro more efficiently than CD3+ T cells. Our data suggest that further studies to investigate the potential therapeutic role of autologous GD-T cells in patients with AML in CR are warranted.
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