Molecular targeted therapies, such as imatinib, represent an exciting new treatment modality for cancer. Unlike chemotherapy, which is nonspecific and can concurrently inhibit cancer and immune cells, imatinib (and other molecular targeted therapies) can suppress cancer cells more than immune cells. We hypothesized that, as leukemic cells decrease under imatinib therapy, immune function is partially restored while apoptotic leukemic cells are present, thus rendering leukemic cells immunogenic at a critical inflection point. Indeed, using leukemic cells (pretreatment peripheral blood mononuclear cells) as targets, we showed that antileukemia T-cell responses develop in the majority of analyzed CML patients in hematologic and cytogenetic remission under imatinib treatment. Furthermore, such responses are predominantly CD4+ T cells producing TNF-?, and in one patient represent 40% of CD4+ T cells. These responses would have been missed by screening for IFN-? responses to the limited set of LAAs currently identified. Use of cryopreserved autologous leukemic cells is a useful, antigen-unbiased approach, which allows broader detection of antileukemia T-cell responses, and TNF-? appears to be an important cytokine in such responses.
Results of in vitro studies on the effect of imatinib on T-cell responses are contradictory.18-23 Mechanisms by which imatinib treatment influences antileukemia T-cell responses, and the molecular targets to which these cells are directed, need to be further investigated. The major subset of the antileukemia T-cell responses in this study are CD4+ T cells, which may play a more important role in the immune response against CML24 than previously thought. They may not only help shape25,26 and sustain an antileukemia CD8+ T-cell response27 but may also help shape antileukemia CD4+ T-cell responses via T helper cell-T helper cell cooperation28 (cooperation of CD4+ T cells). Two key molecules are CD40 and OX40 costimulatory molecules, which are known to play an important role in T-cell activation through B cells as APCs. The underlying mechanism of this cooperation is the up-regulation of CD40L as well as CD28 and OX40 on the surface of helper CD4+ T cells, which leads to binding to CD40 on the surface of APCs followed by an up-regulation of OX40L expression on the APCs and a more efficient presentation of LAAs to CD4+28 and CD8+ T cells.29
The cytokines TNF-? and IFN-?, which were mainly produced by the specific CD4+ T cell in patients in remission, might maintain and sustain the proliferation of antileukemia T cells.28,30,31 Especially TNF-?, which is important for maintaining long-living anti-leukemia memory T cells,32 may be essential in this process. Its significance was also shown in patients with acute graft-versus-host disease who had successfully undergone allogeneic BMT.33 Another mechanism of function is the up-regulation of MHC class I and II molecules on the surface of APCs by TNF-? and IFN-?28,31,34 for a better presentation of LAAs to T cells. TNF-?-producing T cells also contribute to the elimination of leukemic cells through the interaction of TNF-? with TNF-? receptors, which are expressed at high levels on leukemic cells,31 and the production of other proinflammatory cytokines, such as IL-1, IL-2, IL-6, and IL-8.34,35 Therefore, analysis of IFN-? production by antileukemia T cells30,36 alone might not reveal the entire immune response. Other cytokines, such as TNF-? and IL-2, are also important for antileukemia T-cell responses and need to be investigated.
The temporal dynamics of these responses were studied in several patients. T-cell responses develop around the time of clinical remission and are sustained for several months. However, these responses ultimately wane in all patients, even though leukemic cells persist at low levels in a minimal residual disease state. It is puzzling why the antileukemia immune response does not lead to complete eradication of leukemic cells. In one subject, an antileukemia immune response could be amplified on stimulation with irradiated leukemic cells (or lysates) at a time point at which such a response was undetectable directly ex vivo. This suggests that low levels of immune reactivity persist that may be amplified via vaccination strategies.
Together, our results show that robust T-cell responses to CML develop in some patients under imatinib treatment. These responses are dominated by CD4+ T cells producing TNF-?. Mechanisms by which imatinib treatment leads to antileukemia T-cell responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge may be useful for the development of immunotherapeutic strategies against CML, and raises the hope that immunotherapy may synergize with imatinib to eradicate residual leukemic cells for a durable cure of the disease.