Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Abstract

Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured Tcell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand preexisting memory T cells. IntroductionPatients undergoing chemotherapy for cancer are susceptible to infection, particularly in hematologic malignancies such as acute lymphoblastic leukemia (ALL) where infections account for 80% of remission deaths. [1][2][3] However, while infection represents a significant complication of chemotherapy, the number of patients who succumb to infection is low. For instance, fewer than 1% of children undergoing maintenance therapy for ALL die from infection. 3 Although infection prophylaxis and good supportive care are likely to contribute to this low infectious mortality, the majority of patients with ALL appear to retain protective immunity against infection despite prolonged chemotherapy. The nature of this residual immune function in lymphopenic patients is not known.In the normal host the peripheral T-cell compartment consists of naive T cells, which originate in the thymus, and memory T cells, which have differentiated from naive T cells in response to antigen exposure. Memory T cells can rapidly proliferate and acquire effector function on re-exposure to antigen. Together with antibody response, memory T cells are central to the maintenance of protective immunity. However, the fate of the memory T-cell compartment in patients treated with chemotherapy is poorly understood. Seminal studies by Mackall et al 4-7 described the profound depletion seen in the T-cell compartment following chemotherapy. They showed that intensive chemotherapy is associated with a near-total loss of naive CD4 T cells, which do not reappear until several months after the end of treatment. [4][5][6][7] Recent data using assays that quantify thymic output have also shown a marked decrease in thymic output in patients treated with chemotherapy and radiation, suggesting that direct thymic injury may account for this lack of naive T cells. 8,9 Together, these studies...

Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation

“…The recent observation that the memory T-cell compartment is the least affected by chemotherapy may allow for improved immunization by vaccinating prior to high-dose chemotherapy, subsequently using vaccine boosts to induce re-expansion of this memory T-cell compartment. 65 In conclusion, our results demonstrate the feasibility of generating a recipient-derived leukemia vaccine combining transgenic CD40L with IL-2. The vaccine is not only well tolerated but also induces the same pattern of antileukemic immunity predicted from our murine model.…”

Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia

“…Antigen-specific T-cell and B-cell memory was found to be preserved in children treated for ALL (23,24). However, we demonstrated herein for the first time that although their numbers of T cells and T-cell receptor repertoire appeared normal, ALL survivors were deficient in naïve T cell generation, as measured by TREC and CD45RO−/RA+ cells enumeration when compared with their age-equivalent sibling controls.…”

Leukemia-Associated Antigens Are Critical for the Proliferation of Acute Myeloid Leukemia Cells

“…Cytostatic drugs induce cytopenia in the peripheral blood as well as in the bone marrow but the functional impairment of T cells after reconstitution remains to be elucidated. Several studies have shown that the circulating T cells detected early after chemotherapy are functional (74,75). T cells of AML patients after intensive chemotherapy show an increased proliferation when stimulated (76).…”