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...

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Despite profound T cell immunodeficiency, most patients treated with chemotherapy (CT) do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. Understanding the mechanisms underlying persistent immunity in some cancer patients might suggest treatment strategies to enhance immune competence in all. We therefore prospectively studied T cell homeostasis in 73 children (median age 4y; range 1–17) with ALL receiving a protracted, 2-year chemotherapy regimen. T cell frequency and phenotype and TREC levels were measured at diagnosis and every 5 months on therapy, and compared to an age-matched cohort of 805 healthy children. Twenty-three patients (32%) had high-risk features. All patients received a 5-drug induction, consolidation, and a continuation phase with pulses of vincristine and prednisone. High risk patients also received doxorubicin during consolidation. Patients received childhood vaccinations prior to diagnosis and standard PCP prophylaxis during therapy. Most patients had profound defects in CD4 and CD8 T cell compartments at diagnosis that failed to recover during the 2 years of therapy. Absolute counts of CD4 and CD8 T cells in patients remained below 10th %ile for age in 77% and 86% respectively at all timepoints. We evaluated whether this T cell defect affected both naive and memory compartments. Compared to healthy children, the fraction of CD4 cells with a naive (CD45RA/CD62L) phenotype was markedly reduced (77% of patients with <10th %ile values). Consistent with the reduction in naive T cells, thymopoiesis (measured by TREC levels) was significantly lower in ALL patients than in normal controls (p<0.0001). In contrast, the proportion of CD4 cells with a memory phenotype was elevated, and 60% of children had CD45RO% greater than 90th %ile for age. To confirm that this represented preservation of bona fide T cell memory, we studied functional T cell memory in vitro and in vivo. T cell responses to vaccine Ags administered prior to ALL therapy were measured in a sub-set of 10 patients using a novel CFSE-based assay. Proliferation to the vaccine Ags Tetanus and Varicella Zoster Virus was significantly higher in patients than in pediatric controls (p<0.05), suggesting that memory T cells specific for previously-encountered Ags were enriched in the T cell pool. As an in vivo measure of immunity we recorded the frequency of serious infections (positive blood culture or PCP infection). Despite profound T cell lymphopenia, the rate of infection following induction was low at 0.14 infections/patient-year, suggesting that pathogen-specific immunity was largely maintained. We demonstrate that naive and memory T cells show differential sensitivity to CT. Naive T cells and/or thymocytes are most profoundly affected, while the memory T cell pool is relatively spared. Although persistence of T cell memory offers protection from previously encountered pathogens, without replenishment of the T cell pool with naive cells, response to new antigens is likely to be limited. Interventions that specifically protect thymopoiesis and/or naive T cells such as IL7, KGF or androgen inhibitors may lessen the impact of CT on the peripheral T cell pool and improve functional immunity in cancer patients.