Adoptive Immunotherapy

Khatri et al. demonstrated the striking temporal relationship between the endogenous expansion of a TCR Vfi-restricted, CD3+CD8+ population of MHC class I-restricted CTL and the regression of a monoclonal PTLD in a HSCT recipient. Unfortunately, the delay in recovery of such immune surveillance against transformed EBV-positive B cells results in the development of potentially fatal PTLD. T-cell immunotherapy has been reported to be efficacious in the management of PTLD in this setting.39 O'Reilly et al. reported on 18 HSCT patients with EBV-PTLD who were treated with nonspecific donor lymphocyte infusions (DLI): 16 of 18 patients experienced eradication of PTLD. However, only 10 survived in sustained CR and 3 patients died of GVHD, a major side effect of DLI.50 Attempts have been made to improve the efficacy and reduce the risk of GVHD by administering EBV-spe-cific CTLs.51 Rooney et al. detailed the outcome of 39 recipients of matched unrelated donor/partially mismatched related donor transplants who received prophylactic EBV-specific CTLs (EBVs-CTL). None of the treated HSCT recipients developed PTLD, whereas 7 of 61 controls not receiving such therapy developed PTLD.52

In the SOT setting, adoptive immunotherapy has also been evaluated on a limited basis. Nalesnick et al. reported the experience of seven SOT recipients with PTLD; peripheral blood mononuclear cells harvested from the patients were cultured with interleukin-2 (IL-2). The infusion of these lymphokine-activated killer cells into the four patients with EBV-positive tumors resulted in sustained involution of their tumors. Unfortunately, two patients suffered organ rejection.53 Haque et al. reported their experience with three SOT patients whose EBV-specific cells lines were cultured from autologous T cells collected prior to transplant; the prophylactic infusion of these cells after transplant resulted in the suppression of circulating EBV-DNA levels to below pretansplant levels. Interestingly, the EBV-specific CTLs were measurable in the patients' blood for 3 months posttransplant.54 Finally, a phase 1/2 trial with eight SOT patients who had progressive PTLD unresponsive to conventional treatment were given infusions of partly HLA-matched allogeneic EBV-specific CTLs from a frozen bank of CTLs derived from healthy blood donors. Three of the five patients who completed treatment achieved a complete remission, and the EBV load in their peripheral blood fell to undetectable levels in all patients who responded to treatment; no GVHD developed and graft function improved in three cases.55 It was noted that tumor responses were mainly seen in those with early, localized, polyclonal disease.

EBVs-CTL therapy may not find widespread use for several reasons: it requires 2-3 weeks to generate such cells, the technology for larger scale expansion of EBV-CTLs is expensive, such technology is not available in every transplant center, and this approach is not effective in patients who develop EBV deletion mutants.11

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