IN THIS ISSUE. Collins et al' describe the results of' donor lymphocyte infusions (DLI) administered to 14() patients who had relapsed after allogeneic bone marrow transplantation (BMT) for a variety of hematologic malignancies. Their survey of 25 North American transplant centers confirms the findings presented in scattered reports over the past 6 years from a number of' individual centers. namely. that donor Iymphocyte infusions can induce remissions in the majority of patients with chronic myelooenous leukemia (CML) with evidence of cytogenetic or hematologic relapse after BMT. Response of other hematologic malignancies to DLI were decidedly less frequent. but did occur nonetheless. The encouraging results cited in this and other reports invite further investigation. which opens the door to multiple areas of inquiry.
The investigators noted that the development of graft-versus-host-disease (GVHD) appeared to correlate with response to DLI. What is perhaps more interesting are those patients in whom responses occurred in the absence of detectable GVHD, which supports the notion that graft-versus-leukemia (GVL) activity can be generated in the absence of GVHD. Several groups have tried to limit the incidence and severity of DLI-induced GVHD by either reducing the number of T cells infused (by as much as a log) or by selectively depleting certain T-cell subsets (CD8+ cells) postulated to mediate GVHD. In preliminary reports, both these approaches appear to be effective in inducing a significant number of antileukemic responses with a low incidence of GVHD. These observations should help form the framework of future trials designed to separate GVL from GVHD. which, if successful. could dramatically reduce the risk of allogeneic marrow transplantation.
The mechanism that underlies the response to DLI remains unexplained. What is the target antigen against which these donor lymphocytes are directed'? It is possible that the effector cells recognize and react against specific cell- surface tumor antigens. The differential expression of these putative antigens may underlie the discrepancy in sensitivity of various hematologic malignancies to DLI. On the other hand. it may be that antitumor effects of DLI are mediated. not through the specific cytotoxic activity of effector cells directed against particular antigens on leukemic progenitors, but rather as a secondary consequence of the elaboration of cytokines and cellular mediators gene rated during an al logeneic graft-versus-host reaction initiated by donor lymphocytes. Exactly what effector c ells (CD4+ T cells, CD8+ T cells. natural killer (NK) cells. anti gen-presenting cells. and so on) are necessary to initiate or mediate these phenomena is not certain ,, but current investigations into the infusion of' specific cellular subsets may help elucidate the answer.
As important as unraveling the mechanism througl which DLI induces remissions is understanding mechanisms of resistance to its effects Not all patients With stable-phase CML respond to DLI. and the number of' patients with advanced CML acute leukemia. Iymphoma, and myelodysplasia. who achieve a remission with DLI after a post-BMT relapse ranges from () to 50% Indeed, if specific cell-surface tumor antigens trigger response to DLI. decreased or absent expression of these target structures could snake effector cells indifferent to the tumor cells. Such a loss of expression could occur through modulation of antigen off the cell surface or through decreased production/membrane transport of' these antigens to the surface. Another potential mechanism of resistance to DLI could involve the induction of tolerance. Patients who relapse post-BMT may do so despite the persistent presence of T lymphocytes derived from the donor marrow infusion: yet these same patients can achieve a complete response after subsequent Iymphocyte infusions from that original donor. Either the critical T-cell effectors from the original marrow infusion that are capable of suppressing the malignant clone have been "lost" through some unknown mechanism or they have been tolerated in vivo to allow ultimate outgrowth of tumor cells. Such a process could conceivably involve defects in the capacity of antigen-presenting ceils to provide costimulatory signals to effector T cells in the presence of antigen. It is noteworthy that several secondary relapses have been noted in patients who had achieved a complete response to DLI. which suggests that the long term durability of all these observed responses remains in question.
Although the IQW response rate of acute leukemia:' and Iymphoma to DLI may be somewhat discouraging the fact that some patients did respond opens the door to explore ways to improve results. In contrast to slable phase CML. a higher effector: target ratio may be needed to achieve significant responses with these tumors. Increasing the number of cells infused or cytoreducing the patient first with chemotherapy to decrease tumor burden may make DLI more effective in these settings. It has also been suvgested that DLI be used early after BMT for patients with evidence of minimal residual disease. As immunogenic tumor antigens can become better defined. it may he possible to immunize donors against pertinent targets anti then transfer a population of lymphocytes that are enriched for effector cells specific for these tumor targets. Lastly, the administration of cytokines that promote T-cell activation leg, interleukin (IL)-2, IL-nay increase the cytolytic activity of immune effector ;cells directed at tumor targets and may further enhance the efficacy of DLI.
The responses noted with DLI in patients who have relapsed after BMT raises the intriguing possibility of using this modality in patients without a prior marrow transplant. The success of such an approach would depend in part on whether or not the patient as host would reject - infused cells in the absence of prior ablative therapy.
Some degree of immune suppression of the recipient to prevent rejection of these donor cells is necessary, it may be possible to accomplish this with chemotherapy of only modest intensity, which will avoid myeloablative regimens and their potential for severe and possibly fatal organ toxicity. Such an approach, which currently is being evaluated in several centers, may facilitate transmission of GVL activity to patients for whom traditional allogeneic BMT would be contraindicated, perhaps because of advanced age or comorbid illness. The success of DLI also may open the door for treatment of certain solid tumors (ea. melanoma and renal cell carcinoma) that are susceptible to immunomodulatory therapy. However, caution must be exercised because it is possible that profound pancytopenia, a recognized consequence of DLI post-BMT, could occur, leaving the patient without endogenous stem cells for hematopoietic reconstitution.
The potential applications of DLI extend beyond the boundary of oncology. There already is evidence that lymphocytes that are cytotoxic for cytomegalovirus and Epstein-Barr virus can be transferred from donor to host, which could restore antiviral immunity and even eliminate potentially fatal diseases. such as posttransplant Iymphoproliferative disease." Transfer of CD4+ T cells and CD8+ cytotoxic effectors may be possible in patients who are infected with HIV in the treatment or prevention of recurrent infections.
The opportunities that the modality of donor Iymphocyte infusions provides are enormous Their mechanism of action must be dissected and understood so that they can be applied more widely to the treatment of cancer and infectious disease.
Robert I. Soiffer, Dana-Farber Cancer Institute, Harvard Medical School Boston, NM
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