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© 1999 American Society for Clinical Oncology Graft-Versus-Tumor Induction With Donor Leukocyte Infusions as Primary Therapy for Patients With MalignanciesFrom the Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Medical Center, and Department of Pathology and Laboratory Medicine and Molecular Diagnostic Core Facility, University of Pennsylvania Cancer Center, Philadelphia, PA, and Department of Adult Oncology, Dana-Farber/Partners Cancer Care, and Department of Pathology, Massachusetts General Hospital, Boston, MA. Address reprint requests to David L. Porter, MD, Division of Hematology-Oncology, 16 Penn Tower, 3400 Spruce St, University of Pennsylvania Medical Center, Philadelphia, PA 19104; email dlporter{at}mail.med.upenn.edu
PURPOSE: Histocompatible allogeneic donor leukocyte infusions (DLIs) were administered as primary cancer therapy in a phase I trial to determine (1) whether mixed chimerism could be detected without a prior allogeneic transplantation, (2) the toxicity of primary DLI, and (3) whether a graft-versus-tumor (GVT) reaction could be observed. PATIENTS AND METHODS: Eighteen patients were studied. Patients received interferon alfa-2b for a minimum of 4 weeks, followed by DLI (level 1). Patients with no toxicity or engraftment were eligible to receive cytarabine or cyclophosphamide followed by another course of DLI (level 2). Engraftment was determined using polymerase chain reaction amplification of donor and host-specific DNA polymorphisms. RESULTS: Donor cells were detected in the blood in 14 of 16 assessable patients within 1 hour of DLI. Chimerism detectable 4 weeks after DLI was observed in four patients, and five patients were not assessable. Prior autologous transplantation was associated with late chimerism (P = .0014). Acute graft-versus-host disease (GVHD) occurred in four of 16 assessable patients (grade 1, two patients; grade 2, one patient; grade 4, one patient). One patient with grade 4 acute GVHD developed pancytopenia. Only the four patients treated after prior autologous transplantation developed acute GVHD (P = .0005). Three of four patients with acute GVHD and late chimerism responded to primary DLI, and one patient was not assessable for response. CONCLUSION: Allogeneic adoptive immunotherapy resulted in sustained chimerism, acute GVHD, and a GVT response in heavily pretreated patients. This indicates that it may be possible to generate a direct GVT response for patients with malignancies without the need for intensive conditioning therapy immediately before DLI. Immunosuppression may be required for sustained donor cell engraftment.
THE ANTITUMOR potential of allogeneic leukocytes is well documented in animal models1,2 and in clinical hematopoietic stem-cell transplantation.3,4 Indirect evidence supports the existence of this important "graft-versus-tumor" (GVT) reaction associated with allogeneic marrow grafting, including the following observations: (1) abrupt withdrawal of immunosuppression or a flare of acute graft-versus-host disease (GVHD) can re-establish complete remission in some patients with relapsed leukemia5-7; 2) the risk of leukemic relapse is higher for recipients of syngeneic marrow grafts compared with recipients of allogeneic grafts8; (3) GVHD after allogeneic transplantation may be protective against relapse3,9; and (4) T-cell depletion of an allogeneic donor graft results in an increased relapse rate, especially for patients with chronic myelogenous leukemia (CML).3,10 This implies that the GVT effect is, at least in part, mediated by donor T cells. These observations led to the hypothesis that the GVT response is mediated by immunologically competent donor cells and that these cells could be used therapeutically to induce a direct GVT reaction. Recently, evidence has accumulated confirming that donor leukocyte products can induce a direct GVT reaction; for patients who relapse with CML after allogeneic bone marrow transplantation (BMT), the infusion of unmodified donor leukocytes will induce complete remissions in 60% to 80% of patients.11-13 Similar therapy results in complete remissions for the majority of patients treated for posttransplantation B-cell lymphoproliferative disorders.14,15 Complete remissions also occur after donor leukocyte infusions (DLIs) in patients who relapse after allogeneic BMT with other hematologic malignancies, although complete remission rates are lower.12,13,16 The potency of the GVT effect is highlighted by the estimate that responding patients seem to have at least a 6-log reduction in tumor burden.17 It is possible that the GVT properties of donor leukocytes can be used for therapeutic benefit outside the setting of allogeneic transplantation. In allogeneic BMT, although the intensive conditioning regimen provides effective anticancer therapy, it is also immunosuppressive and enhances donor cell engraftment; it is not known whether this intensive immunosuppression is required for HLA-matched donor leukocyte engraftment. For instance, DLIs from HLA-matched siblings given for relapse after allogeneic BMT can result in a significant GVT response and sustained donor cell engraftment many months after BMT, even without the use of additional immunosuppression or conditioning therapy.11 Furthermore, transient engraftment, or engraftment of leukocyte subsets, may be sufficient to generate a GVT effect without the need for preinfusion myeloablation.
Therefore, because it is unclear that intensive immunosuppression is required to prevent immediate rejection, we performed a pilot trial to determine whether HLA-matched sibling DLI would result in stable chimerism and show evidence of antitumor efficacy as primary therapy for patients with various malignancies who have not had an allogeneic transplant. Patients were first pretreated with interferon alfa (IFN
Eligibility Criteria Patients between the ages of 18 and 72 years old were eligible if they had a malignancy that was incurable with standard therapies. All patients were required to have a healthy six-antigen HLA-matched sibling donor; HLA typing was performed by serologic typing for class I antigens and molecular DNA typing for class II antigens in all but one patient whose class II antigens were defined only by serologic studies. Other eligibility requirements included an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate kidney and liver function, and life expectancy of more than 3 months. Patients were not eligible if they were appropriate candidates for allogeneic BMT, if they had received immunotherapy within 3 months of study entry (with the exclusion of IFN  2b), or if they had received therapy for their disease within 4 weeks of study entry. Donors were eligible if they were between 16 and 72 years old with no contraindication for leukapheresis. Written informed consent was obtained from all patients and donors under the guidelines of the institutional review boards at the University of Pennsylvania and Brigham Women's Hospital.
Patient Characteristics
Adoptive Immunotherapy: Level 1
After a minimum of 4 weeks of IFN
Adoptive Immunotherapy: Level 2
Engraftment Analysis Samples were assayed for detectable donor DNA before and within 30 to 60 minutes after MNC infusions. Samples assayed immediately after MNC infusion were scored as negative or positive for detectable donor cells ("early chimerism"). "Late chimerism" is defined as detectable donor DNA from peripheral-blood samples detectable more than 4 weeks after the final MNC infusion.
Evaluation of Patient Response
Data Analysis
Engraftment After therapy on treatment level 1, donor cells were detectable in the blood within an hour after MNC infusion in 14 of 16 assessable patients. There were no detectable cells immediately after infusion in two patients, and samples were not amplified in two patients because of technical difficulty. Results from the 16 patients with available engraftment data treated on level 1 are illustrated in Fig 2. Persistence of donor cells was documented at least 4 weeks after the final MNC infusion (late chimerism) in four patients; in each case, 1% to 5% donor DNA was identified. Late chimerism was not detected in nine patients, and five patients were not assessable for late chimerism (three patients died within 4 weeks of therapy, and engraftment data were not available for two patients because of technical difficulty). All four patients who had long-term chimerism were treated with primary adoptive immunotherapy for relapsed disease after autologous transplantation. No assessable patient who had not received high-dose therapy in the past (n = 10) had late engraftment after treatment level 1. A prior history of autologous transplantation was associated with a higher probability of late chimerism when compared with patients who had not undergone previous high-dose therapy in the 13 patients assessable for late engraftment (P = .0014). Six patients underwent treatment on level 2. Five of these patients had data assessable for engraftment (data not shown). All five patients had evidence of early chimerism. No late chimerism was noted in four patients; one patient had detectable donor cells 5 weeks after the final MNC infusion, but cells were no longer detectable 7 and 8 weeks after therapy.
GVHD and Pancytopenia All four patients treated for relapse after autologous transplantation developed acute GVHD (three after treatment level 1 and one after treatment level 2), and none of 12 assessable patients who did not have a prior autologous transplant experienced GVHD (P = .0005). Two patients died before 15 days of follow-up and were not assessable for GVHD. GVHD was associated with a minor response in two patients and a complete response in one patient. The fourth patient (patient no. 4) was not assessable for response because of early death. Pancytopenia occurred in one patient (patient no. 4) treated with primary adoptive immunotherapy for Hodgkin's disease relapsed after autologous transplantation; his course is described below. He developed grade 4 acute GVHD associated with a hypocellular bone marrow typical for "transfusion-associated GVHD.".22 The patient ultimately died of infectious complications and was not assessable for response to therapy. His clinical course is diagrammed in Fig 3.
Response to Level 1
Responses were observed in three patients. One patient (patient no. 3) with refractory myeloma had a 20% decrease in a large chest wall plasmacytoma and a decrease of 50% in the serum monoclonal protein concentration over the 3 weeks after development of grade 1 acute GVHD. Ultimately, his disease progressed and he died of complications related to myeloma. One patient (patient no. 15) with Hodgkin's disease had regression of several right-sided lung nodules in the setting of grade 2 acute GVHD (Fig 4); unfortunately, he died shortly after MNC infusions from infectious complications related to left-sided obstructive pneumonia. Patient no. 14, with relapsed Hodgkin's disease, had transient improvement in several pulmonary nodules but later developed progressive disease. This patient was then treated on treatment level 2 and had a complete remission. Representative case reports are described below.
Response to Level 2 No patient experienced long-term chimerism or aplasia after a second course of DLI, and four patients had progressive disease 8 to 10 weeks after the final infusion. One patient with relapsed Hodgkin's disease who had progressed after a transient response to level 1 developed grade 1 acute GVHD, responded to therapy, and remains free of disease 34 weeks after the final infusion (see below). One patient treated for chronic phase CML is alive 20 weeks after treatment on level 2 (69 weeks after DLI on level 1) with stable disease.
Case Reports On day 65, a right lower lobe nodule had increased in size, and on day 101 after the first MNC infusion, he was started on treatment level 2. He received cyclophosphamide (500 mg/m2) and 2.08 x 108 MNCs/kg in four doses over 9 days. Donor cells were only detectable immediately after infusions (early chimerism), but late chimerism was not identified. Thirty-seven days after DLI on level 2, there was complete resolution of his pulmonary nodule. On day 43 of treatment level 2, he developed a pruritic rash on his hands, feet, and back. Histologic examination of a skin biopsy confirmed the clinical impression of grade 1 acute GVHD. There were no manifestations of liver or gastrointestinal involvement, and by day 110, the rash had spontaneously resolved without therapy. CT scans performed on days 59, 110, 139, 197, and 239 continue to show no evidence of disease.
Patient no. 15.
A 22-year-old man had a relapse of Hodgkin's disease 3 months after an autologous stem-cell transplant that was conditioned with carmustine, cyclophosphamide, and etoposide. After 3 weeks of IFN On day 23, he developed a pruritic skin rash that progressed to involve more than 80% of his body surface area; the rash was clinically consistent with acute GVHD, and this diagnosis was supported with histologic examination of a skin biopsy. There were no liver or intestinal manifestations of GVHD (overall clinical grade 2 acute GVHD). Donor cells were detectable in the peripheral blood on day 25 (Fig 4B). A CT scan repeated on day 30 showed regression of several pulmonary nodules (Fig 4A, right panel). After the CT scan, high-dose corticosteroids were initiated for a severe rash and pruritus. Despite the improvement on CT scan, he suffered from an acute respiratory deterioration and died 1 week later, 5 weeks after DLI, from progressive infectious pneumonia. Molecular engraftment analysis confirmed the presence of donor DNA (1% to 5% donor cells) throughout follow-up, as seen in Figs 2 and 4B. He did not develop pancytopenia.
Patient no. 4.
A 39-year-old man developed recurrent Hodgkin's disease 6 months after autologous transplantation that was conditioned with carmustine, cyclophosphamide, and etoposide. After he had received IFN His clinical course is diagrammed in Fig 3. Eleven days after the first MNC infusion, he developed a skin rash that was clinically and histologically consistent with acute GVHD. His GVHD progressed and he was started on cyclosporine and high-dose corticosteroids on day 18 for grade 4 acute GVHD; he had more than 4 L of bloody diarrhea a day, a diffuse erythematous rash, and a rising bilirubin level that peaked at 12 mg/dL on day 25. Skin and esophageal biopsies were consistent with the diagnosis of acute GVHD. On day 19, his WBC began to drop and he was neutropenic and febrile by day 24. His bone marrow was hypocellular. Despite initiation of granulocyte colony-stimulating factor, on day 33 he became acutely short of breath and hypotensive. Although his WBC increased to 3.82 x 103/mL and his GVHD was improving, he died a short time later of antibiotic-resistant Pseudomonas sepsis. The response of his Hodgkin's disease was not known and an autopsy was declined.
Patient no. 3.
A 60-year-old man was treated with high-dose melphalan and total-body irradiation followed by autologous stem-cell transplantation for relapsed myeloma. He received maintenance therapy after transplantation with IFN
The GVT activity of allogeneic marrow grafts is well established in both animal models1,23,24 and clinical transplantation3,9 as a critical component of the therapeutic benefits of allogeneic BMT. Indirect evidence has implicated donor T cells as primary mediators of the GVT effect associated with allogeneic BMT. For patients who relapse after allogeneic BMT, donor MNC infusions can induce a direct GVT reaction and re-establish complete remissions for the majority of patients with CML, as well as for many patients with diseases other than CML.12,13,25 Recent trials have attempted to capitalize on the benefits of the GVT effect and DLI by attempting transplantation using an attenuated conditioning regimen, with the hope that transplant-related toxicity can be ameliorated by, in essence, replacing some of the cytotoxic therapy with immunotherapy.26-28 However, to determine the degree of immunosuppression necessary to establish a graft, it was necessary to determine whether a conditioning regimen was necessary at all. Because of the potency of the GVT effect, it was therefore logical to attempt to use DLIs as primary therapy for patients who had not had an allogeneic transplant. In addition, although a potent GVT effect has been identified in patients with CML and, to a lesser degree, myeloma and acute leukemia, it is unclear whether a GVT response can be generated in patients with other malignancies, such as Hodgkin's disease, melanoma, renal cell carcinoma, or other tumors. A critical issue of this trial was whether histocompatible cells survive after infusion into an appropriate host who has not had an allogeneic BMT. Patients who undergo allogeneic BMT establish a state of mixed or complete chimerism through intensive immunosuppression. In the absence of transplant conditioning, it may be that infused donor cells are immediately rejected before a GVT response can be observed. On the other hand, it is possible that only transient engraftment is required if it were associated with an antitumor response. In contrast to allogeneic BMT, in which engraftment is essential, rejection of the donor cells after the antitumor effect would not have serious consequences and might be useful in avoiding chronic GVHD. In animal models, long-term engraftment is possible without myeloablation.29 In human recipients of random donor RBC transfusions, donor leukocytes can be detected in the circulation of immunocompetent recipients for more than 48 hours.30 These cells do not routinely result in transfusion-associated GVHD and are likely rejected within several days. Therefore, we hypothesized that HLA-matched sibling donor leukocytes would not be rapidly rejected by the host and therefore would be capable of tumor recognition, activation and expansion and mediation of an antitumor response. Our data show that HLA-matched donor leukocytes can be detected in the circulation of most recipients for at least several days. In the five patients with long-term chimerism (four patients after level 1 and one patient after level 2), donor cells were detectable 5 to 16 weeks after therapy. We could not determine whether a permanent chimeric state could be induced with primary adoptive immunotherapy. It is also unknown whether this approach results in engraftment of all hematopoietic compartments; DNA was prepared for engraftment analysis in this study only from WBC fractions of peripheral blood. The kinetics of response and GVHD suggest that donor cells may survive below the limit of detection in some patients. In patient no. 3, detectable donor cells disappeared from the circulation shortly after infusion but were again detectable 83 days after DLI. This might reflect rapid clearance of mature cells followed by resurgence of cells derived from either T-cell progenitors of CD34+ cells in the infusion. Alternatively, donor cells present below the limit of detection may recognize alloantigens (and perhaps tumor-specific antigens); antigen recognition could then result in T-cell activation and proliferation until detectable levels were present, and clinical manifestations of GVHD and a GVT effect were evident. Delayed GVT and GVHD induction occurs with similar kinetics when DLI therapy is given to treat relapsed leukemia after allogeneic transplantation,11,12 suggesting that time is needed for the infused cells to be activated and expand to a clinically apparent level. Furthermore, it is not clear that detectable levels of donor cells are required for a response. In several animal species, irradiated human T-cell clones have induced antitumor responses, even when molecular analysis failed to demonstrate long-term donor cell survival.31,32 This implies either that the GVT effect occurred before donor cell rejection or that small numbers of donor cells, below the limit of detection by molecular analysis, may be sufficient to generate an antitumor reaction. In our study, one patient (patient no. 14) had a partial response after level 1 treatment with transient evidence of late engraftment at week 5; after treatment level 2, he had a complete remission and experienced grade 1 acute GVHD, yet no donor cells were detectable (sensitivity of detection, 0.5% to 1%). A second critical issue of this study was whether immunocompetent cells that were not rejected would cause severe GVHD. When "transfusion-associated GVHD" (TA-GVHD) develops outside the setting of BMT, mortality rates are high,22 primarily because of marrow aplasia. However TA-GVHD often results after transfusion of haploidentical cells of a homozygous donor into a heterozygous recipient22; in this study, donors and recipients were completely HLA-matched. In addition, GVHD that occurs when DLI is used to treat leukemic relapse after allogeneic BMT tends to be mild to moderate and responsive to immunosuppressive therapy.4 In other studies, donor leukocyte infusions from family members not fully HLA-matched have be given safely after autologous transplantation; it is not known whether, and for how long, these cells survive, but curiously they result in only mild GVHD.24 Haploidentical cells have been given in conjunction with cyclophosphamide to a small group of patients with various tumors as primary therapy without inducing GVHD, and resulted in a clinical response in one patient with lymphoma33; donor cell survival after 48 hours was not reported. An advantage of this trial was that if aplasia occurred, it could be reversed with marrow or CD34+ hematopoietic stem-cell infusions from the sibling donor. Prophylaxis for GVHD was not used in this trial because we hypothesized that GVHD caused by histocompatible donor cells would be less severe than TA-GVHD. As suspected, patients with evidence of late chimerism experienced GVHD; one patient with only transient molecular evidence of late chimerism also developed GVHD at a time when molecular studies could not detect donor cells. Acute GVHD developed within 3 weeks of DLI in two patients, 12 weeks after DLI in one patient, and 6 weeks after a second course of DLI (21 weeks after the first course of DLI) in the fourth patient. Three patients experienced grade 1-2 acute GVHD, and severe GVHD contributed to death in one patient, illustrating that GVHD may be quite severe in some circumstances. Two patients (patient nos. 3 and 15) had objective tumor responses concurrent with the development of acute GVHD. Four patients were treated for relapse after autologous transplantation. Three of these patients responded to primary adoptive immunotherapy and the fourth experienced grade 4 acute GVHD and pancytopenia and died from infectious complications before an antitumor response could be assessed. One of these patients remains in complete remission over 239 days after DLI. Late chimerism occurred in all four of these patients but was not noted in nine assessable patients assayed after treatment level 1 who did not have a prior autologous transplant (P = .0014). One patient with multiple myeloma had detectable donor cells 5 weeks after treatment level 2 but experienced no response or GVHD; donor cells were not detectable in this patient at 3, 7, or 8 weeks after DLI. These results suggest that patients who have been heavily pretreated and are therefore likely to be immunocompromised are most likely to engraft, develop GVHD, and exhibit a GVT response. Prior autologous transplantation likely results in prolonged immunosuppression, making these patients vulnerable to donor cell engraftment. This suggests that allogeneic donor cells can induce a direct GVT reaction but only if they engraft; preinfusion immunosuppression of the recipient may be critical for donor cell survival. In fact, it has recently been reported that sustained allogeneic hematopoietic engraftment can be achieved after immunosuppressive, but nonablative, conditioning therapy.26-28
IFN A third patient (patient no. 14) experienced a transient response after treatment level 1 and a complete response when treated on level 2. This patient developed evidence of mild GVHD after level 2 but at the time had no detectable donor cells in the peripheral blood. Low-dose cyclophosphamide (500 mg/m2) was used before MNC infusions in treatment level 2 for this patient in an effort to induce transient immune suppression and potentially enhance engraftment.34 It seems unlikely that the sustained complete response in this patient was achieved by treatment with low-dose cyclophosphamide alone. On the basis of trials using DLI to treat relapse after allogeneic BMT, we have shown that donor MNCs can be given safely as primary therapy to patients who have not had an allogeneic transplant. The case reports described above illustrate several important points: mixed chimerism can be established without resulting in the severe marrow aplasia often seen with TA-GVHD; low levels of mixed chimerism (1% to 5% donor MNCs) may be sufficient to achieve a response; MNC infusions can be given as primary therapy without resulting in severe GVHD in the majority of patients; and patients who are immunocompromised may be most likely to engraft, experience GVHD, and respond to GVT induction. However, sustained mixed chimerism was difficult to achieve in the absence of prior high-dose therapy. One patient died of treatment-related complications of GVHD and neutropenia, which indicates that this form of immunotherapy can result in serious complications similar to those observed in DLI administered after allogeneic marrow grafting. Several minor antitumor responses suggest that allogeneic cell therapy will have the potential to induce direct GVT reactions for patients with malignancies. It is also possible that the treatment will be more effective in patients with lower tumor burdens. These data also support the presence of a GVT effect directed against Hodgkin's lymphoma and multiple myeloma. Further trials of allogeneic cell therapy should concentrate on intensifying pretreatment immunosuppression and investigating expanded cell populations, which may provide a more intense GVT response.
Supported in part by an unrestricted grant from Integrated Therapeutics Group, Inc, Kenilworth, NJ. We thank Drs Lynn Schuchter, Selina Luger, and Edward Stadtmauer for their advice, referral, and care of several of these patients.
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ABSTRACT
INTRODUCTION
25% over original measurements or occurrence of new lesions). A minor response was defined as a decrease in measurable disease or index lesion (20% to 50%) that does not meet the above criteria. 
) represent time points with no detectable donor cells (negative chimerism), and a star (
) represents the occurrence of acute GVHD.
