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Department of Medicine [F. H., C. R., W. J., S. T., G. H., A. S., S. B., M. P.] and Institute of Medical Biometrics, Epidemiology, and Medical Informatics [J. K.], Saarland University Medical School D-66421 Homburg, Germany; Unidade de Oncologia, VP-2755 Cascais Portugal [L. d. C.]; and Biotest Pharma A.G., VD-63303 Dreieich, Germany [M. K.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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receptor III (CD16), a trigger molecule on NK cells, the cross-linking of which results in the activation and specific lytic activity of NK cells against CD30+ tumor cells in vitro. Treatment of severe combined immunodeficient (SCID) mice carrying established Hodgkin’s tumors with this antibody and unstimulated human peripheral blood lymphocytes led to the complete disappearance of the tumors in vivo (2)
. In a first dose escalation study with HRS-3/A9 given four times as a 1-h infusion every other day, only mild to moderate side effects (mainly fever) were observed in about one third of patients at doses of up to 64 mg/m2; no higher dose was administered because of the limited amounts of BiMAb available. Antitumor activity in this first trial with a group of 15 patients with refractory and heavily pretreated HD was unequivocal with one CR and one PR (lasting 6 and 3 months, respectively) as well as three minor responses that lasted for 1–15 months. Neither a clear-cut dose-response or dose-toxicity relationship nor a single immunological parameter predictive for treatment outcome could be established in that study. The majority of patients developed human antimouse immunoglobulin antibodies, and retreatment with the BiMAb was prevented by allergic reactions in all five attempted cases (3
, 4)
. Based on these data, the objectives of a second trial with this BiMAb were the reassessment of the clinical efficacy in additional patients and the evaluation of a modified BiMAb application schedule with a prolonged infusion time designed to provide a higher antitumor efficacy and/or a better tolerance of retreatment attempts, respectively. Finally, because patients with advanced HD generally show a severe qualitative and quantitative immunosuppression, and because the number and degree of activation of NK cells are crucial for this immunotherapeutic approach, the influence of additional cytokine costimulation should be evaluated. We therefore decided to retreat those patients who achieved SD after the first course of CD16/CD30 BiMab with a second BiMAb course and concomitant IL-2 and GM-CSF application. The results of this second trial with the CD16/CD30 BiMAb confirm its activity in refractory HD, suggest an increased efficacy of this BiMAb in combination with cytokines, and show perspectives for the further development of this novel immunotherapeutic approach. |
PATIENTS AND METHODS |
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Patients.
Patients were eligible if they had histologically proven CD30+ HD at second or higher relapse or were refractory to at least two different standard polychemotherapy protocols and were judged not to be curable by radiotherapy alone. Further inclusion criteria were age of 18–60 years; Karnofsky performance status 
50%; measurable tumor; a minimum of 40 NK cells and 60 monocytes per microliter of peripheral blood (corresponding to 50% of the lower normal value), respectively; and patients should have never received any immunotherapy and should not have received chemotherapy or radiotherapy within 4 weeks before entering the trial. All patients gave written informed consent.
BiMAb Treatment.
HRS-3/A9 was produced under good manufacturing practice by Biotest Pharma GmbH (D-63276; Dreieich, Germany) and contained 95% intact murine IgG1 BiMAb. The treatment consisted of a total of four HRS-3/A9 i.v. infusions, each with an absolute BiMAb dose of 25 mg in 5% human albumin solution. Infusions were given either as continuous infusions over 24 h on 4 consecutive days or as a 1-h infusion every other day. Patients were assigned to treatment groups in the order of hospital admittance. Four to 5 weeks after the first BiMAb course, a restaging was performed that included the reevaluation of all tumor locations. Patients with progressive disease received no further treatment. In patients with an objective response, the application of another BiMAb course (four infusions, 25 mg each) without additional cytokines was attempted. Patients with SD received their second HRS-3/A9 course after pretreatment with IL-2 that was followed by GM-CSF. To this end, 9 x 106 IU of IL-2 (Proleukin; Chiron GmbH, Ratingen, Germany) were given daily s.c. for 7 days before and during the second BiMAb course. In addition, GM-CSF (Leucomax; Novartis Pharma GmbH, Nürnberg, Germany) was given for 5 days after the last BiMAb infusion at a dose of 300 µg/day s.c. Patients treated previously with continuous HRS-3/A9 infusions received additional courses of continuous infusion, whereas patients in the intermittent infusion group were retreated with a modified application schedule. This modified schedule consisted of a total infusion time of 2.5 h, with one-tenth of the BiMAb dose given during the first hour, four-tenths of the BiMAb dose given during the second hour, and five-tenths of the BiMAb dose given during the remaining 30 min.
Clinical Assessments.
Toxicity was evaluated using the National Cancer Institute CTC as described previously (5)
. The response criteria were defined as follows: (a) CR, disappearance of all known disease for at least 4 weeks; (b) PR, 50% reduction of total tumor size (as determined by the sum of the bidimensional products of all measurable tumor lesions) for at least 4 weeks and no appearance of new lesions or progression of any lesion; (c) SD, decrease of <50% or increase of <25% of total tumor size and no appearance of new lesions for at least 8 weeks; and (d) PD, increase of >25% in any measurable tumor lesion or appearance of new lesions.
Blood Counts, Lymphocyte Subsets, and NK Cell Activity.
Blood counts with differentiation (Coulter STKS) and analysis of circulating lymphocyte subsets (FACScan; Becton Dickinson) were performed before the start of the BiMAb infusions and 1 (end of intermittent infusion), 6, 12, 24, 36, 48, 60, 72, 84, 96 (end of continuous infusion), and 120 h thereafter. Antibodies used were FITC-conjugated anti-CD3, anti-CD4, and goat antimouse immunoglobulin and PE-conjugated anti-CD8, anti-CD16, anti-CD19, and anti-CD56 (all from Becton Dickinson, Heidelberg, Germany). NK cell-mediated cytotoxicity was measured before the first BiMAb infusion, after the last BiMAb infusion, and 4 weeks after the last BiMAb infusion, respectively, using the previously described modifications of time-resolved fluorometry (6)
. The NK-sensitive K562 cell line was used as target. E:T cell ratio was 25:1 with 1 x 104 Eu-labeled target cells and peripheral blood mononuclear cells as effector cells. After 4 h of culture at 37°C, 10 µl of supernatant were collected from each well, mixed with 100 µl of enhancement solution (Pharmacia, Freiburg, Germany), and counted in a time-resolved fluorometer (LKB Wallac, Turki, Finland) at 620 nm. Specific lysis was calculated as: (experimental release - spontaneous release)/(maximum release - spontaneous release) x 100%. Maximum release was determined by adding 2% Triton X-100 solution (Sigma Chemical Co., Deisenhofen, Germany) to labeled cells. Patient groups finally rated as responders, patients with SD, and patients with PD were compared with respect to log NK count before therapy, maximum proportion of NK cells with BiMAb bound during therapy (unlogarithmized values), and maximum NK cell activity in peripheral blood during therapy (unlogarithmized values), respectively, using a linear trend test within the simple ANOVA model.
HAMA and Serum Antibody Levels.
HAMA response to HRS-3/A9 was assayed as described previously (7)
with minor modifications. Briefly, ELISA plates were coated with BiMAb HRS-3/A9 (2 µg/ml, 50 µl/well) overnight at 4°C, nonspecific binding was blocked by 1.5% gelatin (w/v) in PBS at room temperature, dilutions of patient sera were incubated for 1 h at room temperature, and, after washing, 50 µl/well of a 1:5,000 diluted biotinylated goat antihuman IgG-F(ab')2 was added as the secondary antibody for 1 h at room temperature. After extensive washing, a 1:50,000 dilution of alkaline phosphatase-conjugated streptavidin (Boehringer Mannheim, Mannheim, Germany) was incubated for 15 min at room temperature (100 µl/well), and, after additional washing, the reaction product was developed using nitrophenylphosphate (Sigma Chemical Co.) as substrate, stopped with HCl, and read at 405 nm on an ELISA reader (Dynatech MR 4000). Samples were assessed as positive if their extinction was 1.5-fold the extinction of a pool of normal sera.
For evaluation of HRS-3/A9 serum concentrations, ELISA plates were coated with rabbit antimouse antibody (Z259 at 2 µg/ml overnight at 4°C; Dako, Hamburg, Germany); after blocking with 1.5% gelatin, 1:10 dilutions of patient sera from different time points after BiMAb infusion were incubated, a 1:1000 dilution of alkaline phosphatase-conjugated goat antimouse IgG-F(ab')2 (Coulter Immunotech, Hamburg, Germany) was added as secondary antibody, and the reaction was developed as described above. Serial dilutions of HRS-3/A9 served as controls to generate a concentration standard curve.
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RESULTS |
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. The median age of the 12 male and 4 female patients was 35 years (range, 20–45 years), and the median Karnofsky performance status was 80% (range, 60–100%). Thirteen of the 16 patients had stage IV disease, most of them had involvement of the lung or the liver. All patients were in second or higher relapse (median, third relapse) or refractory to at least two chemotherapy protocols. All patients had received extensive pretreatment with a median of 3 (range, 2–6) different previous chemotherapy regimens. In addition, all but two patients had previously undergone high-dose chemotherapy with autologous peripheral blood stem cell support, and all but one also had a history of extended-field radiotherapy.
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. After BiMAb infusion, regardless of the application schedule, no consistent changes in peripheral blood counts of any subpopulation including NK cells (Fig. 2)
and monocytes were observed. The maximal proportion of NK cells with bound HRS-3/A9 varied considerably between individuals, ranging from 6–100%, with a median of 16% (range, 16–100%) after intermittent infusion and 29% (range, 20–100%) after continuous infusion. In the group receiving intermittent BiMAb infusions, NK cell activity in the peripheral blood showed a tendency to increase at the end of the course with a median of 14.5% (range, 0–72%) specific lysis and a median of 19% (range, 5–76%) 4 weeks later compared with pretherapeutic levels (median, 7%; range, 0–26%). In the patients receiving continuous infusion, the respective figures were 16% (range, 1–94%), 12% (range, 0–56%), and 9.5% (range, 0–95%).
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. This quantitative rise was accompanied by a modest increase of NK cell activity from 10 ± 6% to 24 ± 11% specific lysis before and after IL-2. In addition, treatment with IL-2 also caused a considerable increase of CD4+ and CD8+ lymphocytes in the peripheral blood (data not shown).
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Clinical Response to Therapy.
All 16 patients are evaluable for response. The patients received a total of 27 BiMAb courses, including 6 courses with coadministration of cytokines. At reevaluation after the first treatment cycle, 2 PRs and 6 cases of SD were observed, whereas the disease in the remaining eight patients was progressive, and treatment was stopped. Both responders (patients 2 and 9) and (by mistake) the first patient with disease stabilization (patient 1) received further treatment with HRS-3/A9 without additional cytokines, whereas the other five patients with SD received the second BiMAb course after pretreatment with IL-2 followed by GM-CSF at the end of the cycle. After this additional treatment, two of the five patients with SD after the first course entered either a CR (patient 3) or a PR (patient 15), respectively. Therefore, the cumulative response rate to HRS-3/A9 treatment was 25%, with 1 CR lasting for 6 months and 3 PRs lasting for 3, 5, and 9 months, respectively. Three of the four objective responses occurred after BiMAb administration as a continuous infusion, whereas one of the four patients with objective response had received intermittent 1-h infusions. In addition, four disease stabilizations (after documented preceding PD) lasting for 3 to >6 months (the latter in a patient finally undergoing allogeneic bone marrow transplantation with a fatal outcome) were observed (Table 3
; Fig. 4
). With respect to the number of NK cells in peripheral blood before the start of the first treatment cycle, there was a trend toward higher NK cell counts in the four responders as compared with the four patients with SD and the eight nonresponders (P = 0.041). On average, NK cell counts were 2.04 times higher in responders than in patients with PD (95% CI, 1.08–3.85). Inversely, the maximum NK cell activity in peripheral blood measured during the first treatment cycle was higher in the group of patients with PD as compared to patients with SD and responders (P = 0.006). The group of patients with SD appeared to be more similar to the group of responders than to the group of patients with PD with respect to NK cell counts and activity. The maximum proportion of NK cells with BiMAb bound during therapy was not significantly different between groups (P = 0.6).
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DISCUSSION |
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An attractive approach to increase the antitumor efficacy of BiMAb therapy might be the concomitant application of cytokines to increase the amount and/or activation status of targeted effector cells. When designing the study, we were well aware of the fact that the application of IL-2 together with a NK cell-activating BiMAb is well founded both by in vitro and clinical evidence, whereas both the in vitro and in vivo data supporting a concomitant application of GM-CSF are less convincing. Long-term application of IL-2 as a continuous i.v. infusion at low doses leads to a steady increase of circulating NK cells in the peripheral blood. This increase might not be accompanied by considerable activation of the NK cells and occurrence of related side effects due to the preferential binding of IL-2 at low concentrations to the high affinity IL-2 receptor only (8 , 9) . We decided to add GM-CSF for the expansion and stimulation of neutrophils, which are all CD16+, and monocytes, of which a subpopulation is CD16+. GM-CSF has been reported to enhance IL-2-induced NK cell and lymphokine-activated killer cell activity (10 , 11) and counteract the inhibiting effects of monocytes on NK cell activity (10) . Moreover, GM-CSF may enhance antibody-dependent cellular cytotoxicity in several cell types and the generation and cytotoxicity of NK cells (12) . Finally, GM-CSF might augment the capacity of a particular CD16-expressing population of dendritic cells (M-DC8+) that are capable of inducing tumor antigen-specific T-cell activation, and might thus induce a consecutive active immune response against Hodgkin and Reed-Sternberg cells with bound anti-CD16/CD30 BiMAb (13) .
IL-2 for the expansion of NK cells was started 7 days before the injection of the NK cell-activating BiMAb. Otherwise, the sequence of the application of the two cytokines was mostly empiric and followed a report of a similar sequence given together with a monospecific monoclonal antibody for the treatment of colon cancer (14) .
The absolute peripheral blood counts for erythrocytes, thrombocytes, granulocytes, monocytes, and different lymphocyte subpopulations remained largely unaffected by the HRS-3/A9 treatment. Similarly, there were no significant differences between the two infusion schedule groups. This is somewhat contradictory to the results of a clinical trial (15) using another NK cell-activating BiMAb (anti-CD16/Her-2) for the treatment of Her-2/neu-overexpressing tumors, which showed a dose-limiting thrombocytopenia at much lower BiMAb doses (5 mg/m2) than used in our trials. Whereas the mechanisms causing this thrombocytopenia remain unclear, it might be relevant in this regard that the epitopes recognized by the CD16 epitope specificity of the BiMAb used by the other group and our group are different and do not overlap (2) .
The major objective of this second clinical trial with the NK cell-activating BiMAb HRS-3/A9 in heavily pretreated patients with HD was the reassessment of the clinical efficacy and low toxicity we had observed in our initial Phase I trial. Indeed, the toxicity proved again to be very low, with transient mild to moderate fever as the major side effect, which occurred in about one-third of the patients (i.e. 6 of 16 patients in this trial and 4 of 15 patients in the previous trial). Similarly, the antitumor activity observed in the first trial was confirmed, with 4 of 16 patients with CR/PR in this trial and 2 of 15 patients with CR/PR in the previous trial. By combining the data from both studies in which patient populations with very similar characteristics were included, the objective remission rate (CR + PR) for this immunotherapeutic approach in refractory HD was 19% (95% CI, 7–38%), and the overall response rate (including minor responses) was 29% (95% CI, 14–48%), with responses lasting between 1 and 15 months.
With respect to the different BiMAb application schedules (intermittent 1-h infusion versus continuous infusion), there was no difference in incidence and severity of side effects. The issue of whether the different application schedules do result in different response rates, as might be suggested when looking at the patients treated in this trial (three of four objective responses occurred after continuous infusion, and one of four objective responses occurred after intermittent infusion) remains merely speculative and must be answered by treating a larger number of patients. Nevertheless, a potential advantage of slower BiMAb infusion rates might be the possibility of repeated treatment cycles even in the presence of serum antibodies against the murine BiMAbs. This is suggested by the fact that a second treatment cycle had to be terminated prematurely due to systemic allergic reactions in all attempted cases in our previous study (3) , in which BiMAb infusions were given over the course of 1 h, whereas in this second study, a complete second BiMAb course could be administered without adverse reactions in eight of eight patients, and a third BiMAb cycle could be administered without adverse reactions in two of three patients, respectively, when intended, irrespective of IL-2 pretreatment (five of eight patients) or the presence of HAMA at the time of retreatment (three of eight patients). The observation that additional BiMAb courses could be given both by a continuous infusion schedule and by a modified intermittent infusion schedule (total application time of 2.5 h with only one-tenth of the total dose given during the first hour) might be explained by the possibility that by appearing gradually in the patients’ blood, the BiMAbs are able to complex with and neutralize humoral and cellular immune responses against the BiMAb induced by the first application.
Critical for any immunotherapeutic approach is the cytotoxic capacity of the effector cells. Like others before us (16) , we observed a pronounced quantitative and qualitative cellular immune deficiency in these patients with advanced HD. The deficiencies were least pronounced for NK cells, the most relevant lymphocyte population for treatment with HRS-3/A9. The numbers of circulating NK cells were mostly in the lower normal range and did not change significantly after BiMAb therapy, whereas the saturation of NK cells with HRS-3/A9 and spontaneous NK cell activity varied considerably between patients. By restricting the combined application of BiMAb and cytokines to those patients who received a second treatment cycle after achieving SD after the first BiMAb-only course, we intended to gain information on the effects of cytokines in combination with BiMAb. In the respective patients, IL-2 treatment was given at moderate doses daily s.c., which provides IL-2 serum levels comparable to a continuous i.v. infusion. In all five patients treated that way, at least a doubling of circulating NK cells was observed with a kinetic that suggested that a further expansion of NK cells might be achievable with a more prolonged IL-2 application schedule and at even lower doses, which might decrease the mild but unequivocal cytokine-related side effects observed in this study. In addition to NK cells and T cells, CD8+ lymphocytes in particular showed a comparable increase after IL-2 treatment (data not shown), making this approach also attractive for the intensification of immunotherapy approaches with T-lymphocyte-recruiting BiMAbs (17) . Clinically, two of five patients with previous SD who received this combined cytokine/BiMAb treatment and responded with an increase in peripheral blood NK cells had a conversion from SD into a CR and a PR, respectively. These two responses account for half of all objective remissions achieved in the 16 patients treated in this study. Although we cannot definitely exclude the possibility that the improved responses after the second BiMAb course might not have been due simply to the increased total dose of BiMAb these patients received, the latter is rather unlikely because we have never observed delayed responses in patients receiving only one BiMAb course or two BiMAb courses without cytokines. Rather, our results support the notion of an augmented antitumor efficacy of a NK cell-activating BiMAb treatment when combined with cytokines. Whether and to what extent GM-CSF contributed to these augmented antitumor effects can only be determined by additional properly designed trials.
A HAMA response against HRS-3/A9 occurred in 37.5% of our patients within 4 weeks after treatment. This is in line with incidences between 40% and 84% observed in other clinical trials with murine BiMAbs (18 , 19) and our previous study (46%; Ref. 4 ). We did not observe a correlation between the occurrence of HAMA and the BiMAb dose given or the application schedule in our studies. The clinical importance of the HAMA response is still under debate. In addition to possibly accelerated BiMAb elimination due to the formation of immune complexes with antimurine antibodies, neutralizing anti-idiotypic antibodies might inhibit the cytotoxic capacity of immune effector cells (20) . On the other hand, by inducing an anti-idiotypic cascade, BiMAb may lead to a vaccination against the corresponding tumor antigen (21) , and a longer survival for patients who developed high HAMA levels after BiMAb therapy has been described previously (22) . Whereas we could demonstrate the evolution of anti-idiotypic and anti-anti-idiotypic antibodies in HAMA-positive patients in our first trial (4) , we could not establish an association between HAMA induction and clinical response in our studies because all patients with objective remissions in the present trial were HAMA negative, whereas three of five responders in the first trial had developed HAMA.
To our knowledge, only one other clinical trial using IL-2 and a BiMAb has been published. Patients with renal cancer received high doses of IL-2 (18 x 106 IU daily, 5 days/week) for 4 weeks and the F(ab')2-BiMAb BIS-2 (anti-CD3/EGP-2) at increasing doses on days 8 and 22 or 23, respectively. Dose-limiting toxicities at 5 µg/kg BiMAb consisted of transient lymphopenia, chills, vasoconstriction, and dyspnea due to the consecutive release of cytokines by the preactivated lymphocytes. One PR lasting 6 months in a total of 14 treated patients has been observed (23) .
From our two clinical trials with murine tetradoma-derived BiMAb, it becomes evident that besides allergic reactions against murine antibodies, the major obstacle against a successful and widely applicable BiMAb therapy of this kind is the limited amount of available antibody. Therefore, antibody constructs with reduced immunogenicity and broad availability have to be designed, e.g., so-called diabodies or bispecific F(ab')2 fragments that are derived from chimeric or completely humanized antibody gene sequences (24 , 25) . We have recently succeeded in establishing the efficacy of such an anti-CD16/CD30 construct in a SCID mouse model (26) . The large-scale production of this construct is now underway, and we are confident that it will enable us to considerably improve the clinical efficacy of this novel treatment modality for HD by increasing the doses of BiMAb given and the number of treatment cycles.
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FOOTNOTES |
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1 Supported by Grants PF135/3-1 of the Deutsche Forschungsgemeinschaft and W5/93/PF 3 of the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung. 
2 F. H. and C. R. contributed equally to this work.
3 To whom requests for reprints should be addressed, at Medizinische Klinik I, Universität des Saarlandes, D-66421 Homburg, Germany. Phone: 49-6841-16-3002; Fax: 49-6841-16-3002; E-mail: inmpfr{at}med-rz.uni-sb.de
4 The abbreviations used are: BiMAb, bispecific monoclonal antibody; HAMA, human antimouse antibody; NK, natural killer; HD, Hodgkin’s disease; GM-CSF, granulocyte macrophage colony-stimulating factor; CR, complete remission; PR, partial remission; SD, stable disease; IL, interleukin; CTC, Common Toxicity Criteria; PD, progressive disease; CI, confidence interval.
Received 7/28/00; revised 1/24/01; accepted 1/25/01.
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RIII. Cancer Res., 55: 4586-4593, 1995.Commentary
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