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Clinical Trials |
Klinik I fuer Innere Medizin, Universitaet zu Koeln, 50924 Koeln, Germany [R. S., O. S., P. B., C. S., B. M., H. H., V. D., A. E.], and Cancer Immunobiology Center, The University of Texas, Southwestern Medical Center, Dallas, Texas 75235 [J. S., V. G., E. S. V.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The objectives of this Phase I trial were to determine the maximum tolerated dose, the dose-limiting toxicities, pharmacokinetics, and antitumor activity. Seventeen pts with relapsed CD30+ lymphoma were treated with escalating doses (5, 7.5, or 10 mg/m2/cycle) of the IT as four bolus infusions on days 1, 3, 5, and 7 for one to three cycles. All of the pts had progressive disease and were heavily pretreated. Nine had primary progressive disease and 14 had advanced disease with massive tumor burdens. The mean age was 35 years (24–52 years).
Peak serum concentrations of the intact IT varied from 0.23 to 1.1 µg/ml. Side effects and dose-limiting toxicities were related to vascular leak syndrome, i.e., decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. The maximum tolerated dose was 5 mg/m2. Seven of 17 (40%) pts made human antiricin antibodies (
1.0 µg/ml), and 1 pt developed human antimouse antibodies (1.0 µg/ml). Clinical response in the 15 evaluable pts included 1 partial remission, 1 minor response, and 2 stable diseases.
In conclusion, the IT was less well tolerated than other ITs of this type. This might be because of the low number of CD30+ peripheral blood mononuclear cells, and in part because of binding of the IT to soluble CD30 antigen and the resulting circulation of IT/sCD30 complexes.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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80% at present (1)
. However, 30–50% of pts in advanced stages at diagnosis will die from their disease (2)
. Data from other malignancies including myeloid leukemia (3)
and NHL (4)
indicate that small numbers of residual tumor cells, which remain after first-line treatment, are the major source of relapse. It has been demonstrated that residual tumor cells in Hodgkin’s pts can survive standard therapy and cause relapse (5
, 6)
. Thus, the elimination of minimal residual disease after first-line treatment might improve the outcome in pts with HL. Approaches to eradicate residual tumor cells include T-cell stimulation, vaccination, or selective destruction using MAbs or MAb-based immunoconjugates (7 , 8) . Because no effective naked MAbs against H-RS cells have been selected thus far (9) , ITs consisting of a specific cell-binding moiety and a potent toxin were constructed. For several reasons HL is an ideal disease for IT treatment. First, H-RS cells express surface antigens such as CD15 (10) , IRac (11) , CD25 (12) , CD30 (13) , CD40 (14) , and CD80 (B7-1) (15) . These antigens are present on a minority of normal human cells and not on stem cells. Second, the number of H-RS cells that must be killed is relatively small (<1% of lymphoid cells). Third, HL is well vascularized. Fourth, the mechanism of cell destruction by ITs is different from conventional agents, thus circumventing drug resistance. And lastly, ITs are capable of killing dormant nondividing cells.
The lymphoid activation markers CD25 and CD30 are selected targets for ITs in HL. Our group has tested MAbs available against these antigens for their ability to make effective dgA-ITs (16) . The ITs were constructed by linking the MAb via a sterically hindered linker to dgA. The potential efficacy of the most active dgA IT, RFT5.dgA (CD25), might be limited by low CD25 expression in refractory HL pts (17) . In contrast, the lymphocyte activation marker CD30 is expressed consistently and has been shown to be an excellent target for immunotherapy of human HL. The CD30 antigen was originally discovered on cultured H-RS cells using the MAb Ki-1 (18) . The naturally occurring CD30 ligand has been identified and cloned (19) . The CD30/CD30 ligand system triggers cytolytic cell death in malignant lymphoma cell lines and induces proliferation and cytokine production in T cells or neutrophils (20) . Normal human organs revealed no major cross-reactivity of the anti-CD30 MAbs. The most effective IT, Ki-4.dgA, was five times more potent in vitro compared with anti-CD30 dgA-ITs tested previously and demonstrated high efficacy in the treatment of disseminated human HL in SCID mice (21) . Thus, Ki-4.dgA was selected for a clinical Phase I trial in pts with refractory CD30+ HL and NHL.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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35%. In addition, >30% of the H-RS cells had to stain with the anti-CD30 MAb Ber-H2, which binds to the same antigen cluster as Ki-4. Exclusion criteria were uncontrollable infectious disease, collagen vascular disease, vasculitis, active second malignancy, chemotherapy or radiotherapy within 4 weeks, significant impairment of pulmonary function, granulocytes <1,500/µl, platelets <20,000/µl, or any other major organ dysfunction unrelated to lymphoma, pregnancy, and presence of antibodies against mouse immunoglobulin or dgA >1 µg/ml. Concomitant administration of steroids was permitted if pts had been treated with steroids for at least 4 weeks before enrollment. No change in steroid dose was allowed in pts who were evaluable for clinical response.
IT.
The IT Ki-4.dgA was prepared as described (22)
by coupling dgA (Inland Laboratories, Austin, TX) via the heterobifunctional cross-linker sterically hindered linker (Pierce, Rockford, IL) to the IgG1 murine MAb Ki-4, which recognizes the same cluster of epitopes (A) on the CD30 antigen as the MAbs Ber-H2 and HRS-3. The IT was formulated as a sterile solution containing 0.85% NaCl. Vials with 5 ml of IT at 0.5 mg/ml were frozen and maintained at -70°C. Before use, the IT was filtered through a 0.22-µm filter.
Protocol Design and Regimen.
Ki-4.dgA was administered i.v. in 100 ml of isotonic saline over 4 h. The calculated total dose of the IT for one cycle of treatment was divided every other day x 4. We planned to treat cohorts of three pts with escalating doses of 5, 10, 15, and 20 mg/m2/course. This regimen was chosen based on our experience in a recent Phase I trial with a very similar IT (RFT5.dgA) against CD25 (23)
. We added a 7.5 mg/m2 dose level because of high toxicity at the 10 mg/m2. Pts were not entered at the next higher level until all 3 of the pts in the previous cohort had completed study day 14. If 1 pt experienced grade 3 or 4 toxicity 3 additional pts were enrolled at this dose level. If 3 pts experienced grade 3 toxicities at one dose level, then the previous dose level was regarded as the MTD. If 2 pts at a dose level experienced a grade 3 toxicity and 1 pt at the next dose level a grade 4 toxicity, then the MTD was the dose at which the grade 3 toxicities occurred. If 1 pt experienced a grade 3 toxicity and another pt experienced a grade 4 toxicity at a dose level, then the previous dose level was defined as the MTD.
The study design was in accordance with the declaration of Helsinki. This trial was approved by the Ethical Committees at the University of Cologne and the IRB at the University of Texas, Southwestern Medical Center. Before treatment, all of the pts gave written informed consent.
Pathology and Eligibility.
Biopsies of peripheral lymph nodes or bone marrow were obtained to analyze the expression of CD30 (Ber-H2) using the antistreptavidin-biotin-complex method. Pts in whom biopsies or fine-needle aspiration did not yield sufficient material for quantification of CD30 expression on H-RS cells were enrolled without knowledge of the antigen distribution if the diagnosis of HL had been histologically proven within 12 months of study entry.
Assessment of Toxicity.
Adverse events were graded according to the WHO toxicity criteria as grade 1 (asymptomatic, easily tolerated), 2 (mild, tolerable), 3 (moderate, poorly tolerated), or 4 (severe, life threatening). VLS was specifically graded as described elsewhere (24)
. Briefly, grade I was defined as minimal ankle pitting edema, grade 2 as ankle pitting edema and weight gain <7 kg, grade 3 as peripheral edema and weight gain 7–14 kg or pleural effusion without pulmonary dysfunction, and grade 4 as anasarca, pleural effusion or ascites with respiratory deficit or edema >14 kg.
Pharmacokinetics.
To determine the highest levels of intact Ki-4.dgA in the peripheral blood of the pts, a RIA described previously was used (25)
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Flow Cytometry Analyses.
Blood counts, with differentiation and analysis of circulating lymphocyte subsets (FACScan; Becton Dickinson) were performed before treatment and on days 4, 9, and before the second cycle (CD3, CD4, CD8, CD16, CD19, CD25, and CD45RO).
Cytokines and Soluble Antigens.
The following serum cytokines and soluble antigens were analyzed by standard ELISA methods: sCD30 (Dako, Hamburg, Germany), sCD25, sIL-2, and sTNF-
(R & D Systems, Minneapolis, MN). Analyses were performed before commencing treatment and on study day 10 of each cycle. sCD30 levels were determined on study days 0, 1, 3, 6, and 10. To quantify levels of unbound sCD30 after treatment with Ki-4.dgA we used a modified Dako ELISA kit. This test system is based on plates coating with MAb Ki-1, which is directed against cluster B of the CD30 antigen, and using the peroxidase-conjugated MAb Ber-H2, which is directed against cluster A, which is also recognized by Ki-4. Thus, we performed an ELISA using the coating MAb Ki-1 and the peroxidase-conjugated MAb Ki-3, which binds to cluster C and does not interfere with Ki-4. One IU/ml of sCD30 is equivalent to 10–50 pg/ml.4
Detection of HAMA and HARA.
HAMA and HARA were measured as previously described (25)
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Evaluation of Response.
The staging procedure included clinical examination, routine blood analyses, chest X-ray, abdominal ultrasound, thoracal and abdominal computed tomography scans, electrocardiogram, echocardiogram, body plethysmography, and bone marrow biopsy. Clinical staging was performed according to the Ann Arbor system. Clinical status and laboratory parameters were assessed before each cycle. Additional tumor evaluations were performed 28–35 days after completion of treatment to document the duration of responses. Restaging, including computed tomography scans of involved areas, was performed after each second cycle. WHO criteria for response were used. CR was defined as the absence of any clinical or radiological evidence of active disease over a period of 4 weeks without the appearance of new lesions. A PR was defined as a 50% reduction in the sum of the products of the maximal and perpendicular diameters of all of the measurable lesions for at least 4 weeks; MR as a decrease of 25–50% of the measurable tumor mass for at least 4 weeks. SD was defined when the criteria of CR, PR, MR, or PD were not met. PD was defined as enlargement of measurable tumor volumes by >25% or appearance of any new lesion. A minimum of two cycles was required to evaluate treatment efficacy unless there was rapid progression. Responding pts were eligible for retreatment if they had <1 µg/ml HAMA and HARA before the next cycle of treatment.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Ten pts were male and 7 were female. The median age was 35 years (range, 24–52 years). Fourteen pts presented with advanced disease. Histopathology at first presentation was nodular sclerosis in most cases (14)
followed by each one case of mixed cellularity, large cell anaplastic lymphoma, and not classified. In each pt, lymph node biopsies showed a strong staining for CD30. Nine of 17 pts had primary PD. Most pts were heavily pretreated with an average of six different chemotherapies (range, 2–9) including high-dose chemotherapy and autologous bone-marrow transplantation in 13 of 17 pts. All of the pts had received prior radiotherapy. At study entry, the median performance status as measured by the Karnofsky index was 80 (range, 60–90).
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grade 2). At the 10 mg/m2 dose level the first pt experienced a grade 3 VLS and the second pt had a grade 3 VLS presenting with weakness, which was poorly tolerated. Accordingly, 3 additional pts were treated at the 5 mg/m2 dose, and none of these pts experienced a toxicity > grade 2. The first pt treated at 7.5 mg/m2 had a grade 4 myalgia with increase of creatinine kinase to 1200 units/liter (normal: <80 units/liter). Therefore, we decreased the dose level to 5 mg/m2 and treated another 3 pts at 5 mg/m2. The dose was tolerated well with only one grade 3 toxicity (myalgia). The next 5 pts receiving 7.5 mg/m2 had only mild treatment-related side effects except the last pt who experienced a grade 3 VLS. Thus, the MTD of Ki-4.dgA was 5 mg/m2.
Table 2
lists all of the adverse events according to standard WHO criteria. The most frequent side effects ( WHO grade 1) were tachycardia (17 of 17), VLS (16 of 17), hypotension (15 of 17), weakness/fatigue (15 of 17), myalgia (10 of 17), joint pain or diffuse pain (10 of 17), skin reaction including mild erythema and desquamation (10 of 17), fever (5 of 17), and nausea/vomiting (5 of 17). DLTs were VLS, myalgia, and fatigue.
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Flow Cytometric Analysis of Peripheral Blood Cells.
A variety of different antigens were analyzed on PBMCs (CD3, CD4, CD8, CD16, CD19, CD25, and CD45RO) without showing significant changes. Hematologic parameters (leukocytes, hemoglobin, and thrombocytes) were stable.
Cytokines and Soluble Antigens.
Table 3
summarizes the levels of cytokines (IL-2 and TNF-) and soluble antigens (sCD25 and sCD30) detected in the sera of the study pts. sCD30 (median, 101 units/ml; range, 0–623 units/ml) was detected in 16 pts and demonstrated increased levels at the end of treatment. Eight pts had serum levels below 100 units/ml. However, 24 h after start of IT treatment sCD30 was no longer detectable using the conventional Dako ELISA kit with the peroxidase-conjugated MAb Ber-H2, which is directed against the same CD30 cluster as Ki-4. In contrast, this effect was not observed when using a modified ELISA kit using the peroxidase-conjugated MAb Ki-3, which is directed against a distinct CD30 cluster (Fig. 1)
. Thus, sCD30 was noncompetitively targeted by Ki-4.dgA and persisted in the peripheral blood. All of the pts who had a less rapidly growing tumor before enrollment into the present study had concentrations of sCD30 <100 units/ml.
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IL-2 levels varied from 12 to 66 pg/ml (median, 33 pg/ml) before commencing of treatment (normal, 31 pg/ml) and was elevated in 12 pts. Changes during treatment did not correlate with clinical response. Increased TNF- levels (normal, 20 pg/ml) were detected in all of the pts (median, 49 pg/ml; range, 23–120 pg/ml) and were unrelated to the clinical course of the pts.
Development of HAMA and HARA.
Antibody response >1 µg/ml against the MAb or dgA developed in 7 pts. Six pts developed HARA, and 1 pt HAMA and HARA. Of 10 pts receiving two or more cycles of Ki-4.dgA, 60% had a significant HARA response, whereas only 10% made significant HAMA.
Clinical Response.
Of 15 pts evaluable for clinical responses, there was 1 PR, 1 MR, and 2 SDs. One pt at the 5 mg/m2 dose level achieved a PR lasting 5 months. This pt (no. 12) had stage IIA disease with small tumor masses (paratracheal, supraclavicular), which nearly completely disappeared. sCD25 level before treatment was 5344 units/ml and decreased to 2700 units/ml. The MR (pt 11) lasted 4 months. One pt (pt 4) had a regression of neurological symptoms for 3 weeks caused by intraspinal HL but no measurable tumor regression.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The toxicity profile, response rates, and Cmax of the IT used in the present trial are similar to these observed with other IgG.dgA-containing ITs against NHL and HL. However, toxicity observed occurred at a lower MTD compared with similar ITs. In Phase I/II trials reported previously using the anti-CD25 dgA IT RFT5.dgA in refractory HL pts with comparable demographs, the MTD was 15 mg/m2 (17 , 23) . Clinical responses in that trial included 2 PRs, 1 MR, and 3 SDs. The lower MTD of Ki-4.dgA might at least in part be because of the very low number of circulating CD30+ PBMCs. A strong inverse correlation between circulating tumor cells and toxicity has been reported in other trials (26) . On the other hand, binding of the IT to sCD30 and prolonged persistence of sCD30/IT complexes in the blood might also be a factor contributing to higher toxicity. In the RFT5.dgA trial with the higher MTD, binding of RFT5.dgA to sCD25 was not detected, but it bound to CD25+ PBMCs. Thus, before treatment with Ki-4.dgA it might be prudent to infuse the native MAb. Because metalloproteinases induce the shedding of CD30, the blockade by hydroxamic acid-based metalloproteinase inhibitors might also reduce toxicity.5 The moderate response rates in the trial reported here are comparable with those reported for RFT5.dgA and reflect the unfavorable pt selection in the present study. Most pts had advanced and highly active disease, which is reflected by the very high levels of sCD25 and sCD30. Both soluble antigens were lower in the trial performed with RFT5.dgA. The prognostic importance of high serum levels of sCD30 and sCD25, and the high risk of this group of end-stage pts is well documented (27, 28, 29, 30) .
In pts with relapsed NHL treated with the anti-CD22 A-chain IT, Fab'-RFB4.dgA, using an identical schedule (4-hour bolus infusion every second day over 7 days), 5 of 14 (36%) PRs were observed (25) . Using the IgG IT (IgG-RFB4-dgA) in a similar NHL pt group treated with the same dose regimen, 1 CR and 5 PRs (overall 25%) were reported in 24 evaluable pts (31) . In a subsequent Phase I trial, RFB4.dgA was given as continuous infusion over 8 days with comparable clinical results (4 of 18 PR, 22%) and toxicity (24) . In another trial using the anti-CD19 IT HD37.dgA, 1 CR and 1 PR occurred in 23 evaluable pts (overall 9%) on the bolus regimen (MTD, 16 mg/m2) compared with 1 PR (11%) in 9 pts treated with the continuous infusions (MTD, 19 mg/m2; Ref. 32 ). Peak serum concentrations of the IT at MTD were similar as well. However, bolus infusion is less expensive and more convenient. A recent analysis of all of the NHL pts treated in clinical Phase I/II protocols suggests that severe toxicity after treatment with dgA-containing ITs is more frequent at lower doses in pts with prior irradiation (33) . In these trials as well as in the present study DLT was related to VLS. In contrast to IT trials in NHL pts, we observed neither pulmonary edema nor aphasia related to VLS. Because 10 of 17 pts in our trial had pulmonary HL other reasons must be considered. The most obvious reason apart from the different histology is the younger age of pts enrolled in the present trial (35 years) compared with 49 to 60 years in the NHL trials. Thus, different symptoms of VLS might be more or less prevalent in pts of different ages. The symptoms related to VLS occurred at lower IT doses in the present trial as compared with similar trials in NHL. This might be related to the low number of CD30+ PBMCs and the lack of shed antigens such as CD19 and CD22 in NHL pts treated with ITs against CD19 or CD22, respectively. It has been suggested that VLS results from dgA-mediated damage of endothelial cells because of interference with fibronectin receptor-mediated binding (34) . The demonstration of a three amino acid sequence motif in ricin A-chain, IL-2, Pseudomonas exotoxin and diphtheria toxin as the binding site might allow the mutation or deletion of this sequence, and permit the administration of higher IT doses (35) .
The development of HAMA and HARA limits the number of courses of the IT (36) . In the present trial, 6 of 10 pts receiving more than one cycle of IT produced HARA > 1.0 µg/ml. One pt made HAMA after the first cycle. Development of neutralizing antibodies might be reduced by the use of humanized (37) or recombinant constructs with human ligands (38) or toxins (39) .
Falini et al. (40) constructed an anti-CD30 IT by coupling the MAb Ber-H2 to Saporin-S6, a single-chain ribosome-inactivating protein (type 1 RIP). In a clinical trial involving 4 pts with refractory HL, 0.2–0.8 mg/kg Ber-H2-Sap6 was administered in one or two infusions over 4 h. Significant reduction in tumor masses was observed in 3 of 4 pts. Toxicity included fever, malaise, anorexia, fatigue, mild myalgias, weight gain, and a reversible 4–5-fold increase in liver enzymes. Eight pts were subsequently enrolled (41) ; thus, 12 pts have been treated overall. Of these, 4 achieved PRs, and 3 experienced MRs with a rather short median duration of 2 months. In this trial binding of Ber-H2-Sap6 to sCD30 was not analyzed.
Future strategies in the use of ITs could include IT "mixtures," i.e., a combination of MAb-based constructs directed against different antigens on a tumor cell. A mixture of two or more ITs against different antigens (CD25, CD30, IRac) on H-RS cells had superior effects in vitro and in nude mice when compared with the application of single ITs (42) . Similar results were reported against Daudi lymphoma cells in vitro and in SCID mice (43) . This led to a study in which 22 pts with refractory NHL were treated with a continuous infusion of a combination of IgG-HD37.dgA and IgG-RFB4.dgA at doses of 10 to 30 mg/m2 (MTD 10 mg/m2). Two PRs (9%) and 5 MRs were reported (26) . Another approach might be the use of recombinant constructs. In a clinical Phase I trial using the anti-CD25 rIT anti-Tac(Fv)-PE38 (LMB-2) 11 refractory HD pts were treated with doses of 2–63 µg/kg i.v. on alternate days for three doses (44) . The MTD was 40 µg/kg with transient transaminase elevations and fever. Five of 11 pts made HAMA and 7 of 11 pts made antibodies against PE38. Responses include 1 PR, 3 MR, and 6 SD. Our group generated recombinant anti-CD25 and anti-CD30 ITs, which have shown high efficacy in vitro and in SCID mice bearing human Hodgkin tumors (45, 46, 47) .
In conclusion, Ki-4.dgA given to pts with resistant HL had a low MTD and demonstrated only moderate efficacy. The higher toxicity might be because of the low number of circulating CD30+ PBMCs and the formation of sCD30/IT complexes, which could have exacerbated side effects. Thus, before IT treatment directed against CD30 one should explore the use of the native MAb. It is also possible that the modification of the toxin subunit might reduce side effects. Because clinical experience with ITs in advanced refractory HL is still very limited, future clinical trials should evaluate whether modified ITs can be validated in HL pts.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by the Deutsche Krebshilfe Grant 70-1913-En2. 
2 To whom requests for reprints should be addressed, at Klinik I fuer Innere Medizin, Universitaet zu Koeln, Labor fuer Immuntherapie, LFI, EB 4, R 703, Joseph-Stelzmann-Strabe 9, D-50924 Koeln, Germany. Phone: 49-221-478-5933; Fax: 49-221-478-3778; E-mail: a.engert{at}uni-koeln.de
3 The abbreviations used are: HL, Hodgkin’s lymphoma; CD, cluster of differentiation; Cmax, maximum concentration; CR, complete response; dgA, deglycosylated ricin A-chain; DLT, dose-limiting toxicity; HAMA, human antimouse antibody; HARA; human antiricin antibody; H-RS, Hodgkin/Reed-Sternberg; PD, progressive disease; IL-2, interleukin 2; IT, immunotoxin; MAb, monoclonal antibody; MR, minor response; MTD, maximum tolerated dose; NHL, non-Hodgkin’s lymphoma; PBMC, peripheral blood mononuclear cell; PR, partial remission; pt, patient; SCID, severe combined immunodeficiency; SD, stable disease; TNF-, tumor necrosis factor ; VLS, vascular leak syndrome.
4 H. Hansen, personal communication.
5 B. Matthey, H. P. Hansen, M. K. Tur, M. Huhn, H. Lemke, A. Engert, and S. Barth. The deleterious effects of a shedding-inducing recombinant anti-CD30 antibody fused to a deletion mutant of Pseudomonas exotoxin A in tumor-bearing SCID mice can significantly be reduced by addition of a specific metalloproteinase inhibitor, submitted for publication.
Received 8/24/01; revised 3/ 5/02; accepted 3/19/02.
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J. A. Francisco, C. G. Cerveny, D. L. Meyer, B. J. Mixan, K. Klussman, D. F. Chace, S. X. Rejniak, K. A. Gordon, R. DeBlanc, B. E. Toki, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity Blood, August 15, 2003; 102(4): 1458 - 1465. [Abstract] [Full Text] [PDF]
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 K. C.M. Straathof, C. M. Bollard, C. M. Rooney, and H. E. Heslop Immunotherapy for Epstein-Barr Virus-Associated Cancers in Children Oncologist, February 1, 2003; 8(1): 83 - 98. [Abstract] [Full Text] [PDF]
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P. Borchmann, R. Schnell, I. Fuss, O. Manzke, T. Davis, L. D. Lewis, D. Behnke, C. Wickenhauser, P. Schiller, V. Diehl, et al. Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma Blood, October 16, 2002; 100(9): 3101 - 3107. [Abstract] [Full Text] [PDF]
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