|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology Phase I Trial of Concurrent Twice-Weekly Recombinant Human Interleukin-12 Plus Low-Dose IL-2 in Patients With Melanoma or Renal Cell Carcinoma
From the Division of Hematology/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA. Address reprint requests to Jared A. Gollob, MD, Duke University Medical Center, DUMC Box 3441, Durham, NC 27710; email: gollo001{at}mc.duke.edu.
Purpose: To maintain interferon gamma (IFN  ) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study. Patients and Methods: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12.
Results: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFN Conclusion: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12–responsive malignancies.
INTERLEUKIN-12 (IL-12) IS a cytokine that drives cell-mediated immune responses directed against infectious pathogens and tumors.1 IL-12 is active against a variety of solid tumors in mice2 and can eradicate established disease and prevent the development of metastases. Tumor regression mediated by IL-12 is dependent on interferon-gamma (IFN );3 the antitumor effect of IL-12 has also been variably linked to the activation of CD8+ T cells,2 natural killer (NK) cells, or V 24 NKT cells and to antiangiogenic effects mediated by IP-105 or by Fas-dependent endothelial cell apoptosis.6 Furthermore, there is evidence that the inhibition of angiogenesis by IL-12 is IFN-dependent.7
Despite the promising activity of single-agent IL-12 against B16F10 melanoma and Renca renal adenocarcinoma in mice,2 only five major responses have been observed among 157 patients with metastatic melanoma or renal cell cancer (RCC) treated on five published phase I trials using various doses and schedules of intravenous (IV) or subcutaneous (SC) recombinant human IL-12 (rhIL-12).8 The composite response rate of 3% is substantially less than the 15% to 20% response rate reported with high-dose IL-2 in these same malignancies.9,10 Although the reason for this disparity is not clear, those trials of rhIL-12 that have monitored in vivo immune activation have demonstrated that IFN
If IFN
Patient Selection All of the patients were adults with a histologically proven solid tumor that was metastatic or unresectable, and for which standard curative or palliative measures did not exist or were no longer effective. All of the patients had measurable disease. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate organ function defined by WBC more than 4,000/mL, platelet count more than 100,000/mL, creatinine less than 1.5 mg/dL, bilirubin less than 1.5 mg/dL, AST less than two times the upper limit of normal, and ECG without clinically significant abnormalities. Patients with more than two prior chemotherapy regimens, more than two prior immunotherapy regimens, rhIL-12 therapy within the past year, or IL-2 therapy within the past 6 months were ineligible.
Study Design
The treatment schedule is shown in Fig 1
Patients were evaluated for tumor response at the end of the first 6-week cycle; patients without progressive disease could receive additional cycles until there was no evidence of disease or until there was disease progression. A maximum of six cycles was allowed for patients whose best response was stable disease. For second and subsequent cycles, the IL-2 and rhIL-12 were administered together throughout each 6-week period. Patients were allowed up to a 2-week break between cycles for the resolution of any significant toxicity. At the first dose level, 300 ng/kg rhIL-12 was combined with 0.5 MU/m2 IL-2 (300/0.5 dose level). For all subsequent dose levels, the rhIL-12 was increased to 500 ng/kg, whereas the IL-2 was increased from 0.5 to 6.0 MU/m2 in successive cohorts of patients (500/0.5 to 500/6.0 dose levels, respectively). No intrapatient dose escalation was permitted. A minimum of three patients were enrolled at each dose level, and all of the patients had to have completed a full cycle of therapy without a dose-limiting toxicity (DLT) before another patient could start IL-2 at the next dose level. Toxicity was assessed using the National Cancer Institute common toxicity criteria. In general, grade 3 or greater toxicities were considered dose-limiting. However, liver function test (LFT) abnormalities were not classified as dose-limiting until the total bilirubin was more than three times normal or the hepatic AST, ALT, or alkaline phosphatase was more than 10 times normal. In addition, the WBC count and neutrophil count were not considered dose-limiting until criteria for grade 4 toxicity were met, and no degree of lymphopenia was dose-limiting. Grade 2 cardiovascular toxicity (except for hypotension) and grade 2 neurologic toxicity were considered dose-limiting. The rhIL-12 and then the IL-2 dose were escalated when zero of three patients at a dose level had a DLT. If one of three patients experienced a DLT, three more patients were enrolled at that dose level, and the dose was escalated if no more than one of six patients had a DLT. Beginning with the third cohort, the protocol was modified so that any patient who developed a DLT while receiving rhIL-12 alone during the first cycle did not count toward the enrollment for that cohort and did not constitute a DLT for that dose level of rhIL-12 + IL-2. Patients experiencing a DLT during treatment with rhIL-12 alone could resume the rhIL-12 at the 300-ng/kg dose level (or with a 50% reduction if already at that dose level) if the toxicity resolved within 2 weeks. Patients experiencing a DLT during treatment with rhIL-12 + IL-2 could resume the IL-2 at the preceding dose level (or with a 50% reduction if on the first dose level) and resume the rhIL-12 without a dose reduction if the toxicity resolved within 2 weeks. When two or more DLTs occurred during treatment with rhIL-12 + IL-2 at a dose level, the MTD was determined to be the previous dose level. All of the patients received ranitidine for the duration of their treatment. Acetaminophen and indomethacin were administered prophylactically for 48 hours after each rhIL-12 dose and could be taken as needed thereafter.
Assessment of Tumor Response
Measurement of Cytokines, Chemokines, and Soluble Fas Ligand (sFasL)
Analysis of Lymphocyte Subsets and Cytokine Receptor Expression
Statistical Methods
Patient Characteristics Between March 2000 and May 2002, 28 patients were enrolled onto this study. Patient characteristics are shown in Table 1  . The median age was 55 years, with the majority of patients having either melanoma or RCC. Six patients had no prior therapy for metastatic disease, whereas 12 patients had two or more prior therapies. Only five of 20 patients had experienced a major response to prior chemotherapy or immunotherapy. The majority of patients had metastases to only one or two sites, with the most common sites being lung, lymph nodes, and skin or soft tissue.
Treatment Administered and Toxicity Three patients were treated at the first dose level (300/0.5). Side effects during the first 2.5 weeks of treatment with rhIL-12 alone were predominantly grade 2 to 3 elevation of hepatic ALT or AST, grade 1 to 2 fever, grade 1 anemia, grade 1 fatigue, and grade 1 oral mucositis (Table 2 ). These toxicities diminished considerably by the start of week 2, and had largely resolved (except for the anemia) by week 3. The addition of IL-2 did not result in the recrudescence of these side effects. With the escalation of the rhIL-12 dose to 500 ng/kg at the next dose level, grade 2 LFT abnormalities and grade 3 to 4 leukopenia or neutropenia were more frequent but still resolved by weeks 2 to 3, and there was no recrudescence of these toxicities with the addition of 0.5 MU/m2 IL-2 at the end of week 3. None of the eight patients who went on to receive rhIL-12 together with IL-2 on the first two dose levels experienced a DLT. Four patients were treated at the third dose level with the 500/1.0 dose level. Although one patient required a dose reduction of the rhIL-12 because of a more than 10-fold increase in the hepatic ALT and AST after the second dose of rhIL-12, the overall toxicity was no greater than that observed at the previous dose level, and there were no DLTs after the addition of IL-2. The administration of multiple cycles without a break was not associated with any additive toxicity among patients treated on the first three cohorts, including one patient at the 500/1.0 dose level who received six cycles.
At the 500/3.0 dose level, the addition of IL-2 led to the recrudescence of fever and chills and oral mucositis, increased the severity of the anemia, and caused more fatigue (Table 2  ). These toxicities tended to persist through the end of cycle 1; however, with subsequent cycles, the fever and fatigue diminished and the mucositis resolved. Grade 1 to 2 nausea or vomiting occurred in approximately half of the patients, and orthostatic hypotension occurred in approximately one third of the patients, requiring oral antiemetics and, in some cases, IV fluid resuscitation. The addition of 3 MU/m2 of IL-2 caused only a minor elevation of the hepatic ALT and AST and did not induce neutropenia or thrombocytopenia. Reactions at the IL-2 injection sites consisted of erythema and induration that was minimally tender. During the dose escalation phase of the study, three patients were treated at the 500/3.0 dose level without a DLT. These patients each received three to four treatment cycles; multiple cycles were well tolerated, with no additive toxicity. At this dose level, cycles were often separated by breaks lasting 10 days to permit recovery from anemia. Although four patients were enrolled onto the highest dose level (500/6.0), one patient was removed from the study after developing grade 3 cardiac toxicity after the first dose of rhIL-12. This toxicity consisted of atrial fibrillation requiring medical intervention for rate control, and resolved without sequelae several days after the rhIL-12 was stopped. The addition of 6 MU/m2 IL-2 was poorly tolerated by the remaining three patients: one patient developed grade 4 elevation of hepatic ALT and AST and grade 3 hyperbilirubinemia 1.5 weeks after the addition of IL-2 to the rhIL-12; one patient developed grade 3 hypotension and fatigue requiring hospitalization midway through cycle 2; and the third patient had experienced treatment delays for grade 2 anemia, fatigue, cough and sore throat, and renal insufficiency that necessitated an IL-2 dose reduction. All grade 3 to 4 toxicities resolved within 1 to 2 weeks after therapy was stopped. The two DLTs at this dose level established 500/3.0 as the MTD for this schedule of rhIL-12 + IL-2. Eight additional patients were subsequently treated at the MTD on the safety phase of the study; there were no DLTs among these patients during the first cycle of therapy.
Modulation of rhIL-12-Induced IFN
The addition of 3 MU/m2 IL-2 at the end of week 3 (rhIL-12 dose 6) had a pronounced effect on IFN induction by rhIL-12, leading to a three-fold increase (P = .002) in the plasma IFN AUC relative to the last dose of rhIL-12 alone at the start of week 3 (Fig 2B, right). The same effect of IL-2 on rhIL-12–induced IFN production was observed at the start of week 6, demonstrating that IFN induction by rhIL-12 + IL-2 was more resistant to attenuation over a 3-week period than IFN induction by rhIL-12 alone. The kinetics of IFN induction were also altered by the addition of IL-2. As shown in Fig 2A, the IL-2 dose administered 1 hour before the rhIL-12 led to an earlier and more rapid increase in the plasma IFN concentration after the rhIL-12 dose, as well as a more rapid decrease compared with the pattern observed with rhIL-12 alone. The second SC IL-2 dose administered at +20 hours seemed to halt and start to reverse the decrease in plasma concentration 4 hours later. At the 500/6.0 dose level, the addition of 6 MU/m2 IL-2 resulted in a 3.5- to 4.5-fold increase in the IFN AUC compared to rhIL-12 dose 5 (Fig 2B, right panel). This effect was only modestly superior to that achieved with 3 MU/m2 IL-2, and the modulation in the kinetics of IFN induction by rhIL-12 was similar for 3 and 6 MU/m2 IL-2.
Overall, the pattern of IP-10 induction by rhIL-12 alone and by rhIL-12 + IL-2 resembled that of IFN
Induction of TNF- , sFasL, MIP-1a, and IL-10 by rhIL-12 and rhIL-12 + IL-2: Analysis at the MTDThe effect of IL-12 on TNF- , sFasL, and MIP-1 was modest compared with the effect of IL-12 on IFN, and relatively small increases in the plasma AUC were observed with the addition of IL-2 at the MTD (Fig 4). In patients receiving twice-weekly rhIL-12, only a modest amount of IL-10 (peak level approximately 50 pg/mL) was induced by the first dose, with no attenuation between doses 1 and 5. However, the first doses of 3 MU/m2 IL-2 augmented the IL-10 AUC two-fold at the end of week 3, and by the start of week 6 the effect of IL-2 was even more pronounced, with the IL-10 AUC augmented five-fold over baseline (Fig 4A; P = .04).
IL-2 Pharmacokinetics IL-2 was not detected in the plasma during the 24-hour period after the week 1 and week 3 doses of rhIL-12 alone. After the first dose of SC IL-2 at the end of week 3, IL-2 was detectable in the plasma 1 hour later, at the time the IV rhIL-12 was administered (data not shown). Levels were measured every 4 hours thereafter for 24 hours, and this process was repeated at the beginning of week 6. Plasma IL-2 peaked by 4 hours after the rhIL-12 dose and became undetectable by 8 to 12 hours after rhIL-12 with 0.5 to 1 MU/m2 IL-2 and by 16 to 20 hours with 3 to 6 MU/m2 IL-2. The administration of the +20-hour IL-2 dose resulted in the prompt recovery to peak levels within 4 hours. The peak concentrations of IL-2 in the plasma at the four dose levels were as follows: 0.5 MU/m2, 3.4 pM; 1 MU/m2, 9.5 pM; 3 MU/m2, 29 pM; and 6 MU/m2, 65 pM. There was a more than 50% decrease in peak levels and in the plasma IL-2 AUC during week 6 compared with week 3 at the 3- and 6-MU/m2 dose levels (data not shown).
Effects of rhIL-12 and rhIL-12 + IL-2 on T and NK Cells
Neither rhIL-12 nor rhIL-12 + IL-2 modulated the expression of CD69 or CD45RO on T cells, nor was there any detectable change in T and NK cell expression of L-selectin. There was no consistent or dramatic effect of rhIL-12 and IL-2 on the expression of IL-2 or IL-12 receptor subunits by either NK or T cells (data not shown).
Clinical Responses to rhIL-12 + IL-2
Tumor responses were observed in three patients with melanoma. One patient treated at the 500/0.5 dose level had a response in multiple skin metastases. This was documented pathologically with a tumor biopsy after cycle 1 showing replacement of the tumor by an extensive infiltrate of CD4+ and CD8+ T cells relative to a pretreatment biopsy (Fig 6
One patient with ocular melanoma and extensive hepatic metastases was treated at the 500/1.0 dose level and had stable disease through six cycles; he has remained progression-free 1 year after completing treatment. A patient with melanoma metastatic to the lungs who was treated at the MTD had stable disease for two cycles but was then removed from the study because of grade 3 lipase elevation that took more than 2 weeks to resolve.
In this report, we have shown for the first time that IL-12 and IL-2 can be administered concurrently with acceptable toxicity in patients with cancer. Although a few patients developed reversible DLTs during the early phase of treatment with twice-weekly IV rhIL-12 alone at a dose of 500 ng/kg, most tolerated it well and exhibited the expected attenuation of side effects by the third week of therapy. At the MTD, the primary toxicities resulting from the addition of IL-2 included exacerbation of rhIL-12–induced fever and chills, anemia, and fatigue. Additional toxicities that seemed unique to the combination itself included grade 1 to 2 nausea or vomiting and hypotension. Although rhIL-12 + IL-2 was a tolerable outpatient regimen at the MTD, the chronicity of the fatigue, anemia, and nausea or vomiting was difficult for some patients, leading to voluntary withdrawal from the trial after one cycle in two of 11 patients. In prior trials of rhIL-12, LFT abnormalities and oral mucositis were among the primary DLTs.8 At the MTD, the addition of IL-2 had surprisingly little adverse effect on the LFTs, WBC count, or incidence or severity of mucositis; this was likely the result of delaying the start of the IL-2 until the end of week 3. There were no clinically apparent autoimmune complications such as vitiligo or hypothyroidism that have been reported with IL-2,14 or agranulocytosis or hemolytic anemia that have been reported with IL-12.12,15
One of the primary goals of adding IL-2 to the twice-weekly schedule of rhIL-12 was to restore IFN
IL-12 is a weak inducer of TNF-
Treatment with rhIL-12 + IL-2 had a dramatic effect on the number of NK cells, leading to a three-fold expansion after the first cycle that was sustained in patients receiving subsequent cycles of therapy. It is likely that NK cell expansion was due to the combined effect of rhIL-12 + IL-2. This is supported by in vitro data showing that the addition of IL-12 to low concentrations of IL-2 augments the proliferative effect of IL-2 on NK cells.21 In contrast, the addition of IL-12 to high concentrations of IL-2 inhibits NK-cell proliferation21 and actually induces NK-cell apoptosis.22 This indicates that the strategy of adding low-dose IL-2 to rhIL-12 has two important advantages over the use of rhIL-12 or low-dose IL-2 alone. First, it permits the expansion of the entire NK-cell population. This is essential because the CD56dim NK cells have superior cytolytic activity compared with CD56bright NK cells and can mediate antibody-dependent cellular cytotoxicity through the expression of CD16. Second, it maximizes cytolytic activity and cytokine and chemokine production by the expanded NK cells, thereby increasing the ability of NK cells to kill tumors through direct cytotoxicity, through the recruitment of IFN
As anticipated by in vitro experiments,23 treatment with rhIL-12 + IL-2 did not lead to the expansion of CD4+ or CD8+ T cells in the peripheral blood, nor did it induce any discernible upregulation of T-cell activation markers such as CD25. However, the infiltration of cutaneous melanoma metastases by CD4+ and TIA-1+ CD8+ T cells in the patient whose lesions began to regress only after the addition of IL-2 indicates that T-cell activation was an important component of the antitumor effect of rhIL-12 + IL-2. Therefore, it is possible that relatively small numbers of T cells were activated either directly by rhIL-12 + IL-2 or indirectly by NK-cell–derived IFN
Among the 10 patients treated at the MTD who completed at least one full cycle and were assessable for response, there was only one major clinical response. The maintenance of IFN Although rhIL-12 alone has only modest activity in melanoma and RCC, promising results have been reported with the use of twice-weekly rhIL-12 in cutaneous T-cell lymphoma,24 non-Hodgkin’s lymphoma,25 and Kaposi’s sarcoma.26 In that context, the findings in this report, which show that low-dose IL-2 safely enhances and sustains immune activation by rhIL-12, provide a rationale for testing this regimen in those malignancies as well.
We thank the nursing staff on the General Clinical Research Center at Beth Israel Deaconess Medical Center (Boston, MA) for their expert and compassionate care of our patients.
Supported by National Institutes of Health (NIH) grant K23RR15541, the David A. Stulberg Career Investigator Award from the Kidney Cancer Association, NIH grant M01-RR01032, the Beth Israel Deaconess General Clinical Research Center, and by a grant from Chiron Corp.
1. Trinchieri G: Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridges innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251–276, 1995[Medline]
2. Brunda MJ, Luistro L, Warrier RR, et al: Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 178:1223–1230, 1993 3. Nastala CL, Edington HD, McKinney TG, et al: Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 153:1697–1706, 1994[Abstract]
4. Cui J, Shin T, Kawano T, et al: Requirement for Va14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623–1626, 1997 5. Coughlin CM, Salhany KE, Gee MS, et al: Tumor cell responses to IFN-gamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity 9:25–34, 1998[CrossRef][Medline] 6. Wigginton JM, Gruys E, Geiselhart L, et al: IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest 108:51–62, 2001[CrossRef][Medline]
7. Voest EE, Kenyon BM, O’Reilly MS, et al: Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87:581–586, 1995 8. Gollob JA, Mier JW, Atkins MB: Clinical use of systemic IL-12 therapy, in Giaccone G, Schilsky R, Sondel P (eds): Cancer Chemotherapy and Biologic Response Modifiers Annual (vol 19). Amsterdam, the Netherlands, Elsevier Science, 2001, pp 353–369
9. Atkins M, Lotze M, Dutcher J, et al: High-dose recombinant interleukin-2 therapy for metastatic melanoma: Analysis of 270 patients treated from 1985–1993. J Clin Oncol 17:2105–2116, 1999
10. Rosenberg SA, Yang JC, Topalian SL, et al: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271:907–913, 1994 11. Atkins M, Robertson M, Gordon M, et al: Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3:409–417, 1997[Abstract]
12. Gollob JA, Mier JW, Veenstra K, et al: Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: Ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6:1678–1692, 2000
13. Wigginton JM, Komschlies KL, Back TC, et al: Administration of interleukin 12 with pulse interleukin 2 and the rapid and complete eradication of murine renal carcinoma. J Natl Cancer Inst 88:38–43, 1996
14. Phan GQ, Attia P, Steinberg SM, et al: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477–3482, 2001 15. Gollob JA, Veenstra KG, Mier JW, et al: Agranulocytosis and hemolytic anemia in patients with renal cell cancer treated with interleukin-12. J Immunother 24:91–98, 2001[Medline] 16. Smith KA: Rational interleukin-2 therapy. Cancer J Sci Am 3:S137–S140, 1997
17. Cooper MA, Fehniger TA, Turner SC, et al: Human natural killer cells: A unique innate immunoregulatory role for the CD56(bright) subset. Blood 97:3146–3151, 2001
18. Mehrotra PT, Donnelly RP, Wong S, et al: Production of IL-10 by human natural killer cells stimulated with IL-2 and/or IL-12. J Immunol 160:2637–2644, 1998 19. Parato KG, Kumar A, Badley AD, et al: Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10. AIDS 16:1251–1256, 2002[CrossRef][Medline] 20. Ostensen ME, Thiele DL, Lipsky PE: Tumor necrosis factor-alpha enhances cytolytic activity of human natural killer cells. J Immunol 138:4185–4191, 1987[Abstract]
21. Robertson MJ, Soiffer RJ, Wolf SF, et al: Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): Cytolytic activity and proliferation of NK cells is differentially regulated by NKSF. J Exp Med 175:779–788, 1992
22. Ross ME, Caligiuri MA: Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. Blood 89:910–918, 1997 23. Gollob JA, Schnipper CP, Orsini E, et al: Characterization of a novel subset of CD8+ T cells that expands in patients receiving interleukin-12. J Clin Invest 102:561–575, 1998[Medline]
24. Rook AH, Wood GS, Yoo EK, et al: Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T cell responses. Blood 94:902–908, 1999
25. Ansell SM, Witzig TE, Kurtin PJ, et al: Phase I study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood 99:67–74, 2002 26. Pluda JM, Wyvill K, Little R, et al: A pilot/dose-finding study of interleukin 12 (IL-12) administered to patients with AIDS-associated Kaposi’s sarcoma (KS). Proc Am Soc Clin Oncol 18:547a, 1999 Submitted December 20, 2002; accepted April 4, 2003.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
