Alfred Körfer

Chemoimmunotherapy of advanced malignant melanoma: sequential administration of subcutaneous interleukin-2 and interferon-α after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen

Both chemotherapy and interleukin-2 and/or interferon-alpha produce objective responses in a proportion of advanced malignant melanoma patients. While duration of response to chemotherapy is short, i.e. usually below 4 months, immunotherapy has resulted in a small number of long-lasting remissions in patients with metastatic melanoma. In two consecutive phase II trials in a total of 67 patients, we assessed the potential synergism between both modalities, i.e. chemo- and immunotherapy. Treatment consisted of intravenous (i.v.) carboplatin (CBDCA, 400 mg/m2) and dacarbazine (DTIC, 750 mg/m2) given twice (i.v. bolus over 30 min) at 3-week intervals, or 4 cycles of DTIC (220 mg/m2 i.v. 3 days), cisplatin (DDP, 35 mg/m2 i.v. 3 days), carmustine (BCNU, 150 mg/m2 i.v. cycles 1 and 3) and tamoxifen (TAM, 20 mg oral/daily) at 3-week intervals. Chemotherapy was followed by immunotherapy with combined subcutaneous (s.c.) interleukin-2 (rIL-2) and SC interferon-alpha 2 (rIFN-alpha). Among 40 patients who received a full cycle of chemotherapy with CBDCA/DTIC and sequential immunotherapy, there were 3 (7.5%) complete remissions (CRs) with a median duration of 19 months (range 13-26+). Partial remissions (PRs) were noted in 11 (27.5%) patients with a median response duration of 8 (range 5-14) months. Among 27 patients who received DTIC/DDP/BCNU/TAM and rIL-2/rIFN-alpha, there were 3 (11%) complete remissions and 12 (44.5%) partial remissions. Duration of complete and partial remissions ranged from 9+ to 13+ (median, 11+), and 5 to 15+ (median, 7+) months, respectively. Chemotherapy produced mostly moderate toxicity. Thrombocytopenia was common with the nadir after a median time of 18 days following start of CBDCA/DTIC and DTIC/DDP/BCNU, respectively. 10 patients required transfusion of thrombocytes. Nausea and vomiting due to chemotherapy were well tolerated using concomitant ondansetrone (8 mg i.v.). Immunotherapy was self-administered at home with mild to moderate side effects; malaise, fever, chills, nausea/vomiting, diarrhoea, anorexia and arthralgias were most frequent, but were spontaneously reversible after ending rIL-2/IFN-alpha. A mean 87 and 88% of the projected doses of rIL-2 and rIFN-alpha were administered on either protocol. There were no life-threatening complications and no treatment-related deaths. The sequential combination of chemotherapy and rIL-2 plus rIFN-alpha had at least additive therapeutic activity against metastatic malignant melanoma. The schedules produced long-lasting remissions and were tolerated well overall. These trials substantiate a potential role for low to intermediate dose immunotherapy in maintaining and consolidating therapeutic effects of chemotherapy in metastatic melanoma.

Expansion of Peripheral Blood Natural Killer Cells Correlates with Clinical Outcome in Cancer Patients Receiving Recombinant Subcutaneous lnterleukin-2 and Interferon-α-2

Natural killer (NK) cells are believed to contribute to the clinical efficacy of cancer immunotherapy using recombinant interleukin-2 (rIL-2) in humans. In previous trials of high-dose i.v. rIL-2, however, no correlation has been established between circulating NK cells and treatment response. Between January 1989 and October 1990, we treated a total of 47 outpatients with advanced tumors using low-dose s.c. rIL-2 and interferon-alpha-2 (rIFN-alpha). Therapy consisted of a 2-day rIL-2 pulse at 18 million IU/m2/day, followed by 6 weeks of rIL-2 (3.6 x 10(6)-4.8 x 10(6) IU/m2/day x 5 days/week) and rIFN-alpha (5 x 10(6)-6 x 10(6) U/m2 x 3/week). Before and after therapy, we phenotypically evaluated circulating lymphocytes and correlated them with clinical response. During 6-week therapy, peripheral blood lymphocytes bearing the CD56 (NK-cell-associated) surface antigen were increased significantly (p < or = 0.005) in treatment responders [complete response (CR) and partial response (PR), n = 10; 3.8-fold] and stable disease (SD) patients (n = 20; 2.1-fold), while patients with progressive disease (PD, n = 17) exhibited no significant expansion of circulating NK cells (p > 0.1). After one 6-week treatment cycle, CR/PR patients had significantly more peripheral NK cells, when compared with patients in SD (1.6-fold) and PD (1.9-fold) (p < 0.04). The overall number of circulating lymphocytes was also increased upon therapy (1.6-fold; p < or = 0.001), but remained independent of response (p > 0.4). These data demonstrate that s.c. rIL-2 and s.c. rIFN-alpha produce a significant increase in peripheral blood NK cells; this expansion correlates significantly with treatment response in advanced tumor patients receiving long-term combination immunotherapy at outpatient doses.

The development of neutralizing antibodies in a patient receiving subcutaneous recombinant and natural interleukin-2

Systemic administration of interleukin‐2 (IL‐2) in humans may induce antibodies specific to IL‐2. The case is reported of a patient with metastatic rectal carcinoma who was treated with long‐term subcutaneous IL‐2 and a combination of subcutaneous IL‐2 and interferon‐alpha 2b (IFN‐α 2b). This patient developed nonneutralizing and neutralizing anti‐IL‐2 antibodies recognizing both the recombinant and natural cytokine. Detectable serum levels of neutralizing antibodies were accompanied by the inhibition of immune responsiveness to systemic IL‐2 in vivo.

Low-Dose lnterleukin-2 in Combination with Interferon-α Effectively Modulates Biological Response in vivo

Phenotypic characterization of peripheral blood lymphocytes was performed in patients with advanced metastatic cancer receiving low-dose recombinant interleukin-2 (rIL-2) and recombinant interferon-α

Five-day 4′-(9-acridinylamino)methanesulphon-m-anisidide and intermediate-dose cytosine arabinoside in high-risk relapsing or refractory acute myeloid leukemia

SummaryTwenty-two patients with acute myeloid leukemia (AML), having a median age of 48.3 years (range 26–70; 10 male, 12 female), were treated with 4′-(9-acridinylamino)methanesulphon-m-anisidide (m-AMSA) 100 mg/m2 and cytosine arabinoside (AraC) 2×1000 mg/m2 i.v. on days 1–5. There were 2 M1, 8 M2, 9 M4, 2 M4 Eo, and 1 M5a. Of these, 12 achieved a complete remission, 3 a partial remission and 6 did not respond. The median remission duration was 9.0 months and the median overall survival 8.1 months. Side-effects of induction consisted mainly of haematological toxicity and infections with a median duration of WHO-grade-4 granulopenia and thrombopenia of 20 and 28 days respectively. Organ toxicity was mild with mucositis and cutaneous and liver toxicity being experienced by only a few patients. There was one treatment-related death. Five-day m-AMSA and intermediate-dose AraC is an easy-to-handle condensed treatment schedule with tolerable toxicity. Its effectiveness in relapsed and refractory AML is comparable to combinations of high-dose AraC with m-AMSA, anthracyclines or etoposide.

Treatment of High-Risk Relapsing or Refractory AML with M-AMSA and ID-ARAC

The prognosis of patients with refractory or relapsing acute myeloid leukemia (AML) is poor. Easy to handle treatment regimens with high effectivity and tolerable toxicity are warranted. High-dose cytosine arabinoside (HD ara-C) is effective in relapsing or resistant AML [1–9]. However, doses of 3000 mg/m2 ara-C are associated with significant mucositis, cutaneous, liver, and CNS toxicity. Pharmacological data indicate that intermediate doses of ara-C may be as effective as high doses [10]. The therapeutic effect of HD ara-C can be enhanced substantially by combination with anthracyclines [6, 11–17] but this may involve the risk of cumulative cardiotoxicity in heavily pretreated and elderly patients. The antineoplastic, DNA-topoisomerase II-reactive DNA intercalating acridine derivative 4′(9-acridinylamino) methanesulfon-m-anisidine (m-AMSA) is active in AML [18–25]. M-AMSA may be combined with ara-C without a significant negative effect on ara-CTP accumulation, elimination, or total intracellular exposure with ara-CTP [26]. As a single agent m-AMSA is as effective as HD ara-C [3]. In combination with conventional ara-C it is at least as effective as daunorubicin [27, 28]. Against this background we have studied a condensed 5-day combination of m-AMSA and intermediate-dose ara-C (ID ara-C) in a population of patients with high-risk AML.

Immunophenotypic Demonstration of Two Natural Killer Surface Markers, H25 and H366, on Fresh Human Leukemic Cells

Using a modified alkaline-phosphatase/antialkaline-phosphatase method for phenotyping fresh human leukemias, we could demonstrate peripheral blood and bone marrow-derived blast cells to specifically react with two monoclonal antibodies (MoAbs), H25 and H366, previously shown to recognize natural killer cells, activated T lymphocytes and a proportion of normal hematopoietic precursor cells. MoAbs H25 and H366 were found to identify the majority of leukemic cells in patients presenting with T-ALL, LGL leukemia, pre-B-ALL, CML, and AML, respectively.