William H. West

Constant-Infusion Recombinant Interleukin-2 in Adoptive Immunotherapy of Advanced Cancer

Adoptive immunotherapy involving bolus-dose recombinant interleukin-2 (rIL-2) has been reported to induce tumor regression in some patients with cancer, but has been associated with severe fluid retention and cardiopulmonary stress. In an effort to preserve the efficacy but reduce the toxicity of this treatment, we used escalating doses of rIL-2 as a constant infusion rather than as a bolus dose. Forty-eight patients with advanced cancer received rIL-2 as a 24-hour infusion in five-day cycles separated by five-day periods of rest and leukapheresis. Eight patients were removed from the study before receiving cells activated in vitro. In the 40 who could be evaluated for their response, there were 13 partial responses (32.5 percent) and 2 minor responses. Partial responses were observed in Hodgkins disease (one of one), non-Hodgkins lymphoma (one of one), lung cancer (one of five), ovarian cancer (one of one), parotid cancer (one of two), renal cancer (three of six), and melanoma (five of ten). Responses were associated with a good performance status, a base-line lymphocyte count above 1400 per cubic millimeter, and an rIL-2-induced lymphocyte count of at least 6000. Optimal lymphocytosis required a priming dose of rIL-2 of 3 X 10(6) U per square meter of body-surface area per day, and 15 of 28 patients receiving this priming dose responded to treatment. A weight gain of more than 10 percent of total body weight (five patients) and dyspnea at rest (six patients) were unusual events restricted to patients with poorer pretreatment performance. We conclude that the administration of rIL-2 as a constant infusion may preserve the antineoplastic activity of adoptive immunotherapy while increasing the safety and comfort of patients.

Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial.

We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.

Continuous interleukin‐2 and tumor‐infiltrating lymphocytes as treatment of advanced melanoma. A national biotherapy study group trial

Melanoma metastases were harvested from 82 patients for the purpose of growing and expanding tumor‐infiltrating lymphocytes (TIL). Tumor tissue cell suspensions were incubated with interleukin‐2 (IL‐2), followed by repeated exposure to tumor antigen with or without OKT3 monoclonal antibody (MoAb). Initial growth success was achieved in 56 of 82 cultures (72%). Efforts were made to expand 26 of these 56 cultures for therapeutic TIL; 23 of 26 early cultures (88%) were successfully expanded for in vivo therapy. It took a mean of 78.5 ± 25.4 days to grow sufficient TIL for treatment. Therapy included cyclophosphamide (1 g/m2) on day 1, followed by a 96‐hour continuous infusion of IL‐2 (18 × 106 IU/m2/d) on days 2 to 5, and approximately 1011 (mean 1.49 ± 0.93 × 1011) TIL on day 2. Patients who responded received monthly IL‐2 as a 96‐hour infusion. Median patient age was 45 years of age. Sixty‐seven percent of the patients were men. Performance status was 0 to 1 in 77% of patients. Thirty‐four percent of the patients had liver metastases. The usual IL‐2 toxicities were seen. Response rate for 21 patients was 24% (95% confidence interval, 10% to 49%). One complete response was achieved with cells 98% CD4+; four partial responses were achieved with cells 80%, 94%, 98%, and 98% CD8+, respectively. Four of eight patients who received TIL, which had never been stimulated with OKT3, had tumor response. The authors conclude that a treatment plan for IL‐2/TIL is technically difficult, costly, and effective for only a minority of patients. Overall, clinical results are not clearly superior to those obtained with other IL‐2 regimens.

Randomized Trial of Filgrastim, Sargramostim, or Sequential Sargramostim and Filgrastim After Myelosuppressive Chemotherapy for the Harvesting of Peripheral-Blood Stem Cells

PURPOSE The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34(+) cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC). PATIENTS AND METHODS One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81). RESULTS Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 x 10(9)/L or greater (a median of 11 v 14 days; P =. 0001), with fewer patients requiring RBC transfusions (P =.008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P =.013), and less intravenous antibiotic therapy (24% v 69%; P =.001). Patients who received filgrastim yielded more CD34(+) cells (median, 7.1 v 2.0 x 10(6)/kg/apheresis; P =.0001), and a higher fraction achieved 2.5 x 10(6) (94% v 78%; P =.021) and 5 x 10(6) (88% v 53%; P =.001) or more CD34(+) cells/kg with fewer aphereses (median, 2 v 3; P =.002) and fewer days of growth-factor treatment (median, 12 v 14; P =.0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34(+) cells and had faster platelet recovery (P =.015), with fewer patients (P =.014) receiving fewer platelet transfusions (P =.001) than patients receiving sargramostim-mobilized PBSCs. CONCLUSION It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34(+) cells and reduction of toxicities after MC.

Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer

PURPOSE To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m(2)/1.15 mg/m(2) twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m(2)/20 mg/m(2) once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P =.01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P =.354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Breast Cancer

Carcinoma of the breast ends the life of nearly 50,000 women each year in the United States [1]. Refinements in surgery and radiation have improved cosmesis and local control but have failed to deal with the insidious systemic nature of this disease. Conventional dose adjuvant chemotherapy has also failed to impact national mortality figures [2]. At historically applied doses, adjuvant chemotherapy represents inadequate systemic therapy for a large proportion of patients.

Combination chemotherapy with mitomycin C, methotrexate, cisplatin, and vinblastine in the treatment of non-small cell lung cancer.

The combination of mitomycin C, methotrexate, cisplatin, and vinblastine was administered to 45 patients with unresectable non‐small cell lung cancer. Thirty‐nine patients satisfied criteria for assessment of response to chemotherapy. All patients had a performance status of greater than 50%, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 54% with responses seen in 12 of 19 squamous cell, 8 of 16 adenocarcinoma, and 1 of 4 undifferentiated large cell lung cancer patients. Median survival was increased by 3 months in those patients with an objective response to chemotherapy. Drug‐associated toxicity was rare, but apparent mitomycin C‐related pulmonary fibrosis was observed in two patients. This four‐drug combination was shown to be an active regimen in the treatment of non‐small cell bronchogenic carcinoma.

IL-2: a review of current knowledge

A limiting factor in the use of T-cell therapy for cancer has always been the ability to expand T-cells, whether derived from the peripheral blood, spleen or tumor. The availability of r-IL-2 has confirmed the feasibility of expanding T-cells and LAK cells for clinical trials after confirmation of their anti-tumor activity in murine models. While the most promising results using IL-2/LAK cells have been in patients with melanomas and renal cancer, anti-tumor effects have been seen in patients with a wide variety of cancers, even those with bulky tumors. This form of adoptive cellular biotherapy has confirmed that an expanded and activated cell population using the cancer research laboratory can provide a method by which clinicians can effectively treat advanced cancer. In tumor biopsies, the infiltrating lymphocytes have been recognised and are known to be cytolytically active for many years. Using IL-2 stimulation of growth and an ongoing antigen stimulation (tumor cells), we have maintained selective killing of tumor cells. Accessing cells and various factors in the medium which support and enhance T-cell growth and activation are being defined. The role of antigen stimulation is also basic to further progress with this technology. Tumor cell chunks and cultures, nude mouse xenografts, or purified antigen all represent potential sources of repeated antigen stimulation. Thus, the components are now available to develop a broad attack on advanced cancer using this laboratory-based technology of tumor-derived activated cell (TDAC) stimulation, expansion and therapy. These approaches and preliminary results point to the dramatic change in technology which has allowed the cancer research laboratory to be a substantial component in new clinical approaches to cancer treatment. Laboratory scientists have become a major component in the design and conduct of clinical trials using adoptive biotherapy. These techniques are laboratory based and it is only with close and effective communication between the laboratory scientists and the clinician that rapid and effective translation of these technologies to the patient will occur (20).