A phase II clinical trial of interleukin-2 and lymphokine-activated killer cells in advanced colorectal carcinoma.

Patients (n = 22) with metastatic or unresectable colorectal carcinoma were treated with interleukin (IL)-2 and lymphokine-activated killer (LAK) cells in a phase II study conducted by the IL-2/LAK Working Group (ILWG). Eligibility criteria for the study included bi-dimensionally measurable disease, performance status 0 or 1, and normal function of all vital organs. The median age of patients was 49 (range, 28-61) years. Eight (36%) patients had never received prior treatment other than their initial surgery; eight (36%) had received prior radiotherapy, and 12 (55%) chemotherapy. No patients had received prior immunotherapy. Treatment consisted of IL-2, 600,000 IU/kg administered by 15-min intravenous infusion every 8 h on days 1-5 and 12-16. Patients underwent 4-h leukapheresis on days 8-12, and cells were placed in in vitro culture with IL-2 for 3-4 days and the activated LAK cells were infused over 1 h on days 12, 13, and 15. All doses of IL-2 and LAK cells were administered to patients in intensive care unit (ICU) settings. The mean +/- SD number of IL-2 doses administered during days 1-5 was 13.4 +/- 1.2, the mean number of LAK cells reinfused was 6.8 +/- 2.2 x 10(10), and the mean number of IL-2 doses administered during the last phase was 9.8 +/- 2.5. Nineteen patients completed the IL-2 priming phase and received at least one LAK cell infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative radiotherapy with localized radioprotection: diminished duodenal toxicity with intraluminal WR2721.

The radiosensitive duodenum must be treated during IORT of human pancreatic head tumors, leading to an approximately 25% incidence of late bleeding. This study aimed to decrease the toxicity by administering WR2721 directly into the duodenal lumen. Duodenal toxicity in the canine was evaluated after intraoperative radiotherapy (IORT) with and without the intraluminal radioprotector WR2721. Eight adult dogs were divided into two groups. All underwent IORT using a 5.7 cm cone that covered the duodenum and pancreas. 30.0 Gy IORT was given with 6 MeV electrons. Cholecystojejunostomy and gastrojejunostomy were performed. Four dogs served as IORT only controls; one was unevaluable. Four dogs received WR2721, intraluminally at 720 mg/m2, in 16-18 ml Ringer's. Atraumatic clamps were placed on proximal and distal duodenum, without vascular compromise. WR2721 was injected into the duodenal lumen 30 minutes prior to IORT. Immediate postoperative recovery of the dogs receiving WR2721 was faster than controls. Necropsies were performed at 6 months. Grossly increased adhesions were noted in controls. Histopathologically, mucosal atrophy was greater in control dogs. Duodenal ulceration was noted in all controls, but in only one of four WR2721 dogs. Masson's trichrome and Verhoff Van Gieson stains demonstrated increased perivascular fibrosis, intimal proliferation, and fibrinoid medial necrosis of vessels in all controls, and one WR2721 dog. The other three WR2721 dogs had only mild perivascular fibrosis. Radioprotection, evaluated by the presence or absence of pancreatic atrophy, appeared to stop just beyond the bowel wall. In summary, WR2721 provided duodenal radioprotection in most dogs. The intraluminal administration of WR2721 allows decreased systemic side effects, and may eliminate tumor absorption. The study indicates that the intraluminal use of radioprotectors has broad potential application.

Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer.

Hepatic intra-arterial (HIA) infusion of floxuridine (FUDR) via an implanted pump has shown promise in the treatment of colorectal cancer metastasized to the liver. However, the potential benefit of this therapy may be offset by the high incidence of treatment-limiting biliary toxicity. Although weekly HIA bolus of fluorouracil (5-FU) is effective against metastatic colorectal cancer to the liver with no biliary toxicity, it is limited by systemic side effects. In December 1986, we began a phase II trial of alternating HIA FUDR and 5-FU via the implanted pump in an attempt to extend the duration of treatment by obviating the limiting biliary (FUDR) and systemic (5-FU) drug toxic effects. Patients received continuous HIA FUDR at 0.1 mg/kg of body weight per day on days 1 through 8 followed by an HIA bolus of 5-FU at 15 mg/kg given via the pump sideport on days 15, 22, and 29, with the cycle repeated every 35 days. Sixty-eight patients were enrolled in this trial, and 64 were fully evaluable. Of the 64 patients, 30 (47%) previously had received chemotherapy. Major response (complete response plus partial response) was observed in 32 (50%) of 64 patients, and the median survival from pump implantation in all patients was 22.4 months. In contrast to the experience with the single-agent HIA FUDR regimen, no patient had treatment terminated because of drug toxicity. Alternating HIA FUDR and 5-FU has efficacy similar to that of HIA FUDR given alone, but when closely monitored and adjusted appropriately, is not associated with toxic effects requiring treatment termination.

Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen.

Forty-seven patients with metastatic or unresectable renal cell carcinoma were treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK)-cell therapy, using a hybrid IL-2 regimen. IL-2 was administered initially by intravenous bolus (10(5) U/kg [Cetus Corp, Emeryville, CA] every 8 hours for 3 days) during the priming phase, and subsequently by continuous infusion (3 x 10(6) U/m2 for 6 days); during this second treatment period, in vitro-generated LAK cells were administered. Despite selection of patients for good performance status (PS) (29, PS 0; 18, PS 1) prior nephrectomy (43 of the 47 patients), and low tumor burden, the response rate was low (two complete [CRs] and two partial responses [PRs], for an overall objective response rate of 9%). Toxicity was comparable to that experienced with the high-dose bolus regimen. These results suggest that the dose and schedule of IL-2 administration may influence the likelihood of response to IL-2 in renal cell carcinoma.

Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study.

Forty-seven patients with metastatic malignant melanoma were treated with two 5-day cycles of 100,000 U/kg recombinant interleukin-2 (IL-2) intravenously (IV) every 4 hours separated by 1 week. This dose and schedule of IL-2 were identical to those used in a previous combined IL-2 and lymphokine-activated killer (LAK) cell phase II clinical trial of the IL-2/LAK Working Group. Patient eligibility criteria, and clinical management guidelines were similar to those used in the previous trial. Forty-six patients were assessable for response. Objective responses were observed in 10 of 46 patients (two complete responses [CRs], eight partial responses [PRs]) or 22% with responses occurring in lung and liver as well as lymph nodes and subcutaneous sites. The median response duration was 8 months. Toxicity was significant; three patients developed myocardial infarction, and one patient died during therapy. Overall the toxicity and response rate for single-agent IL-2 are similar to that observed with IL-2 administered in combination with LAK cells in the previous trial. These results suggest that single-agent therapy with IL-2 when administered in this schedule has significant antimelanoma activity in humans, and that LAK cells generated from peripheral blood add little to the antimelanoma activity of this dose and schedule of IL-2.

Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells.

Fifty patients with advanced melanoma received high-dose bolus and continuous infusion interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells in an attempt to improve the therapeutic index of this active but toxic therapy. Treatment began with up to nine bolus doses of IL-2 administered over 3 days. After 1 day of rest, patients underwent daily leukapheresis for 4 days, and the leukocytes were cultured with IL-2 in vitro to prepare LAK cells. Continuous infusion IL-2 was begun 1 day after the last leukapheresis and continued for up to 148 hours; LAK cells were administered on days 1, 2, and 4 of the infusion. Responding patients were eligible to receive up to two additional cycles of therapy at 3-month intervals. Most patients completed each cycle without dose reduction. One patient had a complete response and six patients had partial responses (14% response rate). The complete responder and three of the partial responders (8%) remain free from disease progression with follow-up of 21 to 24 months. Of these four patients with durable remissions, one had extensive liver and lymph node metastases, one had lymph node, pleural, and parenchymal lung metastases, and two had disease limited to lymph nodes or subcutaneous tissues. Seventeen patients (34%) required pressors for hypotension, three patients (6%) developed hemodynamically significant arrhythmias, and six patients (12%) developed dyspnea at rest, but none required intubation and there were no treatment-related deaths. Unacceptable toxicity developed in two patients during bolus IL-2 administration and therapy was aborted; both returned to baseline status within 4 days of discontinuing IL-2. Fever, oliguria, and elevated creatinine or transaminase levels occurred frequently but were also transient. Despite less frequent severe toxicity with this modified regimen, these results confirm the ability of IL-2 and LAK cell therapy to induce durable remissions in some patients with advanced melanoma.

High-dose recombinant interleukin-2 alone: a regimen with limited activity in the treatment of advanced renal cell carcinoma.

Sixteen patients with metastatic renal cell carcinoma were treated with high-dose bolus recombinant interleukin-2 (rIL-2) alone at a dose and schedule identical to those that produced a 35% response rate among 72 patients in a trial reported by the Surgery Branch, National Cancer Institute (NCI), Bethesda, Md, in which rIL-2 plus lymphokine-activated killer (LAK) cells was used for the treatment of renal cell carcinoma. Patients received two 5-day cycles of 100,000 Cetus U/kg (600,000 IU/kg) of rIL-2 infused intravenously over 15 minutes every 8 hours; each treatment cycle was separated by 1 week. No objective responses were seen. The toxicity of rIL-2 given alone at these high doses was similar to that noted with high-dose rIL-2-LAK cell therapy. The lack of responses seen in this trial also differed from the 21% response rate observed by the NCI Surgery Branch, using rIL-2 alone at an identical schedule and dose in 56 patients with renal cell carcinoma. Only minor differences in such recognized prognostic variables as performance status, tumor burden, and rIL-2 dose intensity were noted between this study and other trials reported by the NCI Surgery Branch and by the IL-2-LAK Working Group. Our analysis indicates that, because of the smaller number of patients in our trial, not enough subjects were included with the ideal characteristics to attain the 21% response rate seen in the NCI study. However, the precise nature of these characteristics remains unclear.

An outbreak of hepatitis A among cancer patients treated with interleukin-2 and lymphokine-activated killer cells.

An outbreak of hepatitis A virus (HAV) infection occurred among cancer patients treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells between July and September 1986 at six different clinical centers. Among 85 patients tested serologically for recent HAV infection, 22 (39%) of 56 susceptible patients developed acute HAV infection. Only exposure to LAK cells cultured in medium containing human serum from two specific manufactured pools was associated with HAV infection. Attack rates were 85% among patients exposed to pool X, 62% in patients exposed to pool Y, and 50% in those exposed to both pools, compared with none among the 24 susceptible persons exposed to other serum pools (P less than .001). The serum used in production of LAK cell medium was obtained from multiple paid donors. Twenty persons donated plasma to both serum pools X and Y. Although none of 12 donors tested had evidence of recent HAV infection, it is likely that an asymptomatic plasma donor viremic for HAV contaminated both serum pools and the LAK cell medium made from it.

Human spleen and peripheral blood lymphocytes activated by interleukin-2 have similar phenotypic and functional characteristics.

Phenotypic markers and cytotoxic function were monitored in cultures of normal human mononuclear cells obtained from peripheral blood or spleen and stimulated by recombinant interleukin-2 (IL-2; 1,500 U/ml). Fresh spleen cells contained less than 5% natural killer (NK) cells (CD3-NKH1+), which increased about threefold after activation with IL-2. In both spleen and peripheral blood cultures, T cells with the NKH1 marker showed the highest relative increment among all cell types studied. Lymphokine-activated killer (LAK) cells from peripheral blood and spleen displayed very similar cytotoxic activity against K562, Daudi, and COLO carcinoma cell lines. Killing of the three targets peaked at 7 days of culture. Antibody-dependent cell cytotoxicity against a B-cell line was mediated by both circulating and splenic LAK cells from 2 to 14 days of culture. Cell sorting experiments showed that K562 targets were killed by both CD5+NKH1+ and CD5-NKH1+ cells whereas Daudi targets are only killed by CD5-NKH1+ activated NK cells from both spleen and peripheral blood. In summary, human spleen LAK cells have similar phenotypic and functional properties to circulating LAK cells, and they may be used for adoptive immunotherapy of human cancer.

Cytotoxicity of lymphokine-activated killer cells against human neuroblastoma cells: modulation by neuroblast differentiation.

The cytolytic activity of lymphokine-activated killer (LAK) cells against human neuroblastoma (NB) cells was investigated using the continuous NB cell lines, IMR-32, Kelly, and two subclones of SK-N-SH, SH-SY5Y (neuroblastic phenotype), and SH-EP (non-neuronal phenotype). NB cells were found to be sensitive targets of LAK. Of the SK-N-SH subclones, the neuroblasts, SH-SY5Y, were more susceptible to LAK killing than were the non-neuronal cells, SH-EP. Pretreatment of the targets SH-SY5Y and SH-EP with the differentiating agents, retinoic acid (RA, 10 microM), herbimycin A (236 nM), or nerve growth factor (10 ng/ml), did not substantially alter LAK killing. Furthermore, these differentiating agents did not measurably affect LAK activity during the cytolysis assay or with 1-h preincubation of the LAK effectors. However, co-incubation of the LAK cultures over the 3-day activation period with RA (1 microM) or PGE2 (1 microM) inhibited cytolysis by 80%, suggesting that these agents interfere with an early activation step of LAK. These results support the potential use of LAK treatment for neuroblastoma, in combination with differentiation agents that do not affect neuroblastoma sensitivities toward LAK cells. However, some differentiation agents, (e.g., RA) and endogenous prostaglandins (e.g., PGE2) may interfere with LAK activation.

Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.

The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.

Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin 2 and lymphokine-activated killer cells.

Treatment with recombinant interleukin 2 and lymphokine-activated killer cells (rIL-2/LAK) has produced a clinical antitumor effect in preliminary human trials. The cytokines gamma-interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and tumor necrosis factor beta (TNF-beta, lymphotoxin) have potent in vitro antitumor activity and some clinical toxicities similar to interleukin 2 (IL-2)/LAK. This study sought to determine whether these cytokines were detectable in sera of IL-2/LAK-treated patients. Ten patients were treated with a protocol of 5-day i.v. rIL-2 bolus priming (10(5) units/kg, every 8 h), followed by 5 daily phereses with harvested lymphocytes cultured in vitro to generate LAK, and 5 days of rIL-2 bolus with infusion of LAK cells. Five patients were treated with a protocol modified to a 3-day rIL-2 prime and 6-day continuous infusion rIL-2 (3 x 10(6) units/m2/day) with infusion of LAK cells. Serum specimens were obtained prior to and 0.5, 2, 3, and 5 h after IL-2 or LAK cell administrations. IFN-gamma was detected by enzyme-linked immunosorbent assay, TNF-alpha by WEHI 164 bioassay or enzyme-linked immunosorbent assay, and TNF-beta by WEHI 164 cell bioassay. During the prime, few patients manifested in vivo detectable serum cytokines: IFN-gamma, three of ten, 5-day prime (1.03 +/- 0.46 ng/ml), and zero of five, 3-day prime; TNF-alpha, one of ten, 5-day prime, and one of three, 3-day prime; TNF-beta, one of ten, 5-day prime. The supernatants of in vitro LAK generation cultures had detectable levels of cytokines at 24 h which increased progressively until culture harvest at Day 4 (IFN-gamma, 2.56 +/- 0.34 ng/ml; TNF-alpha, 356 +/- 110 pg/ml; TNF-beta, 8.2 +/- 4.4 units/ml). The highest levels of in vivo serum cytokines occurred following LAK cell infusion and were more often elevated in patients receiving rIL-2 by bolus than by continuous infusion: IFN-gamma, four of six bolus, zero of three continuous infusion; TNF-alpha, six of six bolus (maximum 679 pg/ml) versus two of three continuous infusion (maximum, 106 pg/ml). LAK cells in vitro responded with cytokine release on stimulation by tumor cell lines (IFN-gamma, 0.88 +/- 0.06 ng/ml; TNF-alpha, 426 +/- 16 pg/ml; TNF-beta, 0.64 +/- 0.06 units/ml). In summary, this preliminary study has detected circulating cytokines in sera of patients receiving IL-2/LAK therapy. The greatest cytokine elevations followed LAK cell infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans.

Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 10(6) per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (+/- SEM) was 14.3 +/- 0.8 x 10(10). Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 +/- 0.4 x 10(10) (range, 2 to 15.2 x 10(10]. LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.

Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial.

STUDY OBJECTIVE: To confirm the antitumor efficacy of treatment with interleukin-2 and lymphokine-activated killer cells in patients with metastatic renal cancer. DESIGN: Nonrandomized, phase II clinical trial. SETTING: Tertiary care units in university medical centers. PATIENTS: Consecutive trial of 35 patients with metastatic or unresectable renal cell cancer who have bidimensionally measurable disease, performance status 0 or 1, and normal function of all vital organs. Thirty-two patients completed interleukin-2 priming and received at least one lymphokine-activated killer cell infusion. Three patients were removed from the study and did not receive infusion of cells secondary to rapid tumor progression or toxicity. INTERVENTIONS: Patients initially received recombinant interleukin-2, 100,000 units/kg body weight every 8 hours, on days 1 to 5 in a priming phase to stimulate lymphokine-activated killer cell precursors and effector activity in vivo. Leukapheresis was done on days 8 to 12 and lymphocytes were cultured in vitro with interleukin-2 for 3 to 4 days to amplify lymphokine-activated killer cell activity. Finally, interleukin-2, 100,000 units/kg every 8 hours, was infused with cultured cells on days 12 to 16. All doses of interleukin-2 and lymphokine-activated killer cells were administered in intensive care units. MEASUREMENTS AND MAIN RESULTS: The mean number of doses of interleukin-2 administered during the priming phase was 12.9 +/- 0.4; the mean number of lymphokine-activated killer cells reinfused was 7.0 +/- 0.6 X 10(10); and the mean number of interleukin-2 doses administered during the last phase was 10.2 +/- 0.6. The overall objective response rate was 16%; two patients had complete responses and three patients had partial responses with greater than 50% reduction of all measurable tumor. The complete responders remain disease-free at 12 and 9 months. Two partial responders have not had tumor regrowth at 16 and 15 months. The third partial responder relapsed at 4 months. Toxicity was severe but generally of short duration and manageable. There were no treatment-related deaths. Hypotension, weight gain, anemia, and elevations of serum creatinine levels and liver enzymes were common. Two patients required intubation; one patient had a myocardial infarction. CONCLUSIONS: This phase II study confirms the antitumor activity of interleukin-2 and lymphokine-activated killer cell therapy in patients with metastatic or unresectable renal cell cancer. Response rates, especially complete remission rates, are comparable or better than rates achieved with other forms of therapy.

Extravasation. A serious complication of the split-sheath introducer technique for venous access.

The use of split-sheath introducers to place venous access catheters results in the potential for subcutaneous extravasation and tissue injury or necrosis. We present six cases that demonstrate this complication and illustrate the probable mechanism. The safe use of these catheters requires verification that blood can be aspirated from the catheter and a high index of suspicion for extravasation when symptoms develop.

In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy.

Patients with advanced metastatic cancer were given combined autologous lymphokine activated killer (LAK) cell and recombinant interleukin-2 (rIL-2) therapy on a National Cancer Institute extramural phase II trial. Systemic administration of rIL-2 resulted in pronounced lymphocytopenia. Within two days after completion of in vivo rIL-2 therapy, there was a dramatic increase in absolute numbers of circulating lymphocytes, and cytotoxic activity against tumor cell targets was mediated by peripheral blood lymphocytes, indicating in vivo generation of LAK activity. Patients were leukapheresed and cells cultured for three to four days in rIL-2. rIL-2 cultured cells from all patients demonstrated cytotoxic activity. In order to characterize the effector cell, T cells and natural killer (NK) cells were isolated to greater than 95% purity by flow cytometry. Cytotoxic activity was mediated by rIL-2--activated NK cells, whereas T cells demonstrated no substantial activity. The circulating in vivo cytotoxic effectors detected after in vivo rIL-2 therapy were also shown to be rIL-2--activated NK cells. Results from these studies demonstrate that all patients were capable of generating a cytotoxic response, and that the cytotoxic effector cells were rIL-2--activated NK cells, identified by the phenotype CD3--, Leu 19+.

Evidence that the T cell antigen receptor may not be involved in cytotoxicity mediated by gamma/delta and alpha/beta thymic cell lines.

After culture in IL-2, thymocytes expressing either TCR-alpha/beta or -gamma/delta acquired the ability to lyse hematopoietic and solid tumor cell targets without deliberate immunization or apparent restriction by the MHC. Moreover, TCR-alpha/beta- and TCR-gamma/delta-bearing thymic cell lines demonstrated an essentially identical spectrum of cytolysis against several tumor cell targets. Cytotoxicity was not inhibited by antibodies against CD3 or CD2 and modulation of the CD3/TCR complex also failed to affect cytotoxicity. Thus, non-MHC-restricted cytotoxicity can be mediated by thymocytes with either TCR-alpha/beta or TCR-gamma/delta, but the TCR may not be responsible for target recognition.

Immunodeficiency-associated thrombocytopenic purpura (IDTP). Response to splenectomy.

Immunodeficiency-associated thrombocytopenic purpura (IDTP) is a feature of the acquired immunodeficiency syndrome--related complex. Current therapeutic modalities for IDTP include splenectomy and the administration of corticosteroids or other agents. Empiric treatment of IDTP has been analogous to that for immunologic thrombocytopenic purpura (ITP). The present report reviews 15 patients who underwent splenectomy for IDTP, demonstrates the successful use of surgical therapy, and defines our indications for splenectomy in the treatment of this disorder. Thirteen of 15 patients had initially failed to respond to steroid therapy. Fourteen patients (93%) initially responded to splenectomy, with platelet counts increasing to 150 X 10(9)/L (150,000/mm3) or greater. A continuing complete response was achieved in nine patients (60%) following splenectomy. After postsurgical adjunctive therapy, durable remission was achieved in 73% (11/15) of the patients. Complications occurred in three patients, and there were no deaths. The mean follow-up was 12.4 months. Splenectomy may be performed in the treatment of IDTP with acceptable morbidity and likelihood of response.

Clinical effects and toxicity of interleukin-2 in patients with cancer.

Interleukin-2 (IL-2) is a 15,000 dalton glycoprotein produced naturally by human T-cells during an immune response. IL-2 has been demonstrated to have substantial activity alone or in combination with the adoptive transfer of lymphokine-activated killer cells in murine tumor models. IL-2 derived from both natural (Jurkat human T-cell tumor) and recombinant (Escherichia coli) sources has been studied in Phase I protocols designed to evaluate toxicity in patients with a variety of solid tumors and to ascertain improvement in clinical parameters and immunologic status. A total of 16 patients (7 with acquired immune deficiency syndrome [AIDS] and 9 with non-AIDS malignancies) were treated with Jurkat derived IL-2. The total maximum dose (1.3 X 10(5) U/kg) was limited only by supply of this reagent. A total of 25 patients have been treated with recombinant IL-2 (RIL-2) alone. Dose-limiting toxicity manifested by marked malaise and weight gain was achieved with doses of RIL-2 of 10(6) U/kg as a single bolus or 3000 U/kg/hr. IL-2 could be administered intraperitoneally with similar toxicity. Minimal renal or hepatic toxicity was demonstrated. Hematologic toxicity was limited to mild anemia (25/25), thrombocytopenia (10/25), and marked reversible eosinophilia (15/25). Pronounced weight gain greater than 2 kg (16/25) occurred in most patients, primarily those who received cumulative doses of greater than 1-3 X 10(5) U/kg of IL-2. The weight gain amounted to as much as 10% to 20% of the pretreatment weight over 3 weeks of treatment and limited our ability to give higher doses. Two partial responses (greater than 50% decrease in cross sectional diameters) were seen in two patients with melanoma metastatic to the lung.

Home support of patients with end-stage malignant bowel obstruction using hydration and venting gastrostomy.

Palliative terminal care of patients with malignant bowel obstruction is a major clinical and ethical challenge. These patients are often mentally alert and ambulatory, but are kept in the hospital for hydration, nasogastric suction, and pain control. Parenteral nutrition requires frequent metabolic monitoring, is expensive, and is ethically questionable. We have used an alternative method of home management for 27 patients who met the following criteria: inoperable bowel obstruction due to untreatable cancer, an estimated life expectancy of between 2 weeks and 3 months, and understanding of the goals and limits of therapy. Hydration was provided by 10 percent dextrose and electrolyte solutions administered as overnight infusions through long-term central venous catheters. Thirteen patients with complete bowel obstruction required a venting gastrostomy which, when connected to passive drainage, relieved nausea and vomiting. The mean duration of survival was 64 days (range 9 to 223 days). Acceptance by patients and families was excellent, although most acknowledged increased costs due to limited insurance coverage for outpatient care. Seven patients returned to the hospital for terminal care (average stay 3.2 days), and 20 chose to die at home. The mean daily expense for fluids and supplies was +73.50, with an overall cost decrease of $900,000 compared with inpatient care. Home support with fluids and gastric venting is a humane, cost-effective alternative to in-hospital care for selected patients.