Properties of recombinant interleukin 2-cultured tumor-infiltrating lymphocytes in human lung cancer

It is thought that TIL can be activated in vitro by rIL-2 and acquire specific anti-tumor activity. In this study, we investigated this possibility, using lymphocytes isolated from primary lung cancer tissues. In a first series of experiments, TILs and autologous PBLs from 16 patients were cultured in rIL-2 from 7 to 14 days under identical conditions, and were compared for proliferation (16 cases), cytolytic activity (11 cases), gamma interferon (IFN-gamma) production (8 cases), and phenotypes (10 cases). TILs grew in response to rIL-2 as well as PBLs. However, the induced cytolytic activity of TIL was significantly lower than that of PBL against autologous tumor cells and 2 human tumor cell lines. IL-2-mediated IFN-gamma production by TILs was also significantly lower than that of PBLs. TILs were phenotypically characterized by their high CD4/CD8 ratio and lack of Leu11-positive cells. Further investigations with 7 other cases showed that exogenous addition of IFN-gamma to rIL-2 cultures of TILs enhanced cytolytic activity in 4 cases. Our results indicate that IL-2 alone is sufficient for TILs to proliferate but not to acquire new functions (cytotoxicity and production of IFN-gamma).     

Subcutaneous low-dose recombinant interleukin 2 and alpha-interferon in patients with metastatic renal cell carcinoma.

A double-institution phase II study was performed in patients with metastatic renal cell carcinoma treated subcutaneously (s.c.) with interleukin 2 (IL-2) and alpha-interferon (INF-alpha). Thirty-eight patients were treated over a course of 7 weeks. Initially (day 1 + 2) patients received s.c. IL-2 at 18 x 10(6) IU m-2. During the following 6 weeks, patients received s.c. IL-2 at 3.6 x 10(6) IU m-2 for 5 days per week and s.c. INF-alpha at 5 x 10(6) for 3 days per week. Thirty-eight patients were evaluated for response. An objective response was seen in seven patients (18.4 +/- 12.3%), with one complete response and six partial responses. Median duration of response was 6.7 months. Toxicity could be evaluated in 38 patients and was limited. Mild to moderate toxicity included fever (97%), fatigue or malaise (76%), nausea or vomiting (50%), anorexia (32%), hypotension (26%), neurological disturbances (26%) and hypercreatininaemia (39%). In addition, four grade IV haematological toxicities were noted. No cardiac side-effects were seen. IL-2 and INF-alpha given by this schedule can be safely administered in an outpatient setting. The objective response rate was similar to our previous treatments with high-dose IL-2 given as a continuous infusion.     

Prediction of objective response to recombinant interferon-alpha with or without vinblastine in metastatic renal cell carcinoma

Clinical, histopathological and DNA cytometric parameters were analyzed before treatment in 57 patients with metastatic renal cell carcinoma (RCC) with regard to their ability to predict objective response to treatment with interferon-alpha (IFN) with or without vinblastine (VB). No pretreatment factor could be identified which was correlated with response. Patients who had at least 30% size reduction of their indicator lesion(s) after 2 months and did not present with new visible metastases had a significantly higher chance to obtain objective response than those in whom this condition was not fulfilled. We suggest that interferon treatment (with or without VB) should be offered for 2 months to all patients with metastatic RCC who are to receive systemic therapy. If at least 30% tumour size reduction is observed at that time, the patient will most probably respond objectively. If the size reduction is less, IFN with or without VB is likely to be ineffective in terms of response achievement.     

Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.     

A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma.

We have examined the efficacy, toxicity and host immunological response of two different dose schedules of interleukin 2 (IL-2) given subcutaneously, daily for 3 months in patients with renal cell carcinoma (RCC) or metastatic melanoma (MM). We also examined the effect of adding the immune modulator levamisole to the two different schedules of IL-2. Thirty-nine patients were entered into two sequential phase I/II studies. Eighteen patients entered study 1 and were randomised to receive IL-2, 3 x 10(6) IU m-2 day-1, subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Twenty-one patients entered study 2 and were randomised to receive 5.4 x 10(6) IU m-2 day-1 subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Blood was taken for peripheral blood lymphocyte (PBL) phenotype analysis, and measurement of IL-2, soluble IL-2 receptor (sIL-2R) and neopterin concentration. Two patients with metastatic melanoma, one in each study, responded (11.8%); both received IL-2 alone. Observations of immunological parameters showed that treatment with subcutaneous IL-2 resulted in a significant rise in the percentage of PBLs bearing CD25, CD3/HLA-DR, CD56 and levels of IL-2 receptor and neopterin. The total white blood cell count (WBC) and total lymphocyte count rose significantly on day 18 compared with pretreatment levels. The addition of levamisole to either IL-2 schedule resulted in no significant changes in any immunological parameters. This study illustrates that prolonged subcutaneous IL-2 can be given safely in the outpatient setting. There was no evidence that levamisole acts as an immunomodulator in this study.     

Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity

We have described a method for the generation, from fresh human renal cell cancers, of lymphoid cells that are capable of exhibiting significant antitumor reactivity when tested in short term 51Cr release assays. Tumor cell suspensions obtained from 37 consecutive fresh human renal cell cancer specimens (35 patients) could be separated by using enzymatic techniques and culturing in medium containing recombinant interleukin 2 (IL-2). The total cell recovery was 1.5 X 10(9) +/- 2.2 (SE) per tumor with a range of 1 X 10(8) to 5 X 10(9) cells. The percentage of tumor cells in the suspension ranged from 6 to 75% with a mean of 39.1 +/- 3.3%. The remaining cells were predominantly lymphocytes. Viability of mononuclear cells was greater than 90%. Activated tumor-infiltrating lymphocytes (TIL) within these tumors expand and by 10 to 14 days after initiation of culture a 5- to 15-fold increase in the number of lymphocytes could be achieved with elimination of all autologous tumor cells. Lymphocytes were recultured in fresh medium containing IL-2 and continued to expand between 2- and 10-fold every 4 to 6 days for an average of 33.7 +/- 4.5 days, resulting in greater than 50,000-fold increase in the total number of lymphocytes. The average number of splits was 4.9 +/- 0.8, with a range of 0 to 21. In 11 of 11 cases tested, TIL exhibited a far better expansion capability in vitro compared to that of peripheral blood lymphocytes obtained from the same patient and grown under identical conditions. The majority of TIL were T cytotoxic/suppressor cells (Leu 2+ Leu 4+). With continued in vitro expansion (up to 50 days) there was a concomitant increase in the helper T (Leu 3+) and pan T populations (Leu 4+) and decrease in Leu 2+ and HLA-DR+ cells. Compared with expanded peripheral blood lymphocytes, these cells demonstrated higher levels of IL-2+ receptors and HLA-DR+ antigens. Renal TIL effectors expanded in IL-2 could lyse almost all autologous tumor targets in 4-h chromium release assays. Allogeneic renal as well as nonrenal targets were equally lysed. TIL lysis of cultured tumor targets K562 and Daudi was significantly better than lysis of autologous, allogeneic-renal, and nonrenal targets. No statistically significant difference in the cytotoxic activity of renal TIL or peripheral blood lymphocyte effectors in killing autologous or allogeneic targets could be demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)     

重组人源化白细胞介素2治疗转移性肾癌的临床研究

目的 观察重组人源化白细胞介素2皮下注射治疗转移性肾癌的疗效及安全性.方法 入组转移性肾癌患者41例,经重组人源化白细胞介素2皮下注射治疗2～4个周期,每个周期共5周.第1个周期:9百万单位(MIU)、每12 h 1次、第1～5天;第2～4个周期:9 MIU、每12 h1次、第1～2天,9 MIU、每天1次、第3～5天;停药1周后重复.2个周期后评价疗效,有效或稳定的患者继续2个周期治疗.结果 意向治疗人群(ITT)集中,完全缓解(CR)0例,部分缓解(PR)7例(17.1%),病情稳定(SD)19例(46.3%),疾病进展(PD)15例(36.6%),总有效率为17.1%[95%可信区间(CI)为5.6%～28.6%],疾病控制率为63.4%;中位疾病进展时间(TTP)为6个月,中位总生存时间(OS)为22.5个月,1年生存率为71.2%.符合方案人群(PP)集中,CR 0例,PR 7例(19.4%),SD16例(44.4%),PD 13例(36.1%),总有效率为19.4%(95%CI为6.5%～32.3%),疾病控制率为63.9%;中位TTP为6个月,中位OS未达到,1年生存率为66.7%.随访显示,治疗获益能够改善患者的长期生存.患者的不良反应以轻中度为主,包括疲乏感(100%)和发热(82.9%)等,3级以上不良反应少见.结论 重组人源化白细胞介素2治疗转移性肾癌在中国人中具有一定的疗效,且能延长患者的生存期,其不良反应大部分患者能够耐受.     

Subcutaneous recombinant interleukin 2 in a dose escalating regimen in patients with metastatic renal cell adenocarcinoma

Recombinant human interleukin 2 (rIL-2) was administered by s.c. injection daily, 5 days/week to patients with metastatic renal cell carcinoma in an escalating dose regimen. Fifteen patients were entered in this study and are evaluable for toxicity with one patient not evaluable for response because of lack of measurable disease. The patient population had a median age of 63 years with initial performance status (Southwest Oncology Group criteria) of 0 in one patient, 1 in eight patients, and 2 in six patients. The starting dose was 5 x 10(5) Cetus units/m2/day with dose escalation to 1 x 10(6), 2 x 10(6), 4 x 10(6), and 5 x 10(6) Cetus units/m2/day scheduled at 2-week intervals if no significant toxicity or response was noted. Six patients were treated with drug doses of 2 x 10(6) Cetus units/m2/day or higher with a maximum daily dose achieved of 2 x 10(6) units/m2 in two patients, 4 x 10(6) units/m2 in two patients, and 5 x 10(6) units/m2 in two patients. Fatigue with decrease in performance status and elevations in serum creatinine were the most common reasons for limiting the dose or removing a patient from the study. Only one minor anti-tumor response was seen. Subcutaneously administered rIL-2 was able to alter immunological parameters. In two of the three patients tested, development of lymphokine-activated killer cell activity in vivo was seen, and statistically significant enhancement of natural killer cell activity compared to values from a concurrently run normal control was demonstrated. With treatment, there was a trend toward increased numbers of circulating total lymphocytes, OKT 8+, OKT 11+, Leu 7+, and Leu 11a+ cells and decreased numbers of circulating OKT 3+ and OKT 4+ cells. However, for the heterogeneous group of six patients monitored, results were not statistically significant compared to pretreatment values. The levels of rIL-2-specific antibodies were followed in the sera of 10 patients. Six of the 10 developed rIL-2-specific IgG during treatment with five of the six patients also developing neutralizing activity. Recombinant human interleukin 2 given by the s.c. route in the doses and schedule used in this trial can safely be given as an outpatient regimen with manageable toxicity. It may result in enhanced immune function in some patients but also results in a high incidence of antibody formation.     

Selective cytokine gene expression in renal cell carcinoma tumor cells and tumor-infiltrating lymphocytes

The progression of tumors such as renal cell carcinoma (RCC), despite the presence of substantial lymphocytic infiltrates (TIL), suggests that the ability of the local immune response to control tumor growth is impaired. Cytokine gene expression was examined to further investigate the nature of this response. Initial studies were performed with frozen tumors using PCR-assisted mRNA amplification with cytokine-specific primers for interleukin 10 (IL-10), interleukin 2 (IL-2) and interferon-gamma (IFN-γ). IL-2 mRNA was not detected, despite the presence of T cells as defined by the expression of CD3γ mRNA. In contrast, mRNA for IFN-γ was expressed in 4/9 and for IL-10 in 5/9 tumors. To confirm this, 5 fresh tumor specimens were examined, and PCR demonstrated that IL-10 mRNA was detectable in 4/5 tumors from which RNA was isolated at the time of nephrectomy. In these experiments multiple cycles and dilutions were employed to semi-quantitate the expression of IL-10. To identify potential sources of this cytokine in the tumor bed, IL-10 mRNA expression in freshly isolated lymphocytes and tumor cells, TIL lines, cultured RCC and established RCC lines was examined. Our studies demonstrate that within the tumor TIL may be one source of IL-10. Lymphocyte-enriched populations from 4/5 tumors expressed IL-10 mRNA as did 4/6 freshly isolated tumor cell preparations. IL-10 gene expression was not detected, however, in tumor cells after one passage in vitro in short-term cultured RCC tumor cells (passages 2–5) or in established RCC tumor cell lines. Finally, 4/9 CD4⁺ and 2/5 CD8⁺ TIL lines expressed IL-10 mRNA either constitutively or after stimulation with anti-CD3 antibody. This finding was associated with IL-10 production in vitro. Our studies demonstrate that IL-10 mRNA is frequently present in RCC tumors and may originate from the tumor-infiltrating mononuclear cell population. © 1995 Wiley-Liss, Inc.     

Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study.

A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a+vinblastine (VLB). IFN alfa-2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a+VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.     

Involvement of both Tac and non-Tac interleukin 2-binding peptides in the interleukin 2-dependent proliferation of human tumor-infiltrating lymphocytes

Interleukin 2 (IL-2) receptor expression was examined on recombinant IL-2 (rIL-2)-propagated tumor-infiltrating lymphocytes (TIL) from eight metastatic melanoma and three sarcoma samples. All 11 TIL expanded with similar growth rates. rIL-2 propagated TIL from five of eight metastatic melanoma specimens contained no Tac antigen-positive lymphocytes as determined by immunofluorescence and flow cytometry performed multiple times during the 4 to 8 week culture period. However, "Tac-negative" TIL did express the non-Tac IL-2-binding peptide, p70-75 as determined by [125I]IL-2 cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IL-2-binding assays revealed that these "Tac-negative" TIL expressed only an intermediate affinity IL-2 receptor. In contrast, TIL from the other three of eight melanoma and all three sarcoma contained one-third Tac-positive cells as assessed by flow cytometry analysis, and expressed surface non-Tac (p70-75) and Tac (p55) peptides by [125I]IL-2 cross-linking. These "Tac-positive" TIL displayed both the high and intermediate affinity IL-2 receptors. However, rIL-2-dependent growth of both "Tac-negative" and "Tac-positive" TIL was significantly inhibited by anti-Tac mAb, suggesting a transient Tac expression on the "Tac-negative" TIL. Additionally, due to the limits of our methodology, we cannot rule out the possibility of a constitutive expression of a low level of Tac, with an indicible expression of higher levels. Addition of culture supernatants from phytohemagglutinin- and phorbol myristate acetate-stimulated peripheral blood mononuclear cells to the "Tac-negative" TIL-induced detectable Tac expression within 48 h. These results indicate that both non-Tac and Tac IL-2 receptors play important roles during IL-2-dependent proliferation of TIL.     

Isolation and characterization of tumor-infiltrating lymphocytes from cervical carcinoma

The evidence that virus-induced tumors generally elicit T-cell responses prompts the notion that HPV-related cervical carcinoma would be amenable to treatment by T-cell-mediated adoptive therapy. Therefore, we cultured and cloned tumorinfiltrating lymphocytes (TIL) from a patient with cervical carcinoma and studied the in vitro characteristics of these TIL by using the established autologous tumor-cell line. After stimulation of bulk TIL cultures with 1,000 Units/ml recombinant interleukin 2 (rIL-2), followed by limiting dilution, T-cell clones were generated in the presence of 20 U/ml rIL-2 and irradiated autologous tumor cells, PBLs and EBV-transformed B-cell lines. Phenotypically, all clones were CD3/CD8-positive with a heterogeneous CD56 expression. All expressed preferential cytolytic activity against autologous tumor cells, did not lyse autologous lymphoblasts, and were cytotoxic against the NK-sensitive cell line K562. A minor lytic capacity was detectable on allogeneic cervical tumor-cell lines or tumor-cell lines of other histologic types. Cytotoxicity against the autologous tumor could be inhibited by anti-CD3, anti-CD8 and anti-ICAMI but not by anti-HLA class-1 (W6/32, B9.12.I), anti-allele-specific HLA determinants and anti-LFA-3 antibodies. We demonstrate a highly specific autologous lytic activity of cervical carcinoma TIL, in which a CD3-associated surface antigen recognition is involved. These results may prove useful in further studies on adoptive immunotherapy of cervical cancer patients. © 1994 Wiley-Liss, Inc.     

Functional and phenotypic analysis of tumor-infiltrating lymphocytes isolated from human primary and metastatic liver tumors and cultured in recombinant interleukin-2

Tumor-infiltrating lymphocytes (TIL) were isolated from 40 of 51 consecutive human liver tumor samples (primary hepatocellular carcinoma, 16 of 18; metastatic, 23 of 29; benign, one of four). Functional and phenotypic characteristics of fresh and recombinant interleukin-2 (rIL-2)-expanded TIL were evaluated. The expansion of TIL from hepatic tumors in the presence of 1000 units/ml of rIL-2 was possible in 60% of cases. In comparison to TIL from metastatic liver tumors, TIL obtained from primary liver tumors expanded faster and better in rIL-2 cultures. Expanded TIL from primary tumors had significantly higher cytotoxicity against K562 targets, but not Raji targets, than those from metastatic tumors. Cytotoxicity against fresh autologous tumor targets was detected in seven of eight cultures tested. TIL from primary tumors retained antitumor reactivity significantly longer in culture. The optimal in vitro cytotoxicity was achieved between days 20 and 60 of culture in the presence of rIL-2. Antitumor activity was associated with the increase in these TIL cultures of a cell population expressing the Leu19 antigen with or without the CD3 antigen. The frequency of the CD3+Leu19+ population showed a bimodal distribution during culture: the first peak of CD3+Leu19+ cells occurred between days 30 and 60 and was associated with the increased antitumor activity; the second peak occurred after day 60 and was not associated with activity. These findings demonstrate that TIL from most human hepatic tumors can be successfully isolated, cultured in rIL-2, and enriched in Leu19+ effectors. In addition, these TIL upon IL-2 activation in vitro are capable of lysing fresh autologous and/or allogeneic tumor targets.     

Interferon-alpha-2a with or without 13-cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

BACKGROUND: In patients with metastatic renal cell carcinoma (MRCC), interferon-alpha (IFN) monotherapy leads to response rates of 5-15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13-cis retinoic acid (CRA). METHODS: In a randomized Phase II study, patients with measurable MRCC received either subcutaneous IFN (9 MU daily; Arm A) or the same daily subcutaneous dose of IFN plus oral CRA (1 mg/kg; Arm B). A central expert panel reviewed the X-ray documentation of objective responses. RESULTS: In the 50 eligible patients from Arm A, the objective, expert-reviewed response rate was 6% (95% confidence interval [95% CI], 1.3-16.6%; 2 complete responses [CRs] and 1 partial response [PR]). A 19% response rate (95% CI, 9.4-32.0%) was stated for 53 eligible patients from Arm B (2 CRs and 8 PRs). Only one of the four CRs claimed by the clinical investigator was confirmed by the central review committee. Conversely, the expert committee deemed that 3 of 12 investigator-stated PRs were CRs. Constitutional toxicity (flu-like symptoms) and/or side effects from skin, mucosa, or eyes led to discontinuation of treatment in 22% of nonprogressing patients, more often in Arm B than in Arm A. CONCLUSIONS: The results from this randomized Phase II study support expansion of the trial into a Phase III study to evaluate the effect of IFN-CRA combination therapy on the survival of patients who undergo nephrectomy prior to IFN-based immunotherapy. The considerable interobserver variability of response evaluation (individual investigator vs. expert panel) indicates the necessity of a central review of claimed responses in future Phase II studies involving patients with MRCC.     

Subcutaneous recombinant interleukin-2 plus alpha interferon and vinblastine in metastatic renal cell carcinoma

The management of metastatic renal cell carcinoma (RCC) constitutes a therapeutic challenge and no standard therapy has yet been established. This phase II study aimed to verify the efficacy and tolerability of subcutaneous low dose recombinant interleukin-2 (IL-2) plus alpha interferon (IFN) and vinblastine (VLB) in patients with metastatic RCC. Twenty-three evaluable adult patients were enrolled in the study. A total of 19 patients were previously subjected to radical nephrectomy and four had been treated with adjuvant immunotherapy. The I-nest frequent metastatic sites were lung/pleura, bone, liver, lymph nodes, and abdominal mass. The following treatment schedule was administered: VLB at 6 mg/m(2) on day 1: IL-2 at 4.5 million IU twice daily from day 1 to 5 and day 8 to 12; IFN at 3 million IU three times weekly intramuscularly. The therapy was recycled every 21 days, except for the IFN which was administered continuously. Five patients demonstrated remission (21.6%) including one complete response persisting for 6 months, and four partial responses with a duration of 41+, 20, 8, and 18+ months. Moreover, 15 patients (65%) showed stable disease for 4-20 months (median 6 months), and three patients progressed. Overall median survival of the 23 patients was 11 months, with 27+ months for responders, 11 months for patients with stable disease, and 8 months for patients with rapid progression. Regressions occurred in lung, pleura, bone, and abdominal mass. Treatment was relatively well tolerated and easily manageable. This study was mainly administered as outpatient care. This study confirms the manageability and tolerability of subcutaneous IL-2 used in association with IFN alpha and chemotherapy. Even though a minority of patients responded, the duration of responses and the high percentage of long stable diseases represent the most interesting aspect of this study.     

Treatment of recurrent or metastatic renal cell carcinoma

The management of recurrent renal cell carcinoma is challenging as it requires close collaboration between surgeons, radiation oncologists and medical oncologists. To date, treatment options for metastatic disease have been of modest benefit. The disease has therefore been a good model for novel drug development programs. These endeavors are now bearing fruit with exciting preliminary data now emerging in relation to a number of novel agents.     

Correlation between clinical response to interleukin 2 and HLA phenotypes in patients with metastatic renal cell carcinoma.

HLA phenotypes were characterized for 79 patients with metastatic renal cell carcinoma treated with interleukin 2 (IL-2). HLA-A32 was associated with a clinical response (P = 0.025). The frequency of HLA-A3 and/or A32 was higher among responders than non-responders (P = 0.008). Thus, these results suggest that, in vivo, IL-2 may enhance cellular-mediated immunity against a tumour antigen and that some MHC molecules are more efficient than others for endogenous tumour antigen presentation.     

Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-alpha

We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-alpha 2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated.     

Treatment of recurrent or metastatic renal cell carcinoma

The management of recurrent renal cell carcinoma is challenging as it requires close collaboration between surgeons, radiation oncologists and medical oncologists. To date, treatment options for metastatic disease have been of modest benefit. The disease has therefore been a good model for novel drug development programs. These endeavors are now bearing fruit with exciting preliminary data now emerging in relation to a number of novel agents.