Biomedical subjects

B Escudier

Publications and source records attributed to B Escudier.

At least 19 recordsLinked to original sources

PubMed1999

Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy.

Interleukin-2 (IL-2) has been shown to decrease cytochrome P450 (CYP) mRNAs and proteins in cultured rat hepatocytes, and IL-2 administration decreases CYPs in rats. Although high doses of IL-2 are administered to cancer patients, the effect on human CYPs has not yet been determined. Patients with hepatic metastases from colon or rectum carcinomas were randomly allocated to various daily doses of human recombinant IL-2 (from 0 to 12.10(6) units/m(2)). IL-2 was infused from day 7 to day 3 before hepatectomy and the conservation of a non-tumorous liver fragment in liquid nitrogen. Hepatic CYPs and monooxygenase activities were not significantly decreased in 5 patients receiving daily doses of 3 or 6 10(6) IL-2 units/m2, compared to 7 patients who did not receive IL-2. In contrast, in 6 patients receiving daily doses of 9 or 12 x 10(6) IL-2 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37, 45, 60 and 39%, respectively, of those in controls; total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. These observations suggest that high doses of IL-2 may decrease total CYP and monooxygenase activities in man.

Adenocarcinoma↗

PubMed1999

Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study.

BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma. METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy. RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment. CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.

Adolescent↗

PubMed1999

Combination interleukin-2 and doxorubicin in advanced adult solid tumors: circumvention of doxorubicin resistance in soft-tissue sarcoma?

Based on the likelihood of antitumor interactions between cytokines and cytotoxic drugs, we designed a pilot study to evaluate feasibility, clinical, pharmacologic, and immunologic effects of concomitantly administered subcutaneous (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in patients with advanced solid tumors (AST). Patients received one injection of ADR alone (70 mg/m2) and 3 weeks later a combination of r-IL-2 (18 MIU/m2 days 1-5 s.q.) and ADR at the same dose either 3-4 h after the first r-IL-2 injection (arm 1) or 2 days after the last r-IL-2 injection (arm 2). The same combination was repeated every 4 weeks according to the evolution of the disease. Pharmacokinetics were assessed over 48 h after injection of ADR alone and after the first ADR-IL-2 cycle and immunologic monitoring at days 1 and 8 of the first ADR-IL-2 cycle. Tumors were measured at baseline, after ADR alone, and after each ADR-IL-2 cycle until progression. Twenty-one adult patients with various AST including 14 soft-tissue sarcomas (STS) entered the study, 11 in arm 1 and 10 in arm 2. All patients were heavily pretreated; 16 had received an anthracycline-containing chemotherapy regimen. Eleven patients were ADR refractory and 1 ADR resistant. Grade 4 neutropenia occurred in 28, 82, and 40% of patients after ADR alone, ADR-IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7 of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). SQ injections of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1 prevented IL-2-induced lymphocyte rebounds in all patients but did not alter qualitatively non-major histocompatibility complex-restricted cytotoxicity. There was no response after ADR alone. Two patients, one in each arm, experienced a prolonged (8 and 5 months) objective response after ADR-IL-2. Both had ADR-refractory STS with a local relapse and metastatic metastases. Interestingly, both patients had unusually elevated TNF-alpha levels before and after the first ADR cycle. Combination ADR-IL-2, although toxic, is feasible and manageable with routine clinical support. r-IL-2 enhanced ADR hematologic and extrahematologic toxicities. The two objective responses observed in these heavily pretreated patients refractory to ADR supports the hypothesis of a modulation of ADR resistance, possibly mediated by means of a mechanism involving TNF-alpha. Elevated baseline TNF-alpha levels could be predictive of response to ADR-IL-2 and deserves further investigation.

Adult↗

PubMed1999

Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape.

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNalpha2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNalpha2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNalpha2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFNalpha2a was administered three times weekly at 18 x 10(6) IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNalpha2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNalpha2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNalpha2a. CONCLUSION: Cross-over after failure of IL-2 or IFNalpha2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.

Adult↗

PubMed1999

Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates with a poor clinical prognosis.

To establish human renal cell carcinoma (RCC) xenografts for preclinical studies, 55 renal tumors (33 primary and 22 metastatic lesions) were transplanted subcutaneously into severe combined immunodeficient mice. Twenty of 49 evaluable tumors (40.8%) grew with a median latency period of 89 days (36 to 209 days) from the day of engraftment. Tumor growth was stabilized after the fifth passage with a median time between passages of 38 days (19 to 80 days). Tumorigenicity was correlated with the metastatic phenotype of the tumor (54% success rate, p = 0.007) and with reduced survival of patients. Despite a possible evolution of histological features and tumor grading, established RCC xenografts were comparable to parental tumors, as assessed by karyotype and DNA-ploidy analyses. Molecular cytogenetic analysis also revealed specific genetic alterations characterizing distinct RCC types that were constant in parental and corresponding xenografts. In addition, this xenograft model has permitted the selection of minor tumor subclones with a proliferative advantage and minimal overexpressed chromosomal regions. We conclude that severe combined immunodeficient mice are useful recipients for the establishment of long-term RCC xenografts that can be used as valuable tools to evaluate the activity of new therapeutic approaches and to study biological parameters determining in vivo aggressiveness of human RCC.

Adult↗

PubMed1998

Prognostic factors for survival in patients with brain metastases from renal cell carcinoma.

BACKGROUND: Patients presenting with brain metastases from renal cell carcinoma portend a poor prognosis, with a reported median survival of 4-6 months. Given their short life expectancy, these patients generally have been excluded from clinical trials that assess the efficacy of medical treatments. However, clinical impression suggests that some patients may achieve long term palliation. METHODS: The clinical features of 68 patients who were treated at the Institut Gustave Roussy for brain metastases from renal cell carcinoma were collected retrospectively. Using univariate and multivariate analyses, a prognostic model based on independent prognostic factors was established. An external data set of 57 patients was used to validate the model. RESULTS: The median survival was 7 months. On univariate analysis survival was related significantly to the following adverse prognostic factors: no initial nephrectomy, left side and temporal location of brain metastases, presence of fever or weight loss, erythrocyte sedimentation rate > 50 mm/h, and time from initial diagnosis to brain metastases < or = 18 months. Multivariate analyses identified the previous variable as well as the presence of other visceral metastases as independent prognostic factors. Forty-four patients (65%) with no or 1 adverse prognostic factor (average risk group) had a median survival of 8 months and a 26% 1-year survival rate. Twenty-four patients (35%) with 2 adverse prognostic factors (poor risk group) had a median survival of 3 months and a 1-year survival rate of 9%. This model proved to be discriminant in an external data set; the median survival of patients assigned to the average risk group was 11 months (46% 1-year survival rate) compared with 4 months (9% 1-year survival rate) for patients assigned to the poor risk group. CONCLUSIONS: Patients presenting with brain metastases from renal cell carcinoma and poor risk prognostic factors are highly unlikely to benefit from medical treatments except symptomatic procedures. Conversely, the enrollment of patients with average risk prognostic factors into clinical trials dealing with chemotherapy or immunotherapy may be considered.

Adolescent↗

PubMed1998

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie.

BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.

Adjuvants, Immunologic↗

PubMed1998

Phase II study of interferon-alpha and all-trans retinoic acid in metastatic renal cell carcinoma.

Interferon-alpha is an accepted treatment for renal cell carcinoma, with a response rate approximately 14%. Retinoic acid has been claimed to improve such a response rate when combined with interferon. We present the results of a phase II study combining interferon alpha and all-trans retinoic acid (ATRA) in patients with metastatic renal cell carcinoma. Thirty-one patients who were not eligible for a trial of high-dose interleukin-2 treatment (because of low performance status: 7 patients; prior immunotherapy: 11 patients; age > 70: 8 patients, cardiac or respiratory failure: 4 patients; refusal for randomization: 1 patient) were enrolled in this study. Only one partial response was observed (3%). Despite the good tolerance observed with this association, ATRA does not improve the efficacy of interferon in this selected patient population (with poor prognosis). Such a treatment combination should not be further recommended in patients with metastatic renal cell carcinoma.

Adult↗

PubMed1998

Severity-of-illness scores for neutropenic cancer patients in an intensive care unit: Which is the best predictor? Do multiple assessment times improve the predictive value?

OBJECTIVES: To use three severity of illness scores to estimate the probability of hospital mortality among patients with cancer and neutropenia; to compare the performance of these scores, calculated at admission to an intensive care unit (ICU); and to test the improvement in estimation obtained by taking into account the first 72-hr period. DESIGN: Collection of data for every neutropenic patient hospitalized in the ICU during a 4-yr period. SETTING: A comprehensive cancer center. PATIENTS: Ninety-four patients were neutropenic at ICU admission. Their vital status was measured at hospital discharge. MEASUREMENTS AND MAIN RESULTS: The new Simplified Acute Physiology Score (SAPS) II improved the estimation of hospital mortality compared with the original SAPS score. Using a simple score based on the number of acute organ system failures (OSFs) to classify the patients, good discrimination between survivors and nonsurvivors was observed (area under the receiver operating characteristic curves, 79 +/- 5 [SD] %). The relationship between successive scores and outcome was explored using recursive partitioning. Patients were first classified according to their OSF value on the first day of hospitalization in the ICU with a cutoff of two organ failures, and classification was then improved by taking into account the OSF score on the third day. CONCLUSIONS: For cancer patients hospitalized in an ICU for a neutropenic episode, the severity of illness and the risk of death can be accurately assessed by the SAPS II score and the number of acute organ failures at admission. The OSF values on the first and third days of hospitalization both provided information, allowing the classification of patients into groups with different probabilities of hospital mortality.

APACHE↗

PubMed1998

Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Français d'Immunothérapie.

PURPOSE: A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS: The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION: This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.

Adult↗

PubMed1998

Overrepresentation of 7q31 and 17q in renal cell carcinomas.

Xenografts from four metastatic renal cell carcinomas (RCCs) were established in immunodeficient mice. All tumors exhibited cytogenetic features specific for the papillary subtype, namely, partial or total polysomy of chromosomes 7 and 17 and integrity of 3p. Cytogenetic analysis of the initial and xenografted tumors indicated that although clonal characteristics were consistently maintained in xenografts derived from metastases, a minor clone had been selected for in the xenografts derived from the primary tumors. Reverse painting and comparative genomic hybridization (CGH) allowed us to localize minimal overrepresented genomic regions to 7q31, where the MET protooncogene is located, and to 17q. Other overrepresented regions were 8q in all xenografts and Xq22-qter in three of them. The gain of genetic material from these regions may be a key factor ensuring the papillary nature of RCCs and their survival in xenografts.

Aneuploidy↗

PubMed1998

[Cancer of the kidney in the adult].

Renal cell carcinoma is a frequent disease. Recently, its incidence has been rising. Kidney tumors are detected more frequently by the newer radiologic techniques, but the diagnosis is steel difficult and occurs often late in the natural history of the disease. A high proportion of patients have metastases at diagnosis or after initial surgery. Many types of systemic therapy have been studied but resistance to radiotherapy and chemotherapy is the rule. There is a potential role for immunomodulation in the inhibition of tumor growth but clinical issue remain uncertain. In this review we discuss recent developments in epidemiology, histologic classification, tumor biology, methods of diagnosis, surgical techniques and immunotherapy for patients with metastatic disease.

Adult↗

PubMed1997

T-cell receptor CDR3 size distribution analysis to evaluate specific T-cell response to cancer vaccines.

To evaluate immunization procedures in cancer patients, it is important to define which biological parameters reflecting a specific immune response to the vaccine should be followed. One of these may be the recruitment or expansion of clonally amplified T-cell subpopulations previously primed by tumor-specific antigen that could be detected in tiny samples by CDR3 length analysis of T-cell receptor Vbeta transcripts. To evaluate this procedure, we studied one patient with metastatic colorectal adenocarcinoma who had received 4 intradermal injections of irradiated autologous tumor cells plus IL-2 on days 1, 8, 15 and 36. Skin tests for delayed type hypersensitivity (DTH) reaction to irradiated autologous tumor cells were performed on days 1 and 43. Although no change was observed in day 43 PBMCs, some recurrent transcripts were detected with similar CDR3 size patterns in both vaccine and DTH sites. Fine analysis of these Vbeta-Cbeta PCR products with Jbeta primers confirmed that transcripts with similar length were recruited in both vaccine and DTH sites. Induction of an inflammatory response in both DTH and vaccine sites may therefore be associated with the recruitment of few T-cell clonotypes. In addition, a Vbeta15-Jbeta2.5 transcript similar to those detected in vaccine and DTH sites was also identified in enzymatically dissociated tumor cells and in a tumor fragment. Sequencing confirmed that an identical junctional sequence was shared by Vbeta15-Jbeta2.5 transcripts from both DTH and tumor samples. Our results indicate that a T-cell clone similar to the one amplified in the tumor was recruited at the vaccine and DTH reaction sites. We therefore suggest that such an approach would be useful in assessing specific expansion of T-cell clones induced by cancer vaccines.

Adenocarcinoma↗

PubMed1997

Prognostic factors for neutropenic patients in an intensive care unit: respective roles of underlying malignancies and acute organ failures.

The admission of neutropenic patients to an intensive care unit (ICU) is still controversial, especially if mechanical ventilation is required. To avoid useless stays in ICU, the evaluation of the respective role of the underlying malignancy and acute organ failures might be useful for better definition of the categories of patients who could benefit from aggressive ICU support. For this purpose, we carried out a retrospective study of the charts of 107 consecutive neutropenic patients admitted to an ICU in a comprehensive cancer centre over a four-year period. The following characteristics were recorded within 24 h of admission: patient data, characteristics of neutropenia and the underlying malignancy, the type and number of organ system failures (OSFs) and simplified acute physiological scores (SAPS and SAPS II). The impact of each variable on outcome in the ICU was studied by univariate and multivariate (logistic regression) analysis. 59 patients died in the ICU (mortality rate: 55%). Patients with a haematological malignancy (n = 57, 53%) were more likely to experience respiratory failure, an underlying malignancy deemed rapidly fatal, and to have longer lasting neutropenia than patients with a solid tumour (n = 50, 47%). However, the mortality rate did not differ in the two groups (haematological malignancy 61% versus solid tumour 48%, p = 0.16). Respiratory and cardiovascular organ failure (p < 0.001 for both) correlated with mortality in the ICU. In the multiple logistic regression model, only the number of organ system failures and respiratory failure remained predictive of ICU mortality. In conclusion, the characteristics of the underlying malignancy are not relevant when deciding whether or not neutropenic patients should be admitted to an ICU. The main risk factors for death in an ICU are the number of organ failures on admission, and among them the presence of respiratory failure.

Adult↗

PubMed1997

Should the number of pulmonary metastases influence the surgical decision?

OBJECTIVE: To assess, using a large homogeneous retrospective series, the prognostic value of the number of resected pulmonary metastases, and thus, to determine to what extent the number of resectable metastases should influence the surgical decision. METHODS: The survival analysis of all patients operated on for pulmonary metastases at a single center, the comparisons of 2 'histologic' groups (sarcoma and carcinoma) and, within each histologic group, of three subgroups with different numbers of resected metastases (1, 2-4, and > or = 5) were performed. The log-rank test was used to compare survival curves. RESULTS: Among 575 adult patients operated on with curative intent before December 1991, the first operation allowed the complete resection of a known number of histologically proven viable pulmonary metastases in 230 and 151 patients with metastases from carcinoma and sarcoma, respectively. The 5- and 10-year probabilities of survival (Kaplan-Meier) were 37 and 23%, respectively in carcinoma patients, and 31 and 28%, respectively in sarcoma patients (log-rank test: ns). Only the difference between patients with 1 versus 2-4 metastases from carcinoma proved statistically significant (P = 0.02), with 5-year survival estimates of 41 and 25%, respectively. Beside survival, the only significant difference between the subgroups of patients with different numbers of resected metastases was the mean interval between the diagnosis of pulmonary metastases and the resection of pulmonary metastases, which was significantly longer in patients with several metastases in both histologic groups. CONCLUSIONS: In patients with resectable pulmonary metastases from sarcoma or carcinoma, the number of metastases should have little influence on the surgical decision, except for delaying this decision in patients with several metastases until a significant interval, with or without treatment, has shown that metastatic disease remains resectable and confined to the lungs.

Adult↗

PubMed1997

Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Français d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. MATERIALS AND METHODS: The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. RESULTS: Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. CONCLUSION: We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.

Clinical Trials as Topic↗

PubMed1996

In situ demonstration of renal-cell-carcinoma-specific T-cell clones.

Using mixed lymphocyte tumor-cell culture (MLTC) in a selected renal-cell carcinoma, we derived a tumor-specific T-cell line in which Vbeta14+ and Vbeta19+ T cells represented 70% of the whole T-cell population. Selected Vbeta19+ T cells were CD8+ and exhibited a HLA-restricted specific cytotoxicity against tumor cells. Independently, 2 CTL clones were obtained by direct cloning of tumor-infiltrating lymphocytes, VIIIC2 CTL expressing a Vbeta19 and VIIB10 CTL a Vbeta13 T-cell-receptor transcript. VIIB10 lysed autologous tumor cells, normal kidney cells and EBV-transformed B cells. In contrast, VIIIC2 lysed tumor cells exclusively, demonstrating that the antigen structure recognized is tumor-specific. In addition, we used a PCR-based method to search for the presence of these CTL in situ. TCR beta chain of VIIIC2 and VIIB10 CTL were sequenced and primers complementary to their N regions were synthesized. VIIIC2 CTL constituted up to 60% of Vbeta19 transcripts in MLTC T-cell lines derived from tumor-infiltrating lymphocytes, 23% in tumor and 26% in a tumor-draining lymph node, while VIIB10 was not detected. Thus, VIIIC2 CTL was successfully derived from lymphocytes infiltrating a renal-cell carcinoma by direct cloning as well as by MLTC, probably because it was highly expanded in vivo within the tumor composing almost 2% of the TIL.

Base Sequence↗

PubMed1996

T-cell receptor repertoire in neuroblastoma patients.

Spontaneous regression of widespread lesions is a characteristic feature of neuroblastoma. One may postulate that the immune response contributes to these clinical regressions. Accordingly, we studied the T-cell receptor (TCR) repertoire of tumor-infiltrating lymphocytes in eight neuroblastoma tumors. The expression of 29 V alpha and 24 V beta gene segment subfamily specificities was analyzed by PCR and compared by computerized densitometry of Southern blots to values obtained in the blood. Overall, the TCR repertoire of these eight patients was diverse, with virtually all V alpha and V beta specificities expressed. Nonetheless, four of these patients showed V beta 2 gene segment subfamily overexpression in the tumor corresponding to local expansion of polyclonal T-cell subpopulations. In one patient, this expansion could be due to local secretion of superantigenic activity, as suggested by the specific stimulation of murine T cells expressing a human V beta 2 chain by supernatant of the corresponding neuroblastoma cell line. In addition, high-resolution analysis of the TCR beta transcript complementarity-determining region 3 sizes identified three patients (of six studied) with marked clonal T-cell expansion in the tumor not seen in the blood. The specific expression of several dominant clono-types in the tumor may be related to the recognition of neuroblastoma-specific antigens in these patients. Together, these results on the TCR repertoire expressed in vivo may lead to the characterization of putative immune response mechanisms (i.e., antigen- or superantigen-driven stimulation) which participate in tumor regression.

Animals↗