Correlation of serum interleukin-2 levels, soluble interleukin-2 receptors and T lymphocyte subsets in cancer patients

An interleukin-2 (IL-2) in vitro reduced production has been observed in most metastatic cancer patients. At present, however, there are no data on blood IL-2 levels in vivo, because of the too low sensitivity of previous biological and enzyme immunoassay methods. The recent development of a sensitive RIA method allowed us to start a preliminary investigation of IL-2 production in basal conditions in human solid tumors. The study included 42 cancer patients. Breast and lung cancer were the two commonest neoplasms. Serum levels of IL-2 and soluble IL-2 receptors (SIL-2R), and CD4/CD8 ratio were measured in each patient. The control group consisted of 58 healthy subjects. Mean serum levels of IL-2 were significantly lower in metastatic patients (n = 23) than in those without metastases (n = 19). Patients with low CD4/CD8 ratio (n = 16) had significantly lower mean values of IL-2 than those with normal ratio (n = 26). Finally, mean IL-2 concentrations were significantly lower in patients with elevated levels of SIL-2R than in those with normal values. These results would suggest that metastatic dissemination is associated with a decreased IL-2 production in vivo, and that reduced IL-2 production is more frequent in patients with low CD4/CD8 ratio.     

Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2

Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.     

Peripheral blood lymphocyte number and phenotype prior to therapy correlate with response in subcutaneously applied rIL-2 therapy of renal cell carcinoma.

The phenotype of peripheral blood lymphocytes of 27 renal cell carcinoma patients before and at the end of subcutaneously given rIL-2 therapy was determined by two colour flow cytometry. Therapy induced changes in peripheral blood leucocyte composition and phenotypes were comparable to those reported for intravenously given rIL-2. The present paper shows a correlation between the 'activation status' of the patient before therapy and eventual response.     

Molecular markers for incidence, prognosis, and response to therapy

Lung cancer is the most common malignancy in the United States and worldwide. In 2011, it is estimated that more than 221,000 people in the United States will be diagnosed with cancer of the lung and bronchus. For patients with early-stage disease, 5-year survival approaches only 50%. Recent advances using molecular, genetic, and proteomic profiling of lung tumors have enabled refining the prognosis for patients with non-small cell lung cancer. With targeted therapies, there is an opportunity to enhance long-term survival. This article discusses several key molecular markers used in the prognostication and treatment of non-small cell lung cancer.     

Soluble interleukin-2 receptors and other markers in primary lung cancer.

Serum levels of soluble interleukin-2 receptors (sIL-2R), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-chorionic gonadotropin (beta-HCG), pregnancy-specific glycoprotein (SP1), and beta 2-microglobulin (beta 2M) were taken in 92 patients with primary lung cancer and 43 controls. The mean value of sIL-2R in the cancer group was twice as high as that of the controls (P less than 0.001) and the highest values were observed in those with small cell carcinoma (SCC) (P less than 0.0001). Of the cancer patients, 51.1% had CEA values higher than the cutoff level of 5 ng/ml. Extended-disease patients had a higher percentage of increased CEA values than those with limited disease. Adenocarcinoma (ADCC) and SCC groups had the highest percentages of increased CEA levels. There was no significant difference between the groups for beta-HCG, AFP, SP1, and beta 2M, and intermarker correlation was not seen. The results suggest that sIL-2R and CEA may be useful in monitoring the extent of disease and possibly indicate the histologic subtype, thus having a bearing on treatment and prognosis.     

Influence of tumour physico-chemical conditions on interleukin-2-stimulated lymphocyte proliferation.

The proliferative response of murine lymphocytes to interleukin-2 (IL-2) was examined under physico-chemical conditions present in solid tumours, namely low oxygen and glucose concentrations and acidic pH. Lymphocytes were cultured for four days in 30 U ml-1 IL-2 to simulate serum IL-2 concentrations attainable with high-dose systemic IL-2 therapy. Lymphocyte proliferation was significantly (P < 0.05) reduced by low oxygen concentrations (both anoxia [0% O2] and hypoxia [10%, low glucose (6 mg dl-1), or acidic pH (6.7 or 6.4). Moderate glucose concentration (32 mg dl-1), or neutral pH (7.0) did not impair proliferation. This study indicates that impairment of lymphocyte proliferation by tumour physico-chemical conditions may be a factor in the relatively poor success rate of IL-2/LAK cell immunotherapy.     

Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy.

Cancer cells elaborate metalloproteinases which may play a role in invasion and metastasis. The serum level of the M(r) 72,000 type IV collagenase (MMP-2) was measured in 87 lung cancer patients. Stage IV cancer levels were significantly elevated (P less than 0.0001) compared to normal sera. A significant difference (P less than 0.01) was found between enzyme levels in the presence versus the absence of distant metastasis. For 29 patients treated with combination chemotherapy, a positive relationship was noted between response failure and elevated enzyme levels. Serum metalloproteinase levels may provide information relevant to prognosis as well as treatment decisions.     

Thalidomide reduces serum C-reactive protein and interleukin-6 and induces response to IL-2 in a fraction of metastatic renal cell cancer patients who failed IL-2-based therapy

Interleukin-2 (IL-2) has some antitumor activity in patients with renal cell carcinoma. It has been noted that response to IL-2 and prognosis may be adversely affected by elevated serum levels of C-reactive protein (CRP) or interleukin-6 (IL-6). We used thalidomide to treat patients with cancer-induced cachexia and noted that the drug significantly reduced serum levels of CRP and IL-6 to normal or near normal levels in a substantial fraction of patients. We tested whether thalidomide might potentiate the response of patients with renal cell carcinoma to IL-2. Four patients with metastatic renal cell carcinoma and high serum levels of CRP and IL-6 who had experienced disease progression on IL-2 were retreated with the same IL-2 regimen combined with thalidomide 300 mg p.o. daily. Two patients achieved good partial responses and 2 patients had prolonged disease stabilization with the combination of IL-2 plus thalidomide. The regimen was well tolerated without increased IL-2-associated toxicity. Reduction of serum CRP or IL-6 levels with thalidomide may enhance the responsiveness of renal cell carcinoma to IL-2. A Phase II study of the combination is in order. It is possible that the thalidomide-induced normalization of serum acute phase proteins might improve the response of other types of malignancy to IL-2 or other immune-based therapies.     

Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.     

Prediction of response to therapy by biomolecular markers: from the research laboratory to the clinic.

Platinum-based therapy has demonstrated efficacy in the treatmentof several types of epithelial tumors [1–3], althoughresponses to almost all chemotherapeutic drugs have been heterogeneous.It is this heterogeneity in clinical response that motivatesresearchers in efforts to identify tumor biological markersuseful in identifying patients who will actually benefit froma specific treatment. The differential expression of moleculeslikely to be involved in the sensitivity of     

Soluble Tie2 and Flt1 extracellular domains in serum of patients with renal cancer and response to antiangiogenic therapy.

Antiangiogenesis drugs can be difficult to evaluate because they produce disease stabilization rather than tumor regression. Markers of endothelial mass in tumors may be of value to monitor therapy and evaluate such drugs. Soluble domains of the endothelial receptor tyrosine kinases, sTie2 (angiopoietin receptor) and sFlt1 (vascular endothelial growth factor receptor-1) were analyzed by sandwich ELISA in serum samples from 43 patients with advanced renal cancer before and 1 month after antiangiogenic therapy with razoxane. Pretreatment sFlt1 levels were 0.77 ng/ml +/- 0.48 (SD) and sTie2 74.3 ng/ml +/- 15 (SD). Pretreatment sFlt1 levels above the median were associated with a lesser chance of stable disease (P = 0.04) and poorer survival (P = 0.01). Fall of sTie2 on treatment was associated with stable disease (P = 0.05) and improved survival (P = 0.04). The soluble receptors measured weeks before response were assessed and correlated with response and survival, showing they may be useful to monitor and develop antiangiogenic therapy.     

Pretreatment prediction of brain tumors' response to radiation therapy using high b-value diffusion-weighted MRI

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm(2) to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced T1-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, R(D), reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and R(D) were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P <.002 and r = 0.77, P <.001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.     

A literature analysis of prognostic factors for response and quality of response of patients with renal cell carcinoma to interleukin-2-based therapy

OBJECTIVE: To characterize prognostic factors for response of advanced renal cell carcinoma to interleukin-2-based regimens. PATIENTS AND METHODS: Data compiled from 80 published series were examined for associations between patient characteristics and outcomes. RESULTS: Response rates were highest in trials utilizing interleukin-2 combinations. Longer median survivals were associated with high percentages of patients with nephrectomy, good performance status, with publication year, response rates, and inversely with median ages. Associations of performance status and prior nephrectomy with response rates were detected in trials with individual patient details. The response rate was higher for patients older than the median age of patients entering each trial, and also higher for males. Among responders, attainment of complete response was associated with fewer sites of involvement. Pooled response duration of patients reported to have complete responses exhibited durability, but no correlation with prognostic factors. Selection factors may have influenced apparent differences between types of regimens. We confirm the potential for durable remissions from interleukin-2-based regimens.     

Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma.

PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 =.000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 +/- 0.3 doses v 14.5 +/- 0.2 doses; P2 =.0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 =.27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 =.0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 =.01; free T4, P2 =.0049; vitiligo, P2 < 10(-6)), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.