[show abstract][hide abstract] ABSTRACT: The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall survival.
[show abstract][hide abstract] ABSTRACT: An efficient adaptive immunity is critical for a longer survival in cancer. We investigated the prognostic value of tumor infiltration by CD8(+) T cells expressing the chemokine-receptor-7 (T(ccr7)) and the correlation between tumor infiltration by T(ccr7) and regulatory CD4(+)FoxP3(+) T cells (T(reg)) in 76 metastatic colorectal cancer (mCRC) patients enrolled in a phase III trial.
T(ccr7) and T(reg) cell infiltration in tumor samples was quantified by immunohistochemistry. The correlation among T(ccr7), T(reg) tumor infiltration, and patients' outcome was evaluated.
High T(ccr7) tumor infiltration was predictive of prolonged OS [high vs. low T(ccr7) score: median 38 months (95% CI: 24.5-51.4) vs. 20 months (95% CI: 11.4-28.5); HR = 0.48 (95% CI: 0.24-0.96); P = 0.03] and prolonged progression-free survival [PFS; high vs. low T(ccr7) score: median 12 months (95% CI: 7.7-16.2) vs. 7 months (95% CI: 5.2-8.7); HR = 0.54 (95% CI: 0.28-1.01); P = 0.01] after front-line chemotherapy. Regression analysis did not show correlation between T(ccr7) and T(reg) infiltration levels. However, the cluster of patients showing concomitant high infiltration by both T(ccr7) and T(reg) disclosed a favorable outcome [double high vs. double low tumor infiltration score: median OS = 35 months (95% CI: 20.8-49.1) vs. 17 months (95% CI: 4.6-29.3); HR = 0.32 (95% CI: 0.12-0.87); P = 0.02 and median PFS = 11 months (95% CI: 9.4-12.5) vs. 5 months (95% CI: 2.2-7.7); HR = 0.43 (95% CI: 0.17-1.06); P = 0.01].
High T(ccr7) tumor infiltration score is a favorable prognostic factor for mCRC. Our findings underline the relevance of microenvironment-related immunologic events for patient outcome.
Clinical Cancer Research 12/2011; 18(3):850-7. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent findings have disclosed the role of UDP-glucuronosyltransferase (UGT) 1A1*28 on the haematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drug-metabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case (patients experiencing ≥ grade 3 gastrointestinal, (GI) toxicity) - control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 1/17 patients without GI toxicity (P=0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity versus 4/17 patients without GI toxicity (P=0.0135). The heterozygous genotype G/A in the 388G>A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade ≥ 3 GI toxicity vs. 14/17 patients without GI toxicity (P=0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine.
Cancer biology & therapy 11/2011; 12(9):780-7. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bevacizumab, is a humanized monoclonal antibody to vasculo-endothelial-growth-factor, with anticancer activity in non-small-cell-lung cancer (NSCLC) patients. Our previous results from a dose/finding phase I trial in NSCLC patients, demonstrated the anti-angiogenic effects and toxicity of a newest bevacizumab-based combination with fractioned cisplatin and daily oral etoposide. We designed a phase II trial to evaluate in advanced NSCLC patients the antitumor activity and the safety of this novel regimen. In particular, 45 patients (36 males and 9 females), with a mean age of 54 years, an ECOG ≤ 2, stage IIIB/IV and NSCLC (28 adenocarcinomas, 11 squamous-cell carcinomas, 2 large-cell carcinomas, 4 undifferentiated carcinomas), were enrolled. They received cisplatin (30 mg/sqm, days 1-3), oral etoposide (50 mg, days 1-15) and bevacizumab (5 mg/kg, day 3) every three weeks (mPEBev regimen). Patients who achieved an objective response or stable disease received maintenance treatment with bevacizumab in combination with erlotinib until progression. Grade I-II hematological, mucosal toxicity and alopecia were the most common adverse events. The occurrence of infections (17%), thromboembolic events (4.4%) and severe mood depression (6.7%) was also recorded. A partial response was achieved in 31 (68.8%) patients, disease remained stable in 8 (17.8%), and disease progressed in 6 (13.3%) with a progression-free-survival of 9.53 months (95%CI, 7.7-11.46). Our bio-chemotherapy regimen resulted very active in advanced NSCLC, however, the toxicity associated with the treatment requires strict selection of the patients to enroll in future studies.
Cancer biology & therapy 07/2011; 12(2):112-8. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: We designed a translational clinical trial to investigate whether a dose/dense chemotherapy regimen is able to enhance in patients with non-small-cell-lung-cancer (NSCLC) the anti-angiogenic effects of bevacizumab, a murine/human monoclonal antibody to the vasculo-endothelial-growth-factor (VEGF). We also evaluated the antitumor activity of this combination.
The combined treatment induced a significant decline in the blood-perfusion of primary tumor (NMR-study); in serum levels of VEGF, angiopoietin-1, thrombospondin-1; and in the number of VEGF-transporting cells. In the group of 40 patients who received bevacizumab an objective response and a disease stabilization rate of 77.5% (95% CI, 75.63-93.17) and 15%, respectively, were recorded with a time to progression of 7.6 mo. Grade I-II hematological toxicity was the most common adverse event. Four early deaths within 3 mo, three cases of pneumonia, and six cases of mood depression at higher bevacizumab dosage were observed. The most active biological and maximum tolerated dose were 5 and 7.5 mg/kg, respectively.
Forty-eight patients (42 males and six females) with stage III B/IV NSCLC, a mean age of 68 y, and ECOG <or=2 were enrolled in the study. They received every 3 w fractioned cisplatinum (30 mg/sqm, days 1-3) and oral etoposide (50 mg, days 1-15) and were divided in five cohorts receiving different bevacizumab dosages (0; 2.5; 5; 7.5; and 10 mg/kg) on day 3.
The combination of bevacizumab with a dose/dense chemotherapy regimen resulted moderately safe but showed significant anti-angiogenic and antitumor activity.
Cancer biology & therapy 05/2010; 9(9):685-93. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Antitumor immune response and chemotherapy-induced immunomodulation in colon cancer patients represented the rationale to design new strategies, like GOLFIG chemoimmunotherapy (gemcitabine, oxaliplatin, 5-fluorouracil/folinic acid, granulocyte macrophage colony-stimulating factor, and aldesleukine), that resulted a safe and very active regimen. Antitumor activity and immunity feedback to GOLFIG were strictly correlated with the best outcome observed in patients with autoimmunity signs, increase of central memory T cells, and decrease of regulatory T cells (Treg) in the peripheral blood. We thus investigated a potential correlation between the Treg tumor infiltration at diagnosis and the clinical outcome in a current randomized phase 3 trial aimed to compare the GOLFIG regimen with the standard FOLFOX chemotherapy (GOLFIG-2). An immunohistochemistry study was carried out to quantify the infiltration of Treg/FoxP3+ T lymphocytes in tumor samples of 57 patients enrolled in the GOLFIG-2 trial. Treg tumor infiltration scores were correlated with overall survival, treatment-relative survival, and progression-free survival (PFS). Higher Treg tumor infiltration scores were associated with a better prognosis in the whole series (Treg high score vs. low score: overall survival=mean 43.2 mo vs. 28.6 mo, P=0.0005) and a better outcome after treatment (Treg high score vs. low score: PFS=mean 15.8 mo vs. 8.8 mo, P=0.0009; treatment-relative survival=mean 23.1 mo vs. 18.2 mo, P=0.004). PFS was significantly longer in GOLFIG high versus all other subgroups (mean 18.1 mo vs. 9.9 mo, P=0.01). Our results suggest that a higher FoxP3+ T-lymphocyte tumor infiltration score is a favorable prognostic factor in colon cancer patients undergoing chemo or chemoimmunotherapy.
[show abstract][hide abstract] ABSTRACT: Background. The antitumor activity of a novel biweekly gemcitabine (G) + docetaxel (D) regimen +/- granulocyte-macrophage colony stimulating factor (GM-CSF) and aldesleukine (IL-2) has been evaluated in a phase II trial in advanced pretreated non-small-cell lung cancer (NSCLC). Results. The treatment was well tolerated. The 42.3% response rate exceeded the predefined target activity, while time to progression (TTP) and overall survival (OS) were 7 and 11.2 months, respectively. A greater objective response rate (58.3% vs 28.6%) and an increased number of eosinophils, basophils and activated mononuclear blood cells were observed in those patients who also received cytokine administration. Methods. Twenty-six NSCLC patients received second line G (1000 mg/m2) and D (75 mg/m2) every 15 days. 12/26 patients also received s.c. GM-CSF (100µg, days 2-6) and s.c. IL-2 (0.5MIU/ twice daily, days 7-14 and 16-29) by random selection. Conclusion. The biweekly GD regimen is a safe and active second-line treatment in NSCLC. Addition of immune-adjuvant cytokines' may enhance the activity of this therapeutic combination.
Cancer biology & therapy 04/2009; 8(6):497-502. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: GOLFIG chemoimmunotherapy regimen proved to be a safe and very active chemoimmunotherapy regimen in advanced colon cancer patients. We have thus investigated the immunobiological feedback to the treatment and its possible correlation with the clinical outcome of these patients.
This clinical and immunologic study involved 46 patients, 27 males and 19 females, enrolled in the GOLFIG-1 phase II trial who received gemcitabine (1,000 mg/m(2) on days 1 and 15), oxaliplatin (85 mg/m(2) on days 2 and 16), levofolinic acid (100 mg/m(2) on days 1, 2, 15, and 16), and 5-fluorouracil (400 mg/m(2) as a bolus, and 800 mg/m(2) as a 24-hour infusion on days 1, 2, 15, and 16) followed by s.c. granulocyte macrophage colony-stimulating factor (100 mug, on days 3-7) and interleukin 2 (0.5 x 10(6) IU twice a day on days 8-14 and 17-29).
The regimen was confirmed to be safe and very active in pretreated patients with metastatic colorectal cancer. A subgroup analysis of these patients revealed a prolonged time to progression and survival in six patients who developed late signs of autoimmunity. A multivariate analysis validated the occurrence of autoimmunity signs as an independent predictor of favorable outcome. A parallel immunologic study detected in the peripheral blood mononuclear cells of these patients a progressive increase in lymphocyte and eosinophil counts, amplification in central memory, a marked depletion of immunosuppressive regulatory T cells, and activation of colon cancer-specific cytotoxic T cells.
Our results suggest that immunity feedback to GOLFIG regimen and its antitumor activity are tightly correlated.
Clinical Cancer Research 08/2008; 14(13):4192-9. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: No standard chemotherapy has been so far definitely settled for elderly patients with metastatic breast cancer (MBC). In order to identify a regimen with acceptable efficacy and low burden of non-overlapping toxic effects, a combination consisting of liposomal pegilated doxorubicin (PLD) with alternating oral and intravenous vinorelbine (NVB) has been investigated in a phase II study.
Thirty-four consecutive patients (median age 71 years; range 65-82) with MBC have been enrolled. Based on 4-weekly cycles, PLD 40 mg/m(2) plus NVB 25 mg/m(2) i.v., have been administered intravenously on day 1 and oral NVB 60 mg/m(2) on day 15.
All patients were assessable for safety and efficacy. In all, 17 responses were documented with three complete responses (CR) and 14 partial responses, with an overall response rate of 50% (95% CI 36-66). Median overall survival time was 13 months and the median time to progression 8 months. Interestingly, all the patients with CR are still alive with a disease-free survival of more than 1 year. The main toxicity was neutropenia: grade 3 in 15% and grade 4 in 11% of patients, respectively. Febrile neutropenia was recorded in three patients not requiring dose reduction. Other frequently reported adverse events included: anemia, nausea, vomiting, stomatitis, all rarely severe. The evaluation of quality of life (QoL) did not show any significant change during the study.
Our data suggest that this combination is active and well tolerated in elderly patients with MBC and could represent another efficacious chance for the management of this population.
Cancer Chemotherapy and Pharmacology 08/2008; 62(2):285-92. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: The design of novel therapeutic strategies based on tumour molecular features and specific carcinogenetic pathways is a compelling issue. Tumours arising in BRCA1-defective individual carriers constitute a specific entity which resembles the basal-like molecular phenotype for breast tumours, while BRCA1-defective ovarian cancer has a molecular signature which is also shared by a substantial amount of sporadic tumours. Several important issues are derived from the role of BRCA1 gene product in critical cell functions like DNA repair, transcription regulation and cell cycle checkpoint control. It has been recently demonstrated that the loss of such functions in BRCA1-defective tumours results in a specific profile of sensitivity to anti-cancer drugs. Moreover, BRCA1 appears to retain a critical role in the response of cells to stress as well as to the growth promoting stimuli generated by estrogens and peptide growth factors. Therefore, it is conceivable that loss of a functional BRCA1 produces a general de-arrangement of cellular signaling which might allow the identification of specific and high priority targets and lead to individualized signal transduction-based anti-tumour approaches. We will review the most important findings related to BRCA1 effects on cellular signaling in order to depict a general scenario for selective chemopreventive and therapeutic strategies.
Current Signal Transduction Therapy 04/2007; 2(2):165-173. · 0.45 Impact Factor