Sophie Dessureault

Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection.

The priming of an appropriate anti‐tumor T cell response rarely results in the rejection of established tumors. The characteristics of tumors that allow them to evade a T cell‐mediated rejection are unknown for many tumors. We report on evidence that the expression of the immunosuppressive enzyme, indoleamine 2,3‐dioxygenase (IDO) by mononuclear cells that invade tumors and tumor‐draining lymph nodes, is 1 mechanism that may account for this observation. Lewis lung carcinoma (LLC) cells stimulated a more robust allogeneic T cell response in vitro in the presence of a competitive inhibitor of IDO, 1‐methyl tryptophan. When administered in vivo this inhibitor also resulted in delayed LLC tumor growth in syngeneic mice. Our study provides evidence for a novel mechanism whereby tumors evade rejection by the immune system, and suggests the possibility that inhibiting IDO may be developed as an anti‐cancer immunotherapeutic strategy.

Improved staging of node-negative patients with intermediate to thick melanomas (>1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy

Background: Elective lymph node dissection ELND may contribute to a survival benefit in certain stratified subsets of melanoma patients. We hypothesized that lymphatic mapping and sentinel lymph node SLN biopsy with complete node dissection if metastases are present may improve both staging and survival of patients with clinically negative nodes, without subjecting all patients to the morbidity associated with complete ELND.

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer

Objective: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). Background: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. Methods: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. Results: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (&khgr;2 P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. Conclusions: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142)

Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-hodgkin's lymphoma cells

Stromal cells are an essential component of the bone marrow microenvironment that regulate or supports tumor survival. In this study we therefore studied the role of stromal cells in lymphoma cell survival. We demonstrated that adhesion of the B-cell lymphoma cell lines SUDH-4 and 10 to bone marrow stroma inhibited mitoxantrone-induced apoptosis. This adhesion-dependent inhibition of mitoxantrone-induced apoptosis correlated with decreased activation of caspases-8 and 9, and cleavage of caspase 3 and PARP. Electrophoretic mobility shift assays (EMSA) analysis demonstrated significantly increased NF-κB binding activity in lymphoma cells adhered to stroma cells compared to lymphoma cells in suspension. This DNA binding activity could be attributed to cell adhesion-mediated proteolysis of the NF-κB precursor, p100 (NF-κB2). This resulted in the generation of active p52, which translocated to the nucleus in complex with p65 and RelB. Coculture with stromal cells also induced expression of the NF-κB-regulated anti-apoptotic molecules, XIAP, cIAP1 and cIAP2. Inhibition of NF-κB significantly suppressed HS-5-induced protection against apoptosis in lymphoma cell lines as well as in primary lymphoma cells. Thus, bone marrow stroma protects B-cell lymphoma cells against apoptosis, at least in part through activation of NF-κB dependent mechanism involving up-regulation of NF-κB regulated antiapoptotic proteins. Consequently, this study suggests a new approach to decrease the resistance of lymphoma to chemotherapy.

Immunotherapy for melanoma.

BACKGROUND Immunotherapy for cancers is based on the principle that the hosts immune system is capable of generating immune responses against tumor cells. Currently available treatments for melanoma patients are limited by poor response rates. Interferon-a has been approved for adjuvant treatment of stage III melanoma with improved survival. New and more innovative approaches with improved efficacy are needed. METHODS We reviewed the various new approaches and strategies for immunotherapy for the treatment of melanoma. RESULTS Immunotherapy for melanoma includes a number of different strategies with vaccines utilizing whole cell tumors, peptides, cytokine-mediated dendritic cells, DNA and RNA, and antibodies. CONCLUSIONS A variety of approaches can be used to enhance immune reactivity in patients with melanoma. Preclinical studies and initial clinical trials have shown promising results. Additional clinical trials are currently ongoing to evaluate the clinical efficacy and the associated toxicities of these novel treatment strategies.

Survival Outcomes in Node-Negative Breast Cancer Patients Evaluated With Complete Axillary Node Dissection Versus Sentinel Lymph Node Biopsy

BackgroundSentinel lymph node (SLN) biopsy combined with microstaging-associated immunohistochemical staining for cytokeratin more accurately assigns patients to their corresponding diagnostic stage. The purpose of this study was to compare the survival outcomes of node-negative patients who received an SLN biopsy with historical control data of node-negative patients who received routine complete axillary lymph node dissection (CALND) in the pre-SLN biopsy era.MethodsUnder institutional review board approval, 2458 node-negative invasive breast cancer patients between the ages of 25 and 94 years (mean, 60 years) were treated at our institution from January 1986 to May 2004. Of these 2458 patients, 604 (25%) were evaluated with CALND, whereas 1854 (75%) were evaluated with SLN biopsy. All were treated according to the current stage-specific guidelines. Kaplan-Meier graphs of overall survival and disease-free survival were constructed for each group of patients, and the two groups were compared by using the log-rank test.ResultsOverall survival and disease-free survival for the CALND and SLN biopsy groups did not differ significantly (P = .98). The average number of lymph nodes extracted in the pre-SLN biopsy group was 18, whereas the average number of SLNs extracted in the post-SLN biopsy group was 3.ConclusionsThe survival rate among node-negative breast cancer patients who received an SLN biopsy alone has proven to have no significant difference (P = .98) from the survival rate among node-negative patients who received a CALND. SLN biopsy alone should replace CALND as the primary tool for axillary staging of breast cancer in node-negative patients.

Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family in bone marrow stromal cells protects non-Hodgkin's B lymphoma cells from apoptosis

This study explores whether lymphoma cell adhesion-induced B cell-activating factor (BAFF) expression in bone marrow stromal cells (BMSCs) protects B lymphoma cells from apoptosis. We first showed protection of lymphoma cells from apoptosis by conditioned medium of a stromal cell-lymphoma cell coculture, either spontaneous or induced by mitoxantrone, implying a role for soluble factor(s) in lymphoma cell survival. Addition of BAFF counteracted mitoxantrone-induced apoptosis and elicited a reduction in spontaneous apoptosis in primary lymphomas, suggesting a role of BAFF in sustaining B-cell survival. Abundant BAFF was detected in the BMSC cell line (HS-5) and primary BMSCs by flow cytometry, RT-PCR and immunoblotting. BAFF levels were 20- to 200-fold higher in BMSCs than in lymphoma cells, and lymphoma cell adhesion to BMSCs augmented BAFF secretion twofold through upregulation of BAFF gene expression. Finally, neutralization of BAFF by TACI-Ig or depletion of BAFF by small hairpin RNA (shRNA) in BMSCs significantly enhanced lymphoma cell response to chemotherapy and overcame stroma-mediated drug resistance, suggesting that lymphoma cells use BMSC-derived BAFF as a survival factor. These findings support the hypothesis that lymphoma cells interact with BMSCs, resulting in stromal niches with high BAFF concentration, and identify BMSC-derived BAFF as a functional determinant for B lymphoma cell survival in the bone marrow environment.

Toxicities associated with hyperthermic isolated limb perfusion and isolated limb infusion in the treatment of melanoma and sarcoma

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) may play a significant role in the treatment of patients with recurrent or in transit extremity melanoma or sarcoma that is unresectable. These procedures may be indicated when patients are otherwise faced with the possibility of a debilitating amputation. Not entirely benign treatment modalities, HILP and ILI can be associated with regional and systemic toxicities. We conducted a literature search of published studies using HILP and ILI for the treatment of extremity sarcomas and melanomas, and associated toxicities was performed. The regional toxicities of HILP and ILI are similar. The most common toxicities reported are mild to moderate. However, when severe regional toxicity occurs, albeit infrequently (<5%), fasciotomies or even amputation may be necessary. Some studies have showed a relationship between acute regional toxicities and long term regional morbidity. Systemic toxicity appears to be more frequent when TNF-α is used in combination with other drugs during HILP, however the use of TNF-α in the United States is limited to trials. Although regional toxicities are similar, systemic toxicity of ILI is minimal compared to HILP. ILI is easier to repeat, technically less complex, and may be more acceptable in infirmed patients. Long term morbidity and outcomes for ILI are still being evaluated. Both of these techniques may be suitable options in patients with unresectable advanced or recurrent, or in transit extremity melanoma or sarcoma.

Tailored versus Generic Interventions for Skin Cancer Risk Reduction for Family Members of Melanoma Patients

BACKGROUND Improving strategies for risk reduction among family members of patients with melanoma may reduce their risk for melanoma. OBJECTIVE To evaluate the effects of two behavioral interventions designed to improve the frequency of total cutaneous skin examination by a health provider (TCE), skin self-examination (SSE), and sun protection among first degree relatives of patients with melanoma; and to evaluate whether increased intentions, increased benefits, decreased barriers, and improved sunscreen self-efficacy mediated the effects of the tailored intervention, as compared with the generic intervention on TCE, SSE, or sun protection. METHODS Four hundred forty-three family members (56 parents, 248 siblings, 239 children) who were nonadherent with these practices were randomly assigned to either a generic (N = 218) or a tailored intervention (N = 225) which included 3 print mailings and 1 telephone session. Participants completed measures of TCE, SSE, and sun protections at baseline, 6 months, and 1 year, and measures of intentions, benefits, barriers, and self-efficacy at baseline and 6 months. RESULTS Those enrolled in the tailored intervention had almost a twofold increased probability of having a TCE ( p < .0001). Treatment effects in favor of the tailored intervention were also noted for sun protection habits ( p < .02). Increases in TCE intentions mediated the tailored interventions effects on TCE. Increases in sun protection intentions mediated effects of the tailored interventions effect on sun protection. CONCLUSIONS Tailored interventions may improve risk reduction practices among family members of patients with melanoma.

Systemic Therapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future:

BACKGROUND Although approximately 80% of hepatocellular carcinoma (HCC) cases occur in developing countries, the incidence of HCC in Western countries is on the rise due to the impact of hepatitis C. Challenges in developing effective therapies include the inherent chemoresistance of HCC, the pharmacologic challenges presented by a diseased liver, the presentation of most patients at advanced stages, and the difficulty in adequately measuring radiological response. While responses to traditional chemotherapeutic agents have been documented, significant survival benefit is debatable. METHODS The authors review the results of published clinical trials of systemic therapy and immunotherapy that have impacted the present treatment of HCC. RESULTS With recent progress in the elucidation of HCC molecular pathways, targeted agents show promise. The multikinase inhibitor sorafenib has provided survival benefit in patients with advanced HCC and well-preserved liver function. Sunitinib, bevacizumab, epidermal growth factor receptor inhibitors, and mammalian target of rapamycin (mTOR) inhibitors have shown activity in small patient cohorts. Immunotherapy appears to be a promising approach that can result in the regression of bulky, invasive cancer in some patients. CONCLUSIONS New agents with a variety of mechanisms of activity offer promising therapeutic options for patients with advanced HCC.