Control Of Metastases Research Articles

Thoracic Radiotherapy for Renal Cell Carcinoma Metastases: Local Control for the Management of Lung and Mediastinal Disease in the Modern Era.

Radiotherapy (RT) is an alternative local therapy to metastasectomy in the treatment of thoracic metastases from renal cell carcinoma (RCC), including the management of life-threatening disease. We reviewed patients with lung and mediastinal RCC metastases treated with RT at our institution. Overall survival (OS) and metastasis control (MC) was measured from the start of RT using the Kaplan-Meier (KM) method. Seventy-one patients were treated with RT for 89 lung (n=58) or mediastinal (n=31) metastases. Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9). MC at 1, 3, and 5-years was 96.6%, 83.5%, and 67.9%, respectively. For the 58-lung metastasis-directed RT courses, MC rates at 1, 3, and 5-years were 95.0%, 84.5%, and 84.5%, respectively (median MC not reached). For the 31-mediastinum metastasis-directed RT courses, MC rates at 1, 3, and 5-years were 100%, 43.4%, and 43.4%, respectively (median MC 2.9 years). MC was significantly improved for lung lesions compared to mediastinal lesions (P=.046). OS for the entire cohort at 1, 3, and 5 years was 65.2%, 48.5%, and 38.0%. There was no difference in OS based on metastatic sites in the 71 patients. Nineteen patients received RT to 19 lesions with the intention of preventing an event such as airway compromise or vascular invasion. One and two-year MC for these 19 lesions were 88.9% and 71.1%, respectively (median local control 2.4 years). OS in these 19 patients at 1, 2, and 5 years were 62.1%, 48.3%, and 32.2% respectively, with median survival 1.2 years. No patients developed grade 4 or 5 acute or late toxicities. Radiation therapy can safely achieve high metastasis control rates for lung and mediastinal metastases from RCC, including lesions at high risk for causing a life-threatening event.

CD103+ Tissue Resident T-Lymphocytes Accumulate in Lung Metastases and Are Correlated with Poor Prognosis in ccRCC.

Simple SummaryClear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor, with highly heterogeneous responses to immune checkpoint inhibition therapy. The role of immune cells infiltrating distant metastases and their impact on prognosis and response to immunotherapy are still unclear. To elucidate the prognostic value of immune cell subtypes, we analyzed the immune cell infiltrate in ccRCC primary tumors and paired distant metastases. We hypothesized that specific subtypes of immune cells may be involved in the control of metastases and may have an impact on the prognosis of ccRCC.Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor with variable responses to immune checkpoint therapy. The significance of the immune cell infiltrate in distant metastases, their association with the immune infiltrate in the primary tumors and their impact on prognosis are poorly described. We hypothesized that specific subtypes of immune cells may be involved in the control of metastases and may have an impact on the prognosis of ccRCC. We analyzed the immune microenvironment in ccRCC primary tumors with distant metastases, paired distant metastases and non-metastasized ccRCC (n = 25 each group) by immunohistochemistry. Confirmatory analyses for CD8+ and CD103+ cells were performed in a large ccRCC cohort (n = 241) using a TCGA-KIRC data set (ITGAE/CD103). High immune cell infiltration in primary ccRCC tumors was significantly correlated with the development of distant tumor metastasis (p < 0.05). A high density of CD103+ cells in ccRCC was more frequent in poorly differentiated tumors (p < 0.001). ccRCCs showed high levels of ITGAE/CD103 compared with adjacent non-neoplastic tissue. A higher density of CD103+ cells and a higher ITGAE/CD103 expression were significantly correlated with poor overall survival in ccRCC (log rank p < 0.05). Our results show a major prognostic value of the immune pattern, in particular CD103+ cell infiltration in ccRCC, and highlight the importance of the tumor immune microenvironment.

Brain Metastasis Treatment: The Place of Tyrosine Kinase Inhibitors and How to Facilitate Their Diffusion across the Blood–Brain Barrier

The incidence of brain metastases has been increasing constantly for the last 20 years, because of better control of metastases outside the brain, and the failure of most drugs to cross the blood–brain barrier at relevant pharmacological concentrations. Recent advances in the molecular biology of cancer have led to the identification of numerous molecular alterations, some of them targetable with the development of specific targeted therapies, including tyrosine kinase inhibitors. In this narrative review, we set out to describe the state-of-the-art in the use of tyrosine kinase inhibitors for the treatment of melanoma, lung cancer, and breast cancer brain metastases. We also report preclinical and clinical pharmacological data on brain exposure to tyrosine kinase inhibitors after oral administration and describe the most recent advances liable to facilitate their penetration of the blood–brain barrier at relevant concentrations and limit their physiological efflux.

Fe2P nanorods based photothermal therapy combined with immune checkpoint inhibitors for pancreatic cancer

Abstract Treatment of pancreatic cancer is faced with great difficulties and challenges due to high lethality and metastasis. Synergism of targeted therapy and immunotherapy has been considered as ideal strategy to both eliminate primary tumors and control metastases. For the treatment of advanced pancreatic cancer, we demonstrated a local photothermal therapy (PTT) following administration of monoclonal antibody of programmed death ligand 1 (αPD-L1). Fe2P nanorods were employed as a Fenton agent and photothermal agent, which modified with DSPE-PEG2000-Mal for improved biocompatibility and Mal mediated-antigen presentation. Under a low dose laser irradiation at 980 nm, Fe2P-PEG-Mal nanorods (NRs) mediated PTT could induce immunogenic tumor cell death that can cause dendritic cells (DCs) infiltration and maturation. In a bilateral pancreatic tumor model, the local treatment of NRs-PTT on primary tumor could cause the increased infiltration of cytotoxic T lymphocytes (CTLs) and decreased residential of M2 macrophages in untreated distal tumors. Furthermore, subsequently intervened αPD-L1 could enhance cell death triggered by CTLs in distal tumors through reversing immunosuppression. An orthotopic pancreatic tumor model was used to further confirm the therapeutic outcome. Finally, the combination of NRs based PTT and αPD-L1 based immunotherapy was able to significantly eliminate orthotopic pancreatic tumors and reduce mesentery metastases. Thus, the strategy may provide a more effective treatment for pancreatic cancer.

Abstract 2616: RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target

Abstract RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells via influencing motility, invasion, and chemokine secretion, but as yet there is no integrated model of the precise mechanism of how RhoC promotes metastasis. As these processes require disruptions in cell-cell junctions, we use wild-type and CRISPR RhoC and RhoA knockout lines of the breast cancer cell lines SUM-149 (inflammatory breast cancer, IBC) and MDA-MB-231 (triple-negative breast cancer, TNBC) in order to assess the influence of RhoC and RhoA on their cell-cell junctions. Protein lysates from these cell lines were blotted for the adherens junction markers E-cadherin and β-catenin, as well as the tight junction markers ZO-1 and Occludin. Cells were also fixed and stained for these junction markers to further assess expression and localization. In order to measure junction stability, we conducted FITC-Dextran assays, wherein cells were grown to confluency on Transwell plates, the apical chambers were incubated with FITC-Dextran solution for 24 hours, and the fluorescence of the basal chambers was subsequently measured. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM-149 IBC and MDA-MB-231 TNBC cells results in increased epithelial morphology, cell-cell connections, and tight junction marker colocalization, as measured via immunofluorescent staining. Furthermore, RhoC knockout cells have increased junctional proteins compared to wild-type cells, as measured by Western blot. In functional assessments of junction stability, RhoC knockout cells have increased barrier integrity compared to wild-type cells, by the FITC-Dextran leakage assay. These results suggest that high expression of RhoC in cancer cells destabilizes tight junctions, although loose clusters of cells are observed depending on cell type; taken together, upregulation of RhoC activation may contribute to increased metastatic potential, in part through destabilization of tight junctions. We will report on further invasion functional assays and RNA-seq data on the RhoC knockout cell lines. Taken together, these data support an important role for RhoC in tight junction modulation, thereby advancing the evidence for a potential highly specific new therapeutic target in RhoC-driven metastases control. Citation Format: Hannah Abraham, Laura Goo, Andrew Little, Joel Yates, Zhifen Wu, Sofia D. Merajver. RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2616.

Control of Metastases via Myeloid CD39 and NK Cell Effector Function.

Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR and CD73). The antimetastatic activity of anti-CD39 was NK cell and IFNγ dependent, and anti-CD39 enhanced the percentage and quantity of IFNγ produced and CD107a expression in lung-infiltrating NK cells following tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene-targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow-derived myeloid cells was essential for anti-CD39's antimetastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 coexpressing lung alveolar macrophages was specifically reduced 1 day after anti-CD39 therapy. The data provide a mechanism of action involving NK cells and myeloid cells, and anti-CD39 combined with anti-PD-1, NK cell-activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.

Thoracic radiotherapy for renal cell carcinoma metastases.

409 Background: For patients with metastatic renal cell carcinoma (RCC), metastasis-directed local therapies can delay progression and need to initiate/switch systemic therapy. We examined our experience treating lung or mediastinal metastases from RCC with radiotherapy (RT). Methods: We reviewed patients with lung or mediastinal metastases from RCC treated with RT. Overall survival (OS) and local control (LC) was measured from the start of RT using the Kaplan-Meier method. Results: Seventy-one patients were treated with RT for 89 lung or mediastinal metastases. Median follow-up was 2.0 years (range 0.02-11.4 years) after RT for surviving patients. Most patients were male (n=53, 74.6%). Median age was 58.4 years at initial diagnosis. Histology was most frequently clear cell carcinoma (n=62, 89.9%). At the time of treatment, 18 patients (25.4%) had 1-3 metastases, and the remainder (74.6%) had 4 or more metastases. Forty-one patients (57.5%) received systemic therapy prior to thoracic radiation. Initial systemic therapy was most commonly sunitinib (45%) or pazopanib (32.5%). Median time from starting systemic therapy to initiation of radiation was 2.0 years. Fifty-eight lung metastases and 31 mediastinal metastases were treated with a median 5 fractions (range 1-40), to a median total dose of 4800 cGy (range 400-7000), with a median fraction size of 500 cGy (range 150-2000). Thirty-three lesions were treated with concurrent systemic therapy, which was most commonly nivolumab (n=16). Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9 years) after initiation of radiation. 1, 3, and 5 year MC (metastasis control) were 96.6%, 83.5% and 67.9%, respectively. Nine patients were treated with radiation in order to delay initiation of systemic therapy. Of these, 3 eventually received systemic therapy, initiated at a median 2.5 years after radiation. At last follow-up, 41 patients (57.7%) had died. Median OS was 2.6 years. Survival at 1, 3, and 5 years was 65.2%, 48.5%, and 38%, respectively. Conclusions: Radiation achieves high metastasis control rates for lung and mediastinal metastases from RCC, potentially delaying the need for systemic therapy.

Stereotactic body radiation therapy for stage I non-small cell lung carcinomas: Moderate hypofractionation optimizes outcome

ObjectivesIn case of inoperability or refusal of surgery, stereotactic body radiation therapy (SBRT) is the most effective treatment for a stage I non-small cell lung carcinoma (NSCLC). The results obtained by this irradiation technique are considerably superior to those observed in the time of conventional 3D irradiation and its toxicities are much less important, which makes it possible in elderly patients, or those presenting cardio-pulmonary comorbidities and a poor perfomance status. Materials and methodsThis study is a retrospective analysis of 90 patients who underwent SBRT for a stage I NSCLC between 2010 and 2015. Its purpose is to describe its effectiveness in term of overall survival (OS), specific survival (SS), local control (LC), regional control (RC) and metastatic control (MC) as well as their prognostic factors, and its tolerance. ResultsLC, RC, MC as well as OS and SS rate at 4 years were comparable to the main prospective studies, respectively 89%, 92%, 70%, 33% and 66%. No LC prognostic factor could be identified. Radiation pneumonitis was observed with a rate of 61.5%, of which 56% were asymptomatic, and 4% of the patients had a rib fracture. ConclusionsSBRT is an efficient and well-tolerated treatment for stage I non-small cell lung carcinomas

Abstract P5-22-23: Electrochemotherapy : A new local therapy for cutaneous metastases of breast cancer

Abstract Background : Electrochemotherapy (ECT) is a new local therapy combining the administration of an intravenous chemotherapy (bleomycin) followed by the direct application of electric pulses by an electrode to the treated areas. Electric pulses transiently permeabilize the membrane of the tumor cell ( electroporation), improving intracellular diffusion of a poorly permeant chemotherapeutic agent, ithereby ncreasing its cytotoxicity and decreasing systemic toxicity. ECT can be offered to patients with cutaneous or subutaneous metastases of breast cancer who are no longer suitable for extensive surgery or radiotherapy ( e.g. due to past irradiation of the breast or chest wall). ECT 's applications are palliative. It is -, delivered with the aim of local control of the tumor, relief of symptoms associated with cutaneous recurrence -(ulceration, bleeding, pain),i and mproving patients'quality of life. The aim of this study is to demonstrate that ECT has a high efficacity and a low toxicity profile making it an interesting alternative to conventional therapies. Material and methods : our study is a retrospective study (approved by our local ethics committee) which included 8 patients between June 2013 and June 2016. The patients had histologically proven cutaneous and or subcutaneous metastases of their breast cancer, without any sign of lymphangitis. All the tumors expressed ER and /or PgR and 2 of them were HER2 positive tumors. The patients received a single or multiple courses of ECT ; the outcomes were clinical response, toxicity, local and distant recurrence. The two patients whose tumors expressed HER2, also had synchronous controlateral axillary nodal metastases. They underwent axillary dissection performed during ECT course. Among the six other patients, no other metastases than cutaneous lesions were observed. Results : The 8 included patients had already received chest wall irradiation for the treatment of their primary breast cancer. A total of 37 nodules were treated (mean : 4.5 per patient), whose mean size was 17mm (10-34mm). Six patients(75%) had a complete response after a single course of ECT. Two patients exhibited a partial response and underwent a second course of ECT at 6 months. The two patients with Her2 positive tumors received taxane-based chemotherapy and anti HER2 agents. All the patients were also given endocrine therapy. After a median follow up of 26 months (11-47 months), no patient had a local cutaneous recurrence. Overall survival rate was 75% : 2 patients died following progression of systemic disease (pulmonary and hepatic metastases). No complications due to toxicity were observed. Discussion and conclusion :In selected patients with ( cutaneous and subcutaneous metastases of breast cancer with no sign of lymphangitis), ECT offers a very good rate of clinical response and a durable control of metastases. This innovative technique has the advantage of being minimally –invasive and well –tolerated. Citation Format: Berliere M, Raguzzi E, Bernard M, Gerday A, Coyette M, Piette P, Duhoux F, Lengele B. Electrochemotherapy : A new local therapy for cutaneous metastases of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-23.

A novel immunization strategy using cytokine/chemokines induces new effective systemic immune responses, and frequent complete regressions of human metastatic melanoma

ABSTRACTImmune responses have been elicited by a variety of cancer vaccines, but seldom induce regressions of established cancers in humans. As a novel therapeutic immunization strategy, we tested the hypothesis that multiple cytokines/chemokines secreted early in secondary responses ex-vivo might mimic the secretory environment guiding new immune responses. The early development of immune responses is regulated by multiple cytokines/chemokines acting together, which at physiologic concentrations act locally in concert with antigen to have non-specific effects on adjacent cells, including the maturation of dendritic cells, homing and retention of T cells at the site of antigen, and the differentiation and expansion of T cell clones with appropriate receptors. We postulated that repeated injections into a metastasis of an exogenous chemokine/cytokine mixture might establish the environment of an immune response and allow circulating T cell clones to self- select for mutant neo-epitopes in the tumor and generate systemic immune responses. To test this idea we injected some metastases in patients with multiple cutaneous melanoma nodules while never injecting other control metastases in the same patient. New immune responses were identified by the development of dense lymphocytic infiltrates in never-injected metastases, and the frequent complete regression of never-injected metastases, a surprising observation. 70% of subjects developed dense infiltrates of cytotoxic CD8 cells in the center and margin of never-injected metastases; 38% of subjects had complete and often durable regressions of all metastases, without the use of check-point inhibitors, suggesting that, as a proof-of-principle, an immunization strategy can control advanced human metastatic melanoma.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

BackgroundPathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methodsIn this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan–Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal–Wallis/Mann–Whitney U tests.ResultsPatients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal–Wallis/Mann–Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.ConclusionsWe found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

18F-FDG PET response and clinical outcomes after stereotactic body radiation therapy for metastatic melanoma

BackgroundClinical data that support stereotactic body radiation therapy (SBRT) metastatic malignant melanoma (MM) are limited. Furthermore, functional imaging with 18F-fludeoxyglucose positron emission tomography (PET) may offer a more accurate post-SBRT assessment. Therefore, we assessed the clinical outcomes and metabolic response of metastatic MM after SBRT. Methods and materialsPatients with MM who were treated with SBRT and had pre- and post-PET scans (>1) were included in this study. A total of 390 pre- and post-SBRT PET/computed tomography (CT) scans for 80 metastases were analyzed. The PET metabolic response was evaluated per the PET Response Criteria in Solid Tumors (PERCIST), version 1.0, criteria. Single-fraction equivalent dose (SFED) was calculated as per the standard. The Kaplan-Meier method was used for estimates of overall survival (OS) and progression-free survival. The cumulative incidence method was used to estimate metastasis control (MC). A Wilcoxon test was used to compare survival estimates. The prognostic factors for MC and OS were assessed using the Cox proportional hazards model, and the Likelihood Ratio was also used for comparisons between groups. ResultsA median of 6 PET scans (range, 2-6 scans) was evaluated for each metastasis. The median SFED was 42.8 Gy (range, 18-56.4 Gy) and the median biologically effective dose was 254.4 Gy2.5 (range, 100.8-540 Gy2.5). Twenty percent of patients received chemotherapy and 59% received immunotherapy: granulocyte-macrophage colony-stimulating factor (64%) and ipilimumab (34%). MC was 94% and 90% at 1 year and 3 years, respectively. The OS was 74% and 27% and 1 year and 3 years, respectively. Complete response was achieved in 90% at a median of 2.8 months (range, 0.4-25.2 months). SFED >24 Gy correlated with improved MC (93% vs 75%, P = .01). Acute and late grade 3+ toxicities were 4% and 11%, respectively, with no grade 5 toxicity. ConclusionsPost-SBRT PET/CT for extracranial metastatic MM resulted in high rates of complete response at a median of 2.8 months, and durable MC was achieved with SFED >24 Gy. SBRT, in addition to surgery and ablation, should be discussed with patients with MM, especially those with oligometastases.

Long-Term Follow-up in Medullary Thyroid Carcinoma.

After surgery, patients with medullary thyroid carcinoma (MTC) should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperatively, patients with MTC are staged to separate those at low risk from those at high risk of recurrence. The TNM staging system is based on tumor size, extra-thyroidal invasion, nodal metastasis, and distant spread of cancer. In addition, the number of lymph-node metastases, the number of compartments involved, and the postoperative calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented. The postoperative normalization of the serum CTN level is associated with a favorable outcome. When patients have basal serum CTN levels less than 150pg/ml after a thyroidectomy, any persistent or recurrent disease is nearly always confined to lymph nodes in the neck. When the postoperative serum CTN level exceeds 150pg/ml, patients should be evaluated with imaging procedures, including computed tomography (CT) of the neck and chest, contrast-enhanced magnetic resonance imaging (MRI) and ultrasound (US) of the liver, bone scintigraphy, MRI of the bone, and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases by quantifying increases in tumor size over time from sequential imaging studies analyzed with response evaluation criteria in solid tumors (RECIST), and by determining the tumor marker doubling time from sequential measures of serum CTN or CEA levels over multiple time points. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck following thyroidectomy are candidates for neck operations, depending on the tumor extension. Once metastases appear, the clinician must decide which patients require therapy. This requires a balance between the (often) slow rate of tumor progression, which is associated with a good quality of life, and the limited efficacy and potential toxicities of local and systemic therapies. Considering that metastatic MTC is incurable, the management goals are to provide loco-regional disease control, palliate symptoms of hormonal excess, such as diarrhea, palliate symptomatic metastases, like pain or bone fracture, and control metastases that threaten life, such as bronchial obstruction or spinal cord compression. This can be achieved with palliative surgery, external beam radiation therapy (EBRT), or systemic therapy with tyrosine kinase inhibitor (TKI).

Characteristics and Clinical Impacts of the Immune Environments in Colorectal and Renal Cell Carcinoma Lung Metastases: Influence of Tumor Origin

If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors. We analyzed by immunohistochemistry (n = 192) and qPCR (n = 32) the immune environments of colorectal carcinoma and RCC lung metastases. Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP(+) mature dendritic cells (P < 0.0001) and lower densities of NKp46(+) NK cells (P < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8(+) and DC-LAMP(+) cells correlated with longer overall survival (OS) in colorectal carcinoma (P = 0.008) and shorter OS in RCC (P < 0.0001). High NK-cell densities were associated with improved survival in RCC (P = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A TH1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases. Our results show a major prognostic value of the immune pattern (CD8(+)/DC-LAMP(+) cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment.

Maximum tolerated dose versus metronomic scheduling in the treatment of metastatic cancers

Although optimal control theory has been used for the theoretical study of anti-cancerous drugs scheduling optimization, with the aim of reducing the primary tumor volume, the effect on metastases is often ignored. Here, we use a previously published model for metastatic development to define an optimal control problem at the scale of the entire organism of the patient. In silico study of the impact of different scheduling strategies for anti-angiogenic and cytotoxic agents (either in monotherapy or in combination) is performed to compare a low-dose, continuous, metronomic administration scheme with a more classical maximum tolerated dose schedule. Simulation results reveal differences between primary tumor reduction and control of metastases but overall suggest use of the metronomic protocol.

Enhancement of the antigen-specific T cell immune responses and therapeutic antitumor effects generated by therapeutic HPV DNA vaccine by histone deacetylase inhibitor

Objective: Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. Antigen-specific immunotherapy is an attractive approach for the treatment of cancers since it has the potency to specifically eradicate systemic tumors and control metastases without damaging normal cells. A favorable approach for antigen-specific immunotherapy is the use of DNA vaccines due to their safety, stability and ease of preparation.

Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy.

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or α-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/α-CD40, but not IL-2 or α-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/α-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/α-CD40 induced the IFN-γ- and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/α-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/α-CD40-mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease.

Genetic adjuvant therapy for pancreatic cancer and other solid tumours

Cancer malignancies are responsible for approximately a quarter of all deaths in the developed world. Primary tumours can often be treated successfully with surgical resection, chemotherapy or radiation; however, these...

Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.