Menée sur un modèle murin de cancer du pancréas, cette étude met en évidence l'effet synergique antitumoral d'une photothérapie et d'un immunoadjuvant (chitosane glyqué) appliqué localement, puis identifie le mécanisme biologique associé

Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine

Zhou, Feifan ; Yang, Jingxuan ; Zhang, Yuqing ; Liu, Mingyang ; Lang, Mark L. ; Li, Min ; Chen, Wei R.

Purpose : To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice. Experimental Design : Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth [...]

Menée à partir de l'analyse de 32 pièces de résection prélevées sur des patientes atteintes d'un cancer du sein, cette étude évalue la faisabilité et l'intérêt d'une microtomographie durant une chirurgie mammaire conservatrice pour déterminer avec précision les marges de résection

Micro-computed tomography enables rapid surgical margin assessment during breast conserving surgery (BCS): correlation of whole BCS micro-CT readings to final histopathology

McClatchy, David M. ; Zuurbier, Rebecca A. ; Wells, Wendy A. ; Paulsen, Keith D. ; Pogue, Brian W.

Background : Roughly 23% of breast conserving surgery (BCS) patients undergo a second re-excision procedure due to pathologically positive surgical margins. We investigated the feasibility and potential value of micro-Computed Tomography (micro-CT) as a surgical margin guidance tool during BCS. Methods : A cohort of 32 BCS specimens was prospectively imaged with a pre-clinical micro-CT system upon arrival in the surgical pathology laboratory. Reconstructed micro-CT scans were evaluated [...]

Menée notamment sur des modèles murins de lymphome, cette étude met en évidence la possibilité de générer in vivo, à l'aide de vecteurs lentiviraux, des lymphocytes CAR-T ciblant l'antigène CD19, puis montre que cette stratégie induit une réduction du nombre de lymphocytes B et des signes histopathologiques de syndrome de libération de cytokines

In vivo generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome

Pfeiffer, Anett ; Thalheimer, Frederic B. ; Hartmann, Sylvia ; Frank, Annika M. ; Bender, Ruben R. ; Danisch, Simon ; Costa, Caroline ; Wels, Winfried S. ; Modlich, Ute ; Stripecke, Renata ; Verhoeyen, Els ; Buchholz, Christian J.

Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR [...]

Menée in vitro et à l'aide de xénogreffes de carcinome à petites cellules de l'ovaire de type hypercalcémiant, cette étude met en évidence l'effet synergique antitumoral des inhibiteurs d'histone désacétylase et des inhibiteurs catalytiques d'histone méthyltransférase EZH2

Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit anti-tumor activity in small cell carcinoma of the ovary, hypercalcemic type

Wang, Yemin ; Chen, Shary Yuting ; Colborne, Shane ; Lambert, Galen ; Shin, Chae Young ; Dos Santos, Nancy ; Orlando, Krystal A. ; Lang, Jessica D. ; Hendricks, William P. D. ; Bally, Marcel B. ; Karnezis, Anthony N. ; Hass, Ralf ; Underhill, T. Michael ; Morin, Gregg B. ; Trent, Jeffrey M. ; Weissman, Bernard E. ; Huntsman, David G.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways [...]

Menée à l'aide d'un modèle murin de cancer mammaire, cette étude met en évidence l'intérêt d'injecter par voie intraveineuse des polymères lipidiques chargés en nanoparticules de dioxyde de manganèse pour modifier le micro-environnement tumoral, améliorer l'efficacité de la doxorubicine et accroître l'immunité antitumorale

Combining Tumor Microenvironment Modulating Nanoparticles with Doxorubicin to Enhance Chemotherapeutic Efficacy and Boost Antitumor Immunity

Amini, Mohammad Ali ; Abbasi, Azhar Z. ; Cai, Ping ; Lip, HoYin ; Gordijo, Claudia R. ; Li, Jason ; Chen, Branson ; Zhang, Li ; Rauth, Andrew M. ; Wu, Xiao Yu

Background : Tumor microenvironment (TME) and associated multiple factors are found to contribute to the failures in cancer therapies, including chemo- and immunotherapy. Here we report a new multimodal strategy that uses a bioreactive multifunctional hybrid polymer-lipid encapsulated manganese dioxide nanoparticle (PLMD NP) system to remodel the TME, suppress drug resistance factors, reverse immunosuppressive conditions, and enhance chemotherapy efficacy. Methods : The influence of PLMD NPs on [...]

Menée sur des lignées cellulaires de cancer du sein et à l'aide d'une xénogreffe, cette étude montre qu'un nouvel inhibiteur des récepteurs androgéniques augmente l'effet antitumoral des inhibiteurs de PARP en régulant les voies de réparation de l'ADN

Androgen receptor inhibitor enhances the anti-tumor effect of PARP inhibitor in breast cancer cells by modulating DNA damage response

Min, Ahrum ; Jang, Hyemin ; Kim, Seongyeong ; Lee, Kyung-Hun ; Kim, Debora Keunyoung ; Suh, Koung Jin ; Yang, Yaewon ; Elvin, Paul ; Connor, Mark J. ; Im, Seock-Ah

The androgen receptor (AR) is expressed in 60~70% of breast cancers regardless of ER status and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal anti-proliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, [...]

A partir d'une revue systématique des essais évaluant l'efficacité des anti-PD-1/PD-L1 et anti-CTLA-4, cette méta-analyse évalue le risque de toxicités fatales associées à l'utilisation d'inhibiteurs de points de contrôle immunitaire

Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis

Wang, D. Y. ; Salem, J. ; Cohen, J. V. ; et al.,

Importance : Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.Objective  To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. Design, Setting, and Participants :  We retrospectively queried a World Health Organization (WHO) pharmacovigilance database [...]

Mené sur 43 patients atteints d'un chordome de stade avancé, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité d'un traitement combinant imatinib et évérolimus

Imatinib and Everolimus in Patients With Progressing Advanced Chordoma: A Phase 2 Clinical Study

Stacchiotti, Silvia ; Morosi, Carlo ; Lo Vullo, Salvatore ; Casale, Alessandra ; Palassini, Elena ; Maria Frezza, Anna ; Dinoi, Gabriella ; Messina, Antonella ; Gronchi, Alessandro ; Cavalleri, Adalberto ; Venturelli, Elisabetta ; Morelli, Daniele ; Pilotti, Silvana ; Collini, Paola ; Brich, Silvia ; Tamborini, Elena ; Mariani, Luigi ; Casali, Paolo G.

Background : We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma. Methods : In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or [...]

Menée en Corée à partir de données portant sur 167 patients atteints d'un cancer du poumon non à petites cellules, cette étude analyse la présence et les caractéristiques associées au risque de pneumonie induite par les inhibiteurs de points de contrôle immunitaire

Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer

Cho, Jun Yeun ; Kim, Junghoon ; Lee, Jong Seok ; Kim, Yu Jung ; Kim, Se Hyun ; Lee, Yeon Joo ; Cho, Young-Jae ; Yoon, Ho Il ; Ho Lee, Jae ; Lee, Choon-Taek ; Park, Jong Sun

Objectives : Immune checkpoint inhibitors (ICIs) can cause pneumonitis in lung cancer patients. We aimed to identify the clinical and radiologic characteristics, incidence, and risk factors of ICI-related pneumonitis in patients with non-small cell lung cancer (NSCLC). Materials and Methods : Medical records and chest computed tomography scans of NSCLC patients treated with an ICI over a 5-year period at a tertiary hospital were retrospectively analyzed. Clinical characteristics were compared [...]

Mené sur 86 patients atteints d'un cancer du poumon non à petites cellules de stade IV, cet essai de phase Ib évalue la dose maximale tolérée, les caractéristiques pharmacocinétiques, l'activité antitumorale et la toxicité de l'abémaciclib, un inhibiteur de CDK4/6, dispensé en combinaison avec le pémétrexed, la gemcitabine ou le ramucirumab

Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study

Kim, Edward S. ; Kelly, Karen ; Paz-Ares, Luis G. ; Garrido, Pilar ; Jalal, Shadia ; Mahadevan, Daruka ; Gutierrez, Martin ; Provencio, Mariano ; Schaefer, Eric ; Shaheen, Monte ; Johnston, Erica L. ; Turner, P. Kellie ; Kambhampati, Siva Rama Prasad ; Beckmann, Richard ; Hossain, Anwar ; John, William J. ; Goldman, Jonathan W.

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Experimental Design: An initial dose escalation phase was used to determine the MTD of twice-daily [...]

Mené sur 1 254 patientes atteintes d'un cancer du sein HER2+, cet essai de phase III évalue la non-infériorité, du point de vue de la survie sans maladie, et la toxicité d'une administration de courte durée du trastuzumab (9 semaines), dispensé en traitement adjuvant avec une chimiothérapie, en comparaison avec une administration longue (1 an)

9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study

Conte, P. ; Frassoldati, A. ; Bisagni, G. ; Brandes, A. A. ; Donadio, M. ; Garrone, O. ; Piacentini, F. ; Cavanna, L. ; Giotta, F. ; Aieta, M. ; Gebbia, V. ; Molino, A. ; Musolino, A. ; Ferro, A. ; Maltoni, R. ; Danese, S. ; Zamagni, C. ; Rimanti, A. ; Cagossi, K. ; Russo, A. ; Pronzato, P. ; Giovanardi, F. ; Moretti, G. ; Lombardo, L. ; Schirone, A. ; Beano, A. ; Amaducci, L. ; Bajardi, E. A. ; Vicini, R. ; Balduzzi, S. ; D’Amico, R. ; Guarneri, V.

Background : Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment for HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The Short-HER study was aimed to assess the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods : HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT > 2cm, G3, lympho-vascular [...]

Mené sur 116 patientes atteintes d'un cancer du sein triple négatif de stade métastatique (âge médian : 53 ans), cet essai de phase I évalue l'activité antitumorale, l'efficacité, du point de vue du taux de réponse objective, de la durée de la réponse, de la survie sans progression et de la survie globale, et la toxicité de l'atézolizumab en monothérapie (durée médiane de suivi : 25,3 mois)

Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: A phase 1 study

Emens, L. A. ; Cruz, C. ; Eder, J. ; et al.,

Importance : Atezolizumab (anti–programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported. Objective : To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC. Design, Setting, and Participants : Women with mTNBC (defined by investigator assessment) were enrolled [...]

Mené sur 19 patients atteints d'un carcinome urothélial de stade métastatique, cet essai de phase I évalue l'eficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement combinant évérolimus et pazopanib, en fonction de la présence de mutations et du nombre d'anomalies dans le nombre de copies de 300 gènes associés à un risque de cancer

Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma

Bellmunt, Joaquim ; Lalani, Aly-Khan A. ; Jacobus, Sussana ; Wankowicz, Stephanie A. ; Polacek, Laura ; Takeda, David Y. ; Harshman, Lauren C. ; Wagle, Nikhil ; Moreno, Irene ; Lundgren, Kevin ; Bossé, Dominick ; Van Allen, Eliezer M. ; Choueiri, Toni K. ; Rosenberg, Jonathan E.

Background : Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. Methods : mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary [...]

Mené sur 32 patients atteints d'un cancer de la tête et du cou de stade avancé, cet essai de phase I évalue l'efficacité, du point de vue du taux de réponse, de la survie sans progression et de la survie globale, et la toxicité de l'atézolizumab, un anti-PD-L1 dispensé par intraveineuse

Safety and Clinical Activity of Atezolizumab in Head and Neck Cancer: Results From a Phase I Trial

Colevas, A. D. ; Bahleda, R. ; Braiteh, F. ; Balmanoukian, A. ; Brana, I. ; Chau, N. G. ; Sarkar, I. ; Molinero, L. ; Grossman, W. ; Kabbinavar, F. ; Fassò, M. ; O’Hear, C. ; Powderly, J.

Background : Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti–PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods : Patients with [...]

Menée sur 110 patients atteints d'un cancer du poumon non à petites cellules, d'un mélanome métastatique ou d'un carcinome à cellules rénales traité par inhibiteur de points de contrôle immunitaire anti-PD-1, cette étude multicentrique évalue l'effet d'une radiothérapie sur le nombre de lymphocytes et la survie des patients

The impact of radiation therapy on lymphocyte count and survival in metastatic cancer patients receiving PD-1 immune checkpoint inhibitors

Pike, Luke R. G. ; Bang, Andrew ; Mahal, Brandon A. ; Taylor, Allison ; Krishnan, Monica ; Spektor, Alexander ; Cagney, Daniel N. ; Aizer, Ayal A. ; Alexander, Brian M. ; Rahma, Osama ; Balboni, Tracy ; Ott, Patrick A. ; Hodi, F. Stephen ; Schoenfeld, Jonathan D.

Purpose : Therapeutic radiation has conflicting immune effects: radiation (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICI) and whether this impacts outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-lymphocyte-ratio (NTL) in patients being treated with [...]

Menée à partir de données portant sur 2 901 patients atteints d'un carcinome épidermoïde de la tête et du cou de stade III-IVb, cette étude compare l'efficacité, du point de vue de la survie globale, et la toxicité d'une forte dose (administrée toutes les trois semaines) et d'une faible dose (administrée toutes les semaines) de cisplatine en combinaison avec une radiothérapie concomitante

Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck

Bauml, Joshua M. ; Vinnakota, Ravi ; Anna Park, Yeun-Hee ; Bates, Susan E. ; Fojo, Tito ; Aggarwal, Charu ; Limaye, Sewanti ; Damjanov, Nevena ; Di Stefano, Jessica ; Ciunci, Christine ; Genden, Eric M. ; Wisnivesky, Juan P. ; Ferrandino, Rocco ; Mamtani, Ronac ; Langer, Corey J. ; Cohen, Roger B. ; Sigel, Keith

Background : Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. Methods : We examined outcomes of patients with stage III–IVb [...]

Cet article analyse l'intérêt des rétrovirus endogènes humains dans l'immunothérapie des cancers

Human endogenous retroviruses and their implication for immunotherapeutics of cancer

Attermann, A. S. ; Bjerregaard, A. M. ; Saini, S. K. ; Grønbæk, K. ; Hadrup, S. R.

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute about 8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically [...]

Cet article passe en revue les différents obstacles à franchir pour développer une nouvelle génération d'immunothérapies anticancéreuses vraiment personnalisées

The hallmarks of successful anticancer immunotherapy

Galluzzi, Lorenzo ; Chan, Timothy A. ; Kroemer, Guido ; Wolchok, Jedd D. ; López-Soto, Alejandro

Immunotherapy is revolutionizing the clinical management of multiple tumors. However, only a fraction of patients with cancer responds to immunotherapy, and currently available immunotherapeutic agents are expensive and generally associated with considerable toxicity, calling for the identification of robust predictive biomarkers. The overall genomic configuration of malignant cells, potentially favoring the emergence of immunogenic tumor neoantigens, as well as specific mutations that [...]

Cet article analyse le rôle des technologies de séquençage de nouvelle génération dans la médecine personnalisée et identifie les facteurs empêchant l'utilisation de traitements spécifiques chez les patients atteints d'un cancer avec mutations génétiques

The Role of Next-Generation Sequencing in Precision Medicine: A Review of Outcomes in Oncology

Morash, Margaret ; Mitchell, Hannah ; Beltran, Himisha ; Elemento, Olivier ; Pathak, Jyotishman

Precision medicine seeks to use genomic data to help provide the right treatment to the right patient at the right time. Next-generation sequencing technology allows for the rapid and accurate sequencing of many genes at once. This technology is becoming more common in oncology, though the clinical benefit of incorporating it into precision medicine strategies remains under significant debate. In this manuscript, we discuss the early findings of the impact of next-generation sequencing on [...]

Cet article passe en revue les études récentes sur le développement, l'évolution et la chimiorésistance des tumeurs de l'ovaire

Tumor evolution and chemoresistance in ovarian cancer

Kim, Soochi ; Han, Youngjin ; Kim, Se Ik ; Kim, Hee-Seung ; Kim, Seong Jin ; Song, Yong Sang

Development of novel strategies to overcome chemoresistance is central goal in ovarian cancer research. Natural history of the cancer development and progression is being reconstructed by genomic datasets to understand the evolutionary pattern and direction. Recent studies suggest that intra-tumor heterogeneity (ITH) is the main cause of treatment failure by chemoresistance in many types of cancers including ovarian cancer. ITH increases the fitness of tumor to adapt to incompatible [...]