Search

An Antibody-Drug Conjugate (armed antibody) is a vectorized chemotherapy that results from the grafting of a cytotoxic agent on a monoclonal antibody thanks to a judiciously designed spacer arm. ADCs have made considerable progress in 10 years. In 2009, only gemtuzumab ozogamicin (Mylotarg ® ) was used clinically. In 2019, 4 other ADCs have been approved and more than 80 others are in active clinical trials. The first part of this review will focus on Food and Drug Administration-approved Antibody-Drug Conjugates, their limitations as well as their associated toxicity and resistance mechanisms., (© 2019 médecine/sciences – Inserm.)

An Antibody-Drug Conjugate (armed antibody) is a vectorized chemotherapy that results from the grafting of a cytotoxic agent on a monoclonal antibody via a judiciously designed spacer arm. ADCs have made considerable progress in 10 years. In 2009, only gemtuzumab ozogamicin (Mylotarg ® ) was used clinically. In 2019, 4 other ADCs have been approved and more than 80 others are in active clinical trials. The second part of this review will focus on new emerging strategies to address ADCs drawbacks and attempt to broaden their therapeutic window. Finally, combinations with conventional chemotherapy or checkpoint inhibitors will be discussed, in the pursuit to make Antibody-Drug Conjugates the embodiment of Paul Ehrlich's dream of the magic bullet., (© 2019 médecine/sciences – Inserm.)

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) which associates the selective intracellular targeting of the cytotoxic agent, DM1 (maytansine derivative) to the antitumor activity of trastuzumab. T-DM1 targets the epidermal growth factor receptor 2 (HER2), highly expressed in the most aggressive forms of breast cancer. Current standard of care in HER2-positive advanced or metastatic breast cancers has its limitations, particularly after progression on HER2-targeted approved therapies. T-DM1 showed a significant antitumor activity in vitro and in vivo, and in experimental models resistant to HER2-targeted agents. Phase I and II studies showed that the maximum tolerated dose for T-DM1 is 3.6 mg/kg given intravenously every three weeks. At this recommended dose, T-DM1 provided objective tumor responses and favourable safety profile. A phase II randomised study, evaluating T-DM1 in first line vs trastuzumab plus docetaxel, the current standard of care in advanced or metastatic breast cancers, showed improved tolerability and efficacy. Recently, the results of EMILIA, a phase III randomised study assessing, after prior treatment with trastuzumab and a taxane, the efficacy and the safety of T-DM1 vs lapatinib plus capecitabine, confirmed the therapeutic benefit. T-DM1 appears to be an effective therapeutic option to treat patients with HER2-positive metastatic breast cancer.

Microtubules are dynamic filamentous cytoskeletal proteins that are an important therapeutic target in patients with tumors. Microtubule binding agents have been part of the pharmacopoeia of cancer for decades, and until the advent of targeted therapy microtubules represented the only alternative to DNA as a therapeutic target in cancer. There are currently a variety of available vinca alkaloids and taxanes and other agents, such as ixabepilone and eribulin, have also been approved. Maytansinoids have been used for the production of immunoconjugates, monoclonal antibodies covalently bound to antimitotic molecules. The screening of a variety of botanical species and marine organisms continues to yield promising new antitubulin agents with novel properties. Enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms are the three main objectives in the current search for novel microtubule binding agents.

Introduction: Several investigators have addressed the relationship between expression of class III beta-tubulin and outcome in patients with nonsmall cell lung cancer (NSCLC) treated with tubulin-binding agents (TBA)., State of Art: High expression of class III beta-tubulin has been found to be correlated with low response rates and reduced survival in advanced NSCLC patients treated with taxane/vinorelbine--containing regimens. Two studies have shown that patients receiving paclitaxel whose tumours expressed high levels of class III beta-tubulin had a lower response rate and shorter survival, whereas this variable was not found to be predictive in patients receiving regimens without TBA. Conversely, analysis of samples from operable NSCLC patients in the JBR-10 trial showed that cisplatin/vinorelbine chemotherapy seemed to overcome the negative prognostic effect of high class III beta-tubulin expression and that the greatest benefit from chemotherapy was observed in patients with high class III beta-tubulin expression., Perspectives: In advanced NSCLC, high betaIII tubulin expression may prompt selection of taxane-free regimens as the preferred initial treatment approach. The epothilones may fulfil such a role in the treatment of NSCLC., Conclusions: betaIII tubulin expression is emerging as a valuable biomarker for taxane resistance in advanced disease, as well as offering prognostic information for outcomes among patients with earlier stage disease., (Copyright 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Haematological malignancies, although relatively infrequent diseases, have benefited from major advances both in terms of diagnosis, identification of prognostic factors and therapeutic breakthroughs. The combination of morphological, cytogenetic, immunological and molecular approaches has greatly contributed to the identification of homogeneous entities, as well as prognostic subgroups of patients. Targeted therapies, such as monoclonal antibodies and kinase inhibitors, have demonstrated their efficacy in this group of diseases and since then has been generalized to patients with solid tumours. Current efforts include the evaluation of individual characteristics of patients, including their genetic make-up, to reduce treatment toxicity while increasing the quality and the duration of response.

Efflux pumps located in the bacterial membranes are responsible for low level resistance to antibiotics, considered not to be relevant in the clinic and thus often neglected. However, these pumps contribute to the emergence of high level antibiotic resistance mechanisms, which are responsible for severe complications during the treatment of infectious diseases. Therefore it is necessary to take into account these pumps while developing novel antibacterial agents. Among these new research strategies, the development of efflux pump inhibitors seems to be an attractive approach to restore the activity of some "classical" antibiotics and to limit the emergence of multiresistant strains associated with hospital-acquired infections. In this review, we focalise on Staphylococcus aureus efflux pumps and their potential inhibitors.

The heterogeneous vascular distribution and blood flow in solid tumors create areas of low oxygen partial pressure or hypoxic areas. Hypoxia acts as a stressor that perpetuates the malignant phenotype by increasing genomic instability, altering gene expression, and the tumor's metabolic microenvironment. The heterodimeric transcription factor, hypoxia inducible factor, HIF-1 (Hypoxia-Inducible Factor-1), allows tumor cells to adapt to their microenvironment by stimulating the expression of a large number of hypoxia-related genes. Hypoxia has been shown to reduce chemotherapeutic efficacy by causing cells within hypoxic regions to cycle more slowly, and by providing a selection mechanism for cells with reduced susceptibility for apoptosis. Due to limited drug penetration within solid tumors, hypoxic regions (especially those located furthest from blood vessels) are often protected from the cytotoxic effects of chemotherapeutic agents further reducing drug efficacy. Given the contribution of tumor hypoxia to tumor progression and drug resistance, a number of hypoxia-targeted therapeutics are under development. These therapeutics ranges from hypoxic cytotoxins, such as tirapazamine and the pro-drug AQ4N, to the use of obligate anaerobic bacterial spores. Development of methodologies to characterize causes of drug resistance related to the tumor microenvironment has considerable potential to improve the outcome following systemic treatment of solid tumors.

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it. Translational research needs to develop in close connection with the patients in order to enable a bi-directional flow of knowledge from cognitive research toward medical applications and from observations made on patients toward cognitive research. Placed under the aegis of the French National Cancer Institute and Leem Research, the group has put forth a strategy for implementing translational research in cancerology in France to make it attractive, competitive and efficient and to foster the development of public-private partnerships.

Rituximab is now routinely use in clinical practice for B cell lymphoma and chronic lymphocytic leukaemia treatment. Mechanisms of action of this monoclonal antibody are not fully understood. Antibody dependent cellular cytotoxicity (ADCC), complement dependent toxicity (CDC) and apoptosis have been all shown to play a role. But the prominence of each mechanism is considerably varying among the different reports, the studied cell lines and the experimental models. A lack of explanations still exists between the efficacy observed in vivo and the low reproducible cytotoxicity reproduced shown in vitro. Despite an intensive research, most of the mechanisms of resistance to rituximab are unknown.

Cytotoxic nucleoside analogues are widely used in treatment of patients with hematological malignancies as well as for some solid tumors. Resistance developed against these molecules limit their clinical use. Many studies on cell models and clinical samples have identified cellular mechanisms involved in this phenomenon. Here, we describe the available data concerning the proteins involved in the metabolism and the mechanism of action of nucleoside analogues, as well as the clinical studies showing their implication in the resistance to these drugs.

In spite of its close chemical similarities with cytarabine, gemcitabine was first evaluated in the treatment of solid tumors. However recent studies performed in patients with hematological malignancies have shown interesting therapeutic potential. Response to single agent gemcitabine have been observed in patients with Hodgkin's disease, cutaneous T cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and in certain cases of aggressive B cell lymphoma. These preliminary results show high response rates with acceptable toxicity and justify the incorporation of gemcitabine in combination regimens for the treatment of selected lymphoproliferative disorders.

The role of drugs inhibiting viral replication in patients infected with HIV has been confirmed. Until now only dideoxynucleosides, which are reverse transcriptase inhibitors, have demonstrated antiviral activity in humans. A number of compounds acting on other steps of the viral cycle are currently being evaluated and clinical trials are being performed. Some investigators are attempting to inhibit the binding of viral particles to target cells and their penetration into these by acting on the interaction between HIV ant the CD4 molecule. Another approach consists in the characterization of enzymatic activities which are specific of HIV, other than reverse transcriptase, such as ribonuclease H, integrase or protease, in order to prepare specific inhibitors. Attempts are made to inhibit retroviral gene expression and production of viral particles in infected cells. The development of new nucleoside analogues and drugs with mechanisms of action and toxicities different from those of zidovudine should allow in the near future combination chemotherapy of HIV infection.

The 100 patients with aggressive malignant non Hodgkin lymphoma treated with the LNH-80 regimen were evaluated for long-term survival and quality of life. The LNH-80 regimen consisted of three intensive courses of adriamycin, cyclophosphamide, vindesine and bleomycin, followed by consolidation and final intensification, as previously described. Of the eighty-four patients who achieved CR after induction, fifty-two patients are alive in continuous complete remission with a median follow-up of 9.2 years. Twenty-nine CR patients (35%) relapsed. Sixty-six percent of the relapses occurred during the first 18 months following the end of treatment but late relapses were observed up to 7 years off-therapy. Factors adversely correlated with response in multivariate analysis were poor performance status, bone marrow involvement and the presence of more than one extranodal site. Factors adversely correlated with survival were age, high grade subtypes, and bone marrow involvement. The fifty-two long-term responders were evaluated for quality of life parameters such as working ability, sexual function, fertility and absence of long-term sequelae. Of the 41 patients who worked before disease, 66% had resumed their normal job and 24% had retired. Sexual activity was considered to be satisfactory by 66% of the patients. Eleven of the 15 patients (73%) who wanted children had between one and three children. Seven patients (14%) considered having mild long-term sequelae but all long-term survivors reported having an acceptable quality of life. Five of the patients who reached CR (6%) had a second neoplasia. The LNH-80 regimen allowed 52% of the patients to benefit from long-term disease-free survival with minor long-term toxicity.

Gangliosides are glycosphingolipids which contain neuraminic acid. Although they are present in the plasma membranes of all cells, gangliosides are expressed differently, both quantitatively and qualitatively, in certain types of cancer. Modifications in ganglioside composition may account for some of the abnormal interactions between these tumor cells and their environment. Furthermore, some of the gangliosides are shed by tumor cells and may modify host immunity, thus contributing to the development of tumors. In cases of melanoma and neuroblastoma, the modifications in ganglioside expression are such that gangliosides may be used both as tumor markers and as targets for immunotherapy.

Distal metastases are classically situated below the knee or elbow. However, metastases of the extremities: wrist and hand, or ankle and foot, have etiological and histological characteristics. We report one case of bone metastasis and one case of soft tissue metastasis. The distal bone metastases are often solitary. Bronchial cancers represent the most frequent cause of distal metastases (20% of all cases). They are responsible for 50% of distal metastases of the upper limb and more often occurs as a squamous cancer. Their localization may sometimes reveal a bronchial cancer, and so allow curative surgery. The metastases of soft tissue are exceptional. In the literature, only 2 cases of soft tissue metastasis of bronchopulmonary cancer are described. Clinically, it is a painful swelling preserving the under lying bone. The prognosis is always one of bronchial metastasis cancer with an average survival of 3-6 months.

Monoclonal antibodies, produced in vitro from hybridoma supernatants, may be administered to cancer patients either directly or after coupling to an anticancer agent (immunoconjugates). Monoclonal antibodies concentrate in tumor site, where they initiate an anti-tumor effect, either by activation of the patient's immune system or by the cytotoxic agent which is present at high concentration within the tumor, while systemic concentrations of this agent remain low. Monoclonal antibodies which are radiolabelled also allow the immunoscintigraphic study of the immunoconjugates' diffusion within the body. Given certain precautions of administration, the clinical and biological tolerance of this type of treatment is satisfactory, most of the side effects correspond to an allergic response to the murine antibodies used. Clinical studies performed in patients with leukemias have demonstrated a significant antitumor effect although this effect is transitory. Studies performed on small series of patients with solid tumors (gastrointestinal neoplasms, melanoma, leptomeningeal localizations, ovarian peritoneal carcinosis) have shown a few cases of major responses and/or complete remissions having lasted up to periods of many months. These studies as well as the perspectives for the development of this type of therapy are presented and discussed.

Monoclonal antibodies directed against antigens borne by tumors have already been the object of clinical trials in patients with leukemia or solid tumors. These antibodies, generally obtained from murine hybridomask, are used alone or as immunoconjugates, i.e. coupled to a non-specific antimitotic agent. Under the proper conditions they may be administered with a satisfactory clinical and biological tolerance. The antimitotic action of these antibodies, which is specifically directed against neoplastic cells, has been demonstrated in vitro and in animal models and is found inconstantly in leukemias. Studies have been performed in patients bearing solid tumors, with large initial tumoral mass, showing partial regression in a few cases. A number of parameters, including modalities of administration, types of immunoconjugates and mechanisms of action in vivo, must be explored to increase the antineoplastic potential of monoclonal antibodies.