Immunotherapy of breast cancer

Introduction: Immunotherapy of breast cancer has been shown to prevent recurrence, improve survival and eliminate breast cancer in humans.

Areas covered: The reason for this review is to present the current information and the prospects for the future of immunotherapy of breast cancer in humans to include tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy, and immune modulatory agents, such as adjuvants to stimulate the immune response and inhibitors of checkpoint blockade to prevent downmodulation of activated lymphocytes, to enhance these modalities. The research discussed and the literature search undertaken is of the clinical immunotherapy of breast cancer in humans, from 2000 to September, 2011.

Expert opinion: The key message of the paper is that one reason for the failure of the immune system to control macroscopic disease is that the immune escape mechanisms involving both tumor and the tumor stroma prevent the immune system from destroying the tumor. Changing the tumor microenvironment is necessary to eliminate macroscopic tumors. Prospects for improvement are proposals for combining current modalities of therapy with type 1 cellular immunity-inducing agents, all targeting multiple tumor antigens and in the context of minimal disease.     

Sonographic detection of diffuse peripheral nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease characterized by recurrent demyelination and remyelination with resultant thickening of the peripheral nerves. We report a case in which sonography was instrumental in demonstrating diffuse peripheral nerve hypertrophy. On sonography, both brachial plexuses were found to be diffusely hypertrophic and hypoechoic. Similar findings were noted for the median, sciatic, and femoral nerves. The brachial plexus findings were confirmed by MRI.     

Immunotherapy for non-small-cell lung cancer

Activation of the host immune system represents an attractive treatment approach for cancers. In non-small-cell lung cancer (NSCLC), a variety of immunotherapies, including nonspecific immune stimulants, vaccines and checkpoint inhibitors, have been evaluated in clinical trials. Several randomized Phase III trials have failed to demonstrate clinical benefit from nonspecific immune stimulants and vaccines in the overall trial populations. Activity of vaccines in subsets of patients in these trials needs further evaluation. Unlike vaccines aimed at stimulating a cellular immune response to antigens differentially expressed in cancers, checkpoint inhibitors aim at overcoming immune inhibitory signals in the tumor microenvironment via pharmacological inhibition of immune checkpoints – a crucial tumoral immune escape mechanism. Early clinical trials of checkpoint inhibitors showed promising results with some durable responses. Better understanding of the mechanisms of immunosuppression specific to NSCLC will be crucial for successful patient selection for immunotherapy.     

Immunotherapy for the treatment of breast cancer

Introduction: Breast cancer is the most common cancer as well as the first cause of death by cancer in women worldwide. Although routine treatment improves the outcome of early stage breast cancer patients, there is no effective therapy for the disseminated disease. Immunotherapy has emerged as a powerful therapeutic strategy for the treatment of many cancers. Although traditionally conceived as a non-immunogenic tumor, breast cancer is now considered a potential target for immunotherapy.

Areas covered: In this review, the authors discuss different immunotherapeutic strategies that are currently being tested for the treatment of breast cancer: These strategies include: (i) blockade of immunological checkpoints, (ii) antitumor vaccines, (iii) regulatory T cell blockade, (iv) adoptive T cell transfer therapy, (iv) adoptive immunotherapy with monoclonal antibodies, and (v) combination of immunotherapy with chemotherapy.

Expert opinion: A growing body of evidence indicates that immunotherapeutic strategies can benefit a larger cohort of breast cancer patients than hitherto anticipated. Since breast tumors entail multiple mechanisms to impair antitumor immunity, the immunological characterization of individual tumors and the selection of suitable combinations of chemotherapeutic and immunotherapeutic approaches are required to achieve significant clinical benefit in these patients.     

Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective

Introduction: Conventional chemotherapies seemed to have reached a therapeutic plateau in the treatment of solid tumors and many metastatic diseases are still incurable. Events of chemo-resistance and relapses appear to be sustained by a subset of putative cancer stem cells (CSCs). New anticancer strategies need to face this new challenge exploring their efficacy against CSCs. Immunotherapy has raised enthusiasms in cancer therapy and its potential against CSCs is an intriguing field of research.

Areas covered: In this work we reviewed the immunotherapy approaches directed against CSCs in solid tumors. We schematically divided adaptive immunotherapy strategies, mainly based on dendritic cell-vaccination, and strategies exploiting MHC-unrestricted effectors like natural killer cells, γδ T lymphocytes and cytokine-induced killer cells. Findings, strength and limitations of these models are discussed and compared highlighting their potential clinical relevance.

Expert opinion: The important biologic role and clinical relevance of CSCs introduced a ‘noble target’ for immunotherapy and cancer treatments in general. Initial evidences suggest that CSCs may be susceptible to various types of immunotherapy attacks, overcoming their chemo-resistance. Investigation of important safety issues, based on shared features with ‘normal’ stem cells, along with intriguing synergisms with modulatory agents are open challenges for the next future and effective clinical translation.     

Immunotherapy of ovarian cancer

Epithelial ovarian cancer remains the leading cause of death due to gynaecological malignancy. Although patients with advanced ovarian cancer have a good response to surgery and platinum-based chemotherapy, long-term survival remains poor. Immunotherapy techniques currently under investigation for treatment of recurrence include antitumour monoclonal and bispecific antibodies. Antibodies to ovarian cancer antigens have also been combined with radioisotopes, immunotoxins and chemotherapeutic drug conjugates to provide improved targeting of these agents. Anti-idiotypic antibodies and vaccines have also been developed to initiate humoral and cellular immune responses against ovarian cancer. Cytokines have been administered alone as well as in combination with other immunotherapy agents in patients with ovarian cancer. Finally, antigen-presenting cells are being modified by a variety of methods to stimulate an antitumour immune response. This review summarises the latest published clinical data and highlights promising areas of research in this exciting field.     

Long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy with plasma exchange or intravenous immunoglobulin

To assess long-term treatment of chronic idiopathic demyelinatingpolyradiculoneuropathy (CIDP) with plasma exchange (PE) andintravenous immunoglobulin (IVIg), we studied 105 patients retrospectivelyby case-notes and follow-up. Thirty-three were treated withPE; 23 responded well. Twenty-two were treated with IVIg; 14responded well and one had a hypotensive reaction during thefirst infusion. For both treatments, responders were more likelyto be female and younger, and to have a shorter duration ofsymptoms. Most patients required only one course of treatment.Seven patients received repeated courses of PE for 8.1–59.7months; seven received repeated courses of IVIg for 6–51months. Transient complications occurred with PE: hypotensionin three, difficulty in gaining venous access in three, andhaematoma, bleeding diathesis, hypocalcaemia, and septicaemiain one patient each. Four patients transferred from long-termPE to IVIg, but the fifth responded to PE only. Two patientswho were transferred from PE to IVIg were eventually able tostop all treatments. Long-term use of IVIg was free of any significantcomplications. Both PE and IVIg are possible long-term treatmentsfor CIDP, but both are expensive, and PE had more side-effects.     

慢性炎症性脱髓鞘性多发性神经根神经病患者自主神经症状评估的临床研究

目的探讨慢性炎症性脱髓鞘性多发性神经根神经病（CIDP）患者自主神经症状评估的临床研究。方法应用交感神经皮肤反应（SSR）、R—R间期变化率（RRIV）及自主神经功能量表（ASP）对29例CIDP患者（实验组）和30例健康对照组分别进行评估,并分析CIDP患者SSR、RRIV及ASP之间的相关性。结果两组SSR、RRIV及ASP异常率比较,差异均有统计学意义（P均〈0．05）。实验组有自主神经症状的患者与无自主神经症状的患者SSR异常率比较,差异有统计学意义（P〈0．042）,而RRIV及ASP异常率比较,差异均无统计学意义（P均〉0．05）。此外,实验组患者SSR、RRIV及ASP间均存在显著相关性（P均〈0．05）。结论SSR、RRIV与ASP均可用于CIDP患者的自主神经功能评估,且SSR对CIDP患者自主神经症状的检测敏感性较高。     

Plasmapheresis in the treatment of acute relapsing inflammatory demyelinating polyradiculoneuropathy associated with human immunodeficiency virus infection: a case report

Neurologic complications, including both the acute and chronic forms of inflammatory demyelinating polyradiculoneuropathy (IDP) are becoming more prevalent among patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related-complex (ARC). Although the etiology of the above radiculoneuropathies is not known, an autoimmune process has been postulated. Plasmapheresis has been reported to be of benefit in both the acute and chronic forms of these neuropathies. In this report we describe the use of plasmapheresis in the treatment of a patient with ARC and the acute relapsing form of IDP. The treatment consisted of an intensive course of plasmapheresis following his initial presentation and after an acute relapse which occurred several weeks after his initial presentation. Both the initial presentation and relapse involved respiratory compromise necessitating intubation and mechanical ventilation. In both instances marked clinical improvement was achieved after initiation of plasmapheresis. Thus, plasmapheresis may have a role in the management of acute relapsing IDP associated with human immunodeficiency virus infection.     

Vaccines of the Future: From Rational Design to Clinical Development

The Institut Pasteur (France) sponsors and organises a series of Euroconferences on important topics in biology, medicine and environmental sciences which facilitate a large exchange of ideas between basic and applied scientists from the Institut Pasteur, other academic institutions, and pharmaceutical companies. This Euroconference focused on the most recent advances currently affecting the way vaccine development is approached. The identification of new target antigens for vaccination purposes is presently facilitated by the availability of genome sequences from a growing number of important pathogens and tumours. The identification of T-cell epitopes and the subsequent optimisation of these target sequences allows the design of vaccines which are significantly improved with respect to their capacity to stimulate cellular immunity. In parallel, various antigen formulations, adjuvants and delivery systems are being developed and tested with the aim of eliciting broad immune responses in humans. These new orientations capitalise on recent major advances in the understanding of the use of therapeutic vaccines and expands on their use from being solely profilactic. Specific issues related to the development of therapeutic vaccines directed against diseases such as cancer or chronic infectious disease were presented.     

Immunotherapy of cancer: A perspective view

The current intense interest in cancer immunotherapy is largely based on the fact that progress in the clinical treatment of solid tumors has been less spectacular than anticipated, whereas efforts in basic and preclinical cancer research made some rather remarkable strides during the last two decades. The major challenge that now faces research investigators in cancer immunotherapy is to determine the functional characteristics of potentially new molecules, important for cancer immunotherapy in both structural and functional terms, to attempt a correlation of their structure with function and to develop, at the basic and preclinical levels, approaches suitable for potential therapy regimens that can be transferred to the clinic for further development.     

Isokinetic assessment of muscular strength in subjects with acute inflammatory demyelinating polyradiculoneuropathy]

OBJECTIVE: To evaluate the feasibility and the interest of isokinetic measures tests in subjects with inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndromes (GBS). METHODS: Nine patients with GBS are tested at the beginning and after 6 months of recovery stage. They benefit from (1) isokinetic assessment of muscular strength of knee, elbow, ankle: flexion/extension and shoulder abduction/adduction ranging 30 per s at 180 per s angular velocity; (2) isometric assessment of the same muscular groups; (3) manual muscle testing; (4) functional independence measure. RESULTS: Isokinetic tests were tolerated at 60 and 120 per s. Fatigability appears since the third second of isometric test. The relationships between isokinetic, manual tests and isometric tests are variables (0.29 < r < 0.97). The evaluation after 6 months of recovery showed a good sensibility of isokinetic test. CONCLUSION: The continuation of this motor isokinetic evaluation, in a large population, will permit to establish longitudinal and evolutive profile of each patient and will facilitate to chose the rehabilitation program.     

Optimized Systemic Dosing with CpG DNA Enhances Dendritic Cell‐Mediated Rejection of a Poorly Immunogenic Mammary Tumor in BALB/c Mice

To model a clinical trial of dendritic cell (DC) therapy of a poorly immunogenic mammary tumor, we treated BALB/c mice bearing an established TS/A mammary tumor with lysate‐pulsed DCs and CpG DNA. We observed that the dose of CpG DNA required to activate DCs in vitro was insufficient to mediate tumor rejection in vivo. We therefore undertook in vivo studies to identify an optimized dose of CpG DNA for tumor therapy, defined as the lowest and least frequently administered dose of CpG DNA that mediated complete tumor rejection. We show that one priming dose of 15 nanomoles and one booster dose of 10 nanomoles of CpG DNA given 7 days apart, respectively, with lysate‐loaded DCs were sufficient to mediate complete tumor rejection in vivo. This dose of CpG DNA was 42‐fold higher than that required to activate DCs in vitro but was not associated with any toxicity in mice. Also, the cured mice rejected a subsequent challenge with fresh TS/A tumor, and both CD4⁺ and CD8⁺ T cells were required for tumor rejection. We conclude that effective DC‐based therapy of a poorly immunogenic TS/A tumor is enhanced by optimized dosing of CpG DNA. Our data have important implications for DC‐based clinical trials of breast cancer immunotherapy.     

Spinal canal decompression for hypertrophic neuropathy of the cauda equina with chronic inflammatory demyelinating polyradiculoneuropathy: A case report

BACKGROUNDHypertrophic neuropathy of the cauda equina (HNCE) is a rare disease, especially in children. It can be caused by different etiological agents such as inflammation, tumor or hereditary factors. Currently, there is no uniform standard for clinical treatment of HNCE. Furthermore, it is unclear whether spinal canal decompression is beneficial for patients with HNCE.CASE SUMMARYWe report the case of a 13-year-old boy with enlargement of the cauda equina. The onset of the disease began at the age of 6 years and was initially marked by radiating pain in the buttocks and thighs after leaning over and weakness in the lower limbs when climbing a ladder. The child did not receive any medical treatment. As the disease slowly progressed, the child needed the help of others to walk, and he had a trendelenburg gait. He underwent spinal canal decompression and a nerve biopsy during his hospital stay. A diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy was made based on electrophysiological findings and pathological examination results. Immunoglobulin or hormone therapy was recommended during hospitalization, but his mother refused. After discharge, the boy’s mother helped him carry out postoperative rehabilitation training at home. His lower-limb muscle strength gradually increased, and he could stand upright and take steps. Six mo after surgery, the child was readmitted and began immunoglobulin therapy. Long-term oral steroid treatment was initiated after discharge. The movement and sensation of the lower limbs were further improved, and the boy could walk normally 1 year after surgery. CONCLUSIONSpinal canal decompression can improve the clinical symptoms of HNCE caused by inflammation, even in children. When combined with specific etiological interventions, spinal cord decompression can lead to optimal outcomes.     

Clinical applications of recombinant virus-based cancer immunotherapy

Cancer immunotherapy looks back over one century of clinical applications. In spite of major advances in the comprehension of oncogenesis and treatment of cancer, malignant tumours remain a leading cause of disability and death worldwide. Since 1991, a breakthrough in immunology allowed the identification of tumour-associated antigens, opening the era of specific immunotherapy. On the other hand, recombinant virus are powerful vectors that are able to express various gene products in vivo, including cytokines and tumour antigens. Therefore, many groups have implemented clinical trials of active specific tumour immunotherapy. Phase I trials have demonstrated favourable safety profiles. However, major tumour responses remain anecdotal in heavily metastatic patients. This review will critically present and discuss the clinical achievements of recombinant virus-based cancer immunotherapy. This paper will attempt to shed some light on the perspectives opened by advanced cancer immunotherapy protocols, review the drawbacks of this approach and the reasons why it is believed that recombinant virus-based cancer immunotherapy may be of relevance in the treatment of human malignancies.     

First International Symposium on Melanoma and Other Cutaneous Malignancies

The First International Symposium on Melanoma and Other Cutaneous Malignancies, held in New York City on 23 – 25 April 2004, brought together researchers and clinicians from all over the world to discuss recent advances in the prevention, treatment and diagnosis of melanoma and other cutaneous malignancies. Discussion topics included primary and secondary prevention; advances in surgical therapy, including sentinel and elective lymph node dissection; the biology and pathogenesis of melanoma, including pathways of drug resistance; genomic analysis of melanoma, serum and tumour cell markers; with point and counterpoint sessions debating therapeutic controversies. The role of vaccines in the management of melanoma was discussed, including cell vaccines, dendritic cell-based vaccination and present research to improve the generation of melanoma vaccine-specific immunity. Adjuvant immunotherapy with high-dose IFN-α and an ongoing trial with biochemotherapy were debated. In addition, the role of chemotherapy and novel targeted agents in metastatic melanoma were discussed. Among the emerging agents and therapeutic targets presented were Bcl-2 antisense therapy, RAF kinases, heat-shock proteins, thalidomide and newer immunomodulatory drugs, cytotoxic T lymphocyte antigen-4 antibody and topical imiquimod. The symposium also provided an overview of existing and emerging agents and modalities in the management of patients with cutaneous T cell lymphomas, ocular melanoma and melanoma involving brain metastases. Sessions also included case-based learning and devoted ample time to providing ‘how to’ information for practising physicians.     

Immunotherapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, with over a million new cases annually. It is generally advanced upon detection due to underlying liver disease, which further complicates treatment. Most of the therapeutic strategies in current use (surgery, transplantation, irradiation or chemotherapy) are either palliative or only of benefit to a small percentage of patients. This article reviews the biology of HCC, including many of the molecular changes and mechanisms leading to HCC development. This article discusses the recent innovative strategies to interfere with the progression of HCC, including novel gene therapy strategies. The most recent data supporting the use of immunotherapy for hepatocellular cancer is reviewed in detail.     

Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma

Dendritic cells (DCs) are considered to be promising adjuvants for inducing immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma patients, who were progressive despite standard chemotherapy, received five DC vaccinations at 14-d intervals. The first three vaccinations were administered into the skin, 3 x 10(6) DCs each subcutaneously and intradermally, followed by two intravenous injections of 6 x 10(6) and 12 x 10(6) DCs, respectively. Only minor (less than or equal to grade II) side effects were observed. Immunity to the recall antigen was boosted. Significant expansions of Mage-3A1-specific CD8(+) cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients. Curiously, these immune responses often declined after the intravenous vaccinations. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients. Resolution of skin metastases in two of the patients was accompanied by erythema and CD8(+) T cell infiltration, whereas nonregressing lesions lacked CD8(+) T cells as well as Mage-3 mRNA expression. This study proves the principle that DC "vaccines" can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8(+) CTL-tumor cell interaction in situ as well as escape by lack of tumor antigen expression.