Cyclooxygenase Inhibition in Cancer Immunotherapy: Combination of Indomethacin with Cancer Vaccines Is Not Always Beneficial

Cyclooxygenase (COX)-1, but preferable COX-2 catalyzes the synthesis of PGE2 in several tumors, promoting angiogenesis and a suppressive inflammation in their microenvironments. Different types of cancer vaccines have been combined with COX-2 inhibitors, assuming that its particular mechanism of action will not influence the overall results of the combination. In this research, a possible relationship between the type of cancer vaccine and the outcome of the combination with a COX inhibitor was experimentally addressed. We investigated whether nonsteroidal anti-inflammatory drugs (NSAIDs) affect the immune response to vaccination. Three adjuvants were evaluated for humoral and cellular response using ovalbumin (OVA) as antigen. We evaluated also the impact of indomethacin in five tumor models and the correlation of this effect with the secretion of prostaglandin E2 (PGE2) of these cells. We finally studied the combination of indomethacin with two cancer vaccines in three different experimental settings. COX inhibitor did not interfere with dendritic cells maturation in vitro and did not affect the frequency of splenic immune cell populations in mice. However, the induction of OVA-specific antibodies is affected by the COX inhibitor but its impact on cytotoxic CD8+ T cell response is adjuvant-dependent. In contrast, the antitumor effect of the COX inhibitor in the 3LL-D122 tumor model is not mediated by CD4+ or CD8+ T cells. Interestingly, the in vivo effect observed in this model and others didn’t correlate with levels of PGE2 secretion by the tumor cell lines in vitro. Finally, the combination of a COX inhibitor with cancer vaccines may depend on the type of the cancer vaccine.

Preclinical Efficacy of Nimotuzumab, an Anti-Egfr Monoclonal Antibody as a Single Agent Therapy in Human GBM u87mg Xenografts

Background: The poor prognosis of patients with high-grade glioma multiform (GBM) has led investigators to the search of new therapeutic strategies. Current treatment includes surgery when possible, radiotherapy and chemotherapy. Molecular-targeted therapies are in the process of clinical testing, and promising agents include monoclonal antibodies. Our study examined the antitumor activity of three different single therapies in nude mice bearing both subcutaneous and orthotopic brain xenografts of the U87MG human GBM cell line. Methods: Cell culture, Histology, Immunohistochemistry, Animal experiments, Statistical analysis. Results: Different groups of treatment included nimotuzumab, a humanized monoclonal antibody that inhibits the EGFR tyrosine kinase activity, or total body irradiation, or the chemotherapeutic agent temozolomide (TMZ). For the control group animals received saline solution instead of the antibody. For the subcutaneous model, only nimotuzumab or TMZ produced a significant delay in tumor growth. In the intracranial model, unlike TMZ, the systemic administration of the antibody did not reduce the tumor growth, despite both therapies inhibited the formation of microsatellites in the brain of mice. The antitumor activity of nimotuzumab was accompanied by a decrease in the microvessel density and the proliferative activity of tumor cells. TMZ only inhibited the tumor cell proliferation but not the formation of new tumor-associated microvessels in xenografts. For radiation therapy, neither antiproliferative nor antiangiogenic activity was found, in accordance with the lack of antitumor activity. Only nimotuzumab reduced the frequency of chemo and radioresistant CD133+ population. Conclusion: Our results illustrate the potential efficacy of nimotuzumab as a single agent against an EGFR-amplified human GBM, a tumor resistant to the therapy with all well-known forms of treatment.

Comparability Assessments of Process Changes Made during Development of Anti-Idiotype Vaccine

Racotumomab monoclonal antibody is a murine anti-idiotypic antibody. This monoclonal antibody mimics N-glycolyl-GM3 gangliosides has been tested in several clinical trials Phase I/II for breast, melanoma and non-small cell lung cancer patients as an anti-idiotypic cancer vaccine. The early production process was performed in vivo from mice ascites fluid. This process was transferred to bioreactor-based method at pilot scale followed to the scale-up of the fermentation. In this work we present a comprehensive molecular characterization of racotumomab MAb produced by the two different production scales in order to determine the impact of the manufacturing process in vaccine performance. We observed differences in glycosylation pattern and charge heterogeneity between racotumomab produced in both scales. Interestingly, these modifications had no significant impact on biological activity elicited in chickens. So, changes in primary structure like glycosylation, charge heterogeneity and oxidation did not affect biological activity of the vaccine.

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy?

Despite the availability of different treatments for advanced NSCLC, all of them have a palliative intention and a cure for the disease is unlikely. Thus, advanced lung cancer remains as an unmet medical need. Chemotherapy has been used as the therapy of choice for advanced NSCLC patients, but it is mainly limited by the patient’s performance status. More recently, targeted therapies have introduced more specific treatment options that show efficacy in specific niche of patients, but precisely due to their target specificity, they usually provoke early resistance. In addition to these limitations, most of the best drugs currently used for treatment of advanced NSCLC show small increases in patient survival with severe associated toxicity. Novel drugs with low toxicity that could be given chronically to control the advanced disease can make a difference. They could allow the management of advanced cancer as a chronic disease that, even when not cured, it can be controlled for long periods of time offering patients a good quality of life. Active-specific immunotherapy is an area of oncology that is rapidly expanding with encouraging results. Cancer vaccines against many potential targets have shown to increase patient survival in clinical trials at all stages NSCLC, when included as first-line, maintenance, or second-line therapy. Safety of cancer vaccines supposes a new hope for cancer therapy, and this unique characteristic makes it possible to be used in sub-sets of patients that cannot receive other approved treatments because of their high toxicity. In this paper, authors propose how active immunotherapy could be included in the current algorithm for treatment of advanced NSCLC patients.

Safety and Efficacy of Racotumomab-Alum Vaccine as Second-Line Therapy for Advanced Non-Small Cell Lung Cancer

Despite extensive clinical research in non-small cell lung cancer (NSCLC), overall survival is still poor. Racotumomab-alum is an anti-idiotypic cancer vaccine that targets NeuGcGM3 tumor associated ganglioside. The aim of this study was to evaluate safety and efficacy of racotumomab-alum in advanced NSCLC patients with progressive disease. This expanded access program included 86 histologically confirmed NSCLC patients, 18 years or older age, with advanced disease and without therapeutic option, with ECOG performance status ≤3, adequate organ functions and signed informed consent. The primary endpoint was overall survival and toxicity was measure assessed treatment-related toxicity according CTCAEv3. The study was approved by ethical review boards of participant institutions. Racotumomab-alum treatment consisted in 5 biweekly intradermal doses (1 mg/mL) during the induction phase of treatment (2 months). The maintenance phase consisted in monthly re-immunizations until unacceptable toxicity or PS worsening. The median overall survival time of all patients treated with racotumomab-alum was 8.96 months. The survival rates at 12 and 24 months were 42.8% and 28.0%, respectively. Patients that completed the induction phase of treatment (five doses or more) reached a median OS of 12.1 months. The most common adverse events were injection site reaction, bone pain, cough and asthenia. Racotumomab-alum cancer vaccine could be considered an effective and safe treatment option as second-line therapy for advanced NSCLC. Further clinical studies should be conducted to confirm this result.

Pharmacokinetics Evaluation of Nimotuzumab in Combination with Doxorubicin and Cyclophosphamide in Patients with Advanced Breast Cancer

EGFr （Epidermal growth factor receptor） overexpression has been detected in many tumors of epithelial origin, specifically in breast cancer and it is often associated with tumor growth advantages and poor prognosis. The nimotuzumab is a genetically engineered humanized MAb （monoclonal antibody） that recognizes an epitope located in the extracellular domain of human EGFr. The aim of this study was to assess the pharmacokinetics of nimotuzumab in patients with locally advanced breast cancer who are receiving neoadyuvant therapy combined with the AC chemotherapy regimen （i.e., 60 mg/m2 of Doxorubicin and 600 mg/m2 of Cyclophosphamide in 4 cycles every 21 days）. A single center, non-controlled, open Phase I clinical trial, with histopathological diagnosis of locally advanced stage III breast cancer, was conducted in 12 female patients. Three patients were enrolled at each of the following fixed dose levels： 50, 100, 200 and 400 mg/week. Multiple intermittent short-term intravenous infusions of nimotuzumab were administered weekly, except on weeks 1 and 10, when blood samples were drawn for pharmacokinetic assessments. Nimotuzumab showed dose-dependent kinetics. No anti-idiotypic response against nimotuzumab was detected in blood samples of participants. There was not interaction between the administration of nimotuzumab and chemotherapy at the dose levels studied. The optimal biological doses ranging were estimated to be 200 mg/weekly to 400 mg/weekly.

Importance of Pharmacoeconomics in the Pharmacovigilance for National Health Systems

The objective of this study is to conduct a literature review to assess the importance of pharmacoeconomics in developing pharmacovigilance activities as a working tool to guide the process of decision making in the health field. The authors have done a literature review in order to find information about pharmacovigilance and their relationship with the pharmacoeconomics field, as an important element to assess the economic and health consequences because of the use of drugs in health systems. From this study, it can be found that pharmaeoeconomics applied to the pharmacovigilance activities should be considered as an aspect that contributes to improving the rational use of medicines, because it allows to compare the costs and consequences （beneficial and detrimental） with the use of different pharmacotberapeutic alternatives, in order to assess the negative effects due to ADRs （adverse drug reactions）, which directly increase the morbidity and mortality in patients, increase the direct health costs and indirectly decrease the productivity labors. It can be also concluded that pharmacoeconomics constitutes an important aspect to the pharmacovigilance activity in the health systems, in order to evaluate the negative impact of ADR, both on patient health as its economic implications, due to associated costs with these adverse effects.

Stratified Cox Regression Analysis of Survival under CIMAvax^(■)EGF Vaccine

Background: The Center of Molecular Immunology (CIM) is a center in Cuba devoted to the research, development and manufacturing of biotechnological products. CIMAvax?EGF is a vaccine for the treatment of non-small cell lung cancer patients (NSCL). Purpose: The aim of this work is to evaluate the effects of some potential prognostic factors on the overall survival of patients treated with CIMAvax?EGF vaccine, based on data collected in a phase II and a phase III clinical trials. Methods: The stratified Cox regression model is used to evaluate the effects of these prognostic factors, based on separate analysis for each trial, and on the combined data from both trials. Results: Patients with Performance status 0 or 1, with IV stage of tumor and male under 60 years obtain more benefit in terms of overall survival if they receive CIMAvax?EGF. Conclusions: Vaccinated group has a better performance if patients have a performance status 0 or 1, stage IV and age under 60 years. These prognostic factors influence overall survival in a positive way for those patients that received CIMAvax?EGF.

Specific Immunotherapy in Advanced Cervical-Uterine Cancer Using Humanized Monoclonal Antibody Nimotuzumab and CIMAvax-EGF^®Therapeutic Vaccine

Cervical uterine cancer represents the fourth most common malignant neoplasm worldwide in the female sex in terms of incidence, principally from epithelial origen. The high expression of EGFR in this tumor leads to the search for therapeutic alternatives. An Expanded Access Clinical Program was carried out in parallel groups, randomized, multicenter and prospective study, to evaluate the survival of patients with advanced cervical carcinoma, without therapeutic alternative, who would be treated with the therapeutic vaccine CIMAvax-EGF®, the humanized mAb nimotuzumab or the combination of both products, which targeted EGF and EGFR respectively. The patients were included between 2008 and 2010 with a more than five years follow-up. The results show that the serious adverse events related to the experimental treatments were 0.9%;1.1% and 2.6% and a median ITT survival of 9.1, 23.5, and 16.3 months for CIMAvax-EGF®, nimotuzumab and the combination of both, respectively. Thus fulfilling the hypothesis of safety and efficacy proposed in the investigation was achieved. The three therapeutic regimens achieved overall survival rates greater than 35% at 60 months, encouraging results for advanced uterine cervical cancer. A phase III clinical trial is proposed to consolidate these results in a greater number of patients with nimotuzumab as study drug.

GM3-containing nanoparticles in immunosuppressed hosts:Effect on myeloid-derived suppressor cells

Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tu-mor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppres-sor cells （MDSCs） are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8＋ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be criti-cal for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes （VSSP） is a nanoparticulated adjuvant specifcally designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8＋ T cells, Th1 polar-ization, and enhances CD8＋ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase？Ⅰ？and Ⅱ clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specifc CD8＋ T cell responses in two immunocompromised sce-narios; in tumor-bearing mice and during chemother-apy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vac-cine adjuvants currently in preclinical or clinical studies.

CIMAvax^(█)EGF vaccine therapy for non-small cell lung cancer:A weighted log-rank tests-based evaluation

Time-to-event has become one of the primary endpoints of many clinical trials. Comparing treatments and therapies using time-to-event (or “survival”) data requires some care, since survival differences may occur either early or late in the follow-up period, depending on various factors such as the initial potency or the duration of efficacy of the drugs. In this work, we investigate the effect of the CIMAvax?EGF vaccine therapy on the survival of patients with non-small cell lung cancer, using stratified and unstratified weighted log-rank tests. Weighted log-rank tests are designed to identify early and late survival differences between treatments. Using these tests, we conclude that the vaccine is more efficient than the standard therapy among patients less than 60 years of age.