HER1 therapeutic cancer vaccine: An active immunotherapy treatment for patients with tumors expressing the receptor of epidermal growth factor (EGF-R)

Her1 vaccine: It consists of immunizing patients with positive tumors for the epidermal growth factor receptor (EGF-R) with a preparation of EGF-R extracellular domain(HER1-ECD) adjuvanted in VSSP (very small size proteoliposomes) and Montanide ISA51. VSSP adyuvant confers to vaccine the capacity to activate dendritic cells and polarize the immune response towards a TH1 immune pattern, developing TCD8+ cells and antibodies with anti-metastatic effect. The extracellular domain of the epidermal growth factor receptor was obtained from HEK293 transfectome by using a productive process in a bioreactor in perfusion as mode of fermentation. The protein was purified by immune-affinity chromatography by using specific anti-EGF-R antibody. Phase I trial, uncontrolled, open and sequential, was conducted in 25 with hormone refractory prostate cancer patients. Five dose levels of HER1-ECD were scaled: 100, 200, 400, 600 and 800 µg in each immunization. The trial showed that the vaccine was safe, not causing severe or very severe related events. The vaccine preparation was shown to be immunogenic. There was a trend towards the survival benefit in some patients. At the present time another clinical trial is underway in three locations of advanced solid tumors that overexpress the EGF receptor: prostate, colon and head and neck cancer

Diacylated Sulfoglycolipids Are Novel Mycobacterial Antigens Stimulating CD1-restricted T Cells during Infection with Mycobacterium tuberculosis

Mycobacterial lipids comprise a heterogeneous group of molecules capable of inducing T cell responses in humans. To identify novel antigenic lipids and increase our understanding of lipid-mediated immune responses, we established a panel of T cell clones with different lipid specificities. Using this approach we characterized a novel lipid antigen belonging to the group of diacylated sulfoglycolipids purified from Mycobacterium tuberculosis. The structure of this sulfoglycolipid was identified as 2-palmitoyl or 2-stearoyl-3-hydroxyphthioceranoyl-2′-sulfate-α-α′-d-trehalose (Ac2SGL). Its immunogenicity is dependent on the presence of the sulfate group and of the two fatty acids. Ac2SGL is mainly presented by CD1b molecules after internalization in a cellular compartment with low pH. Ac2SGL-specific T cells release interferon γ, efficiently recognize M. tuberculosis–infected cells, and kill intracellular bacteria. The presence of Ac2SGL-responsive T cells in vivo is strictly dependent on previous contact with M. tuberculosis, but independent from the development of clinically overt disease. These properties identify Ac2SGL as a promising candidate to be tested in novel vaccines against tuberculosis

Safety and Immunogenicity of a Human Epidermal Growth Factor Receptor 1 (HER1)-Based Vaccine in Prostate Castration-Resistant Carcinoma Patients: A Dose-Escalation Phase I Study Trial

Metastatic castration-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Activation of the human epidermal growth factor receptor 1 (HER1) in prostate cancer contributes to metastatic progression as well as to disease relapse. Here, we determined the toxicity and immunogenicity of a HER1-based cancer vaccine in CRPC patients included in a phase I clinical trial. CRPC patients (n = 24) were intramuscularly vaccinated with HER1 vaccine consisting of the extracellular domain of HER1 molecule (ECD) and very small size proteoliposome from Neisseria meningitidis (VSSP) and Montanide ISA-51 VG as adjuvants. Patients were included in five groups according to the vaccine dose (100, 200, 400, 600, and 800 μg). The primary endpoints were safety and immunogenicity. The anti-HER1 antibodies were measured by an ELISA, the recognition of an HER1 positive tumor cell line and the inhibition of HER1 phosphorylation by sera were determined by flow cytometry and western blot analysis, respectively. The HER1-specific T cell response was assessed by determination of IFN-γ-producing T cells using ELISpot assay. The vaccine was well tolerated. No grade III or IV adverse events were reported. High titers of anti-HER1 antibodies were observed in most of the evaluated patients. There were no significant differences regarding the geometric means of the anti-HER1 titers among the dose groups except the group of 100 μg in which antibody titers were significantly lower. A Th1-type IgG subclasses pattern was predominant in most patients. Only patients receiving the higher doses of vaccine showed significant tumor cell recognition and HER1 phosphorylation inhibition by hyperimmune sera. Forty two percent of the patients showed a specific T cell response against HER1 peptides pool in post-treatment samples. There was a trend toward survival benefit in those patients showing high anti-HER1 specific antibody titers and a significant association between cellular immune response and clinical outcome

Assessment of non-classical lymphocyte populations in patients with advanced lung cancer treated with Biomodulina T following platinum-based chemotherapy

Aim: Currently, malignant diseases represent a health issue worldwide. Among these, lung cancer is of growing importance, due to its high incidence and mortality. Chemotherapy, one of the most frequently used treatments, has shown its ability to induce accelerated immunosenescence in classic and as well non-classic lymphocyte compartments, being less described in the latter. The immune restoration strategies have demonstrated their ability to reverse immunosenescence and exhaustion markers in conventional lymphocyte subpopulations after chemotherapy. However, the possible immunorestorative effect on non-classical lymphocytes has not been widely reported. The aim of this study was to evaluate the effect of chemotherapy and the administration of a thymic polypeptide factor on non-classical lymphocyte populations in patients with advanced lung cancer. Methods: Eighteen patients with advanced lung cancer, were evaluated at baseline before and after platinum-based chemotherapy (4–6 cycles). All patients could complete treatment with a thymic polypeptide factor [Biomodulina T (BT)] at the end of chemotherapy. Blood from patients was collected by venipuncture in heparinized tubes before and after chemotherapy and at the end of BT treatment to analyze the frequencies of non-classical immune subpopulations by flow cytometry. Results: Natural killer (NK), natural killer T cells (NKT), and double-positive T lymphocyte (DPT) proportions reached normal values in patients diagnosed with advanced lung cancer before receiving cytotoxic treatment. Chemotherapy did not induce modifications in the total percent of NK, NKT, and DPT populations in these patients. However, the administration of BT decreased DPTs and NK cells expressing the cluster of differentiation (CD)57 molecule, which is considered a marker of immunosenescence. Conclusions: These results suggest a lower influence of platinum-based chemotherapy on non-classical lymphocytes and the potential to generate a reconstitution of lymphocyte subpopulations in patients with advanced lung cancer by using the thymic factor BT, which reveals a new possibility for improving the response to cancer immunotherapies [Cuban Public Registry of Clinical Trial (RPCEC, https://rpcec.sld.cu/en/trials/RPCEC00000358-En) identifier: RPCEC00000358]

GM3 ganglioside: a novel target for the therapy against melanoma

ABSTRACT Malignant melanoma is a tumor with a steeply increasing incidence and scarce therapeutic options once metastatic. Currently, no vaccine is widely commercially available for melanoma treatment or prevention. The overexpression of GM3 ganglioside in murine and human melanomas and its important role in tumor progression makes this self antigen a potential target for preventive immunotherapy of this neoplasm. Previously, we have shown that preventive vaccination with GM3/VSSP induced a specific antitumor response; and elicited the rejection of syngeneic GM3-positive melanoma cells in immunized mice. In the present paper, we published the induction of a potent antitumor effect of this vaccine administered in a minimal residual disease B16 melanoma model. These findings propose the GM3/VSSP vaccine as a therapy designed to elicit and/or boost antitumor immunity in patients with minimal residual disease after surgery; thereby preventing or prolonging the time to recurrence. This is an important issue of the clinical setting because patients with stage II melanoma were reported to have 60% chance of survival 5 years after surgery. In addition, we examined the mechanisms by which this immunogen confers tumor protection. Surprisingly, in spite of the glycolipidic nature of this antigen, we have found that induction of anti-GM3 IgG antibodies and tumor-specific IFN γ secreting CD8+ T cells correlated with tumor protection. As a result, these findings demonstrate, for the first time, the direct involvement of the cellular immune response in the anti-tumor protection induced by a ganglioside-based vaccine