orabase and Melanoma

Peptide vaccines designed to stimulate melanoma-reactive CD4. An adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.. Forty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.. 6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.

Topics: Administration, Metronomic; Administration, Oral; Antibodies; Cancer Vaccines; Carboxymethylcellulose Sodium; CD4-Positive T-Lymphocytes; Combined Modality Therapy; Cyclophosphamide; Female; Freund's Adjuvant; Humans; Lipids; Male; Melanoma; Neoplasm Staging; Poly I-C; Polylysine; T-Lymphocytes, Regulatory; Treatment Outcome; Vaccines, Subunit

Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4

Topics: Adjuvants, Immunologic; Aged; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cross-Priming; Female; Humans; Immunity, Cellular; Immunity, Humoral; Interferon Inducers; Male; Mannitol; Melanoma; Membrane Proteins; Middle Aged; Oleic Acids; Patient Safety; Poly I-C; Polylysine; Skin Neoplasms; Treatment Outcome

Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8. Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).. Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.. LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.. The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.

Topics: Adjuvants, Immunologic; Cancer Vaccines; Carboxymethylcellulose Sodium; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Freund's Adjuvant; Humans; Lipids; Lipopolysaccharides; Male; Melanoma; Poly I-C; Polylysine; Toll-Like Receptors; Vaccines, Subunit

Melanoma is the most aggressive type of skin cancer with high rates of mortality. Despite encouraging advances demonstrated by anticancer drug carriers in recent years, developing ideal drug delivery systems to target tumor microenvironment by overcoming physiological barriers and chemotherapy side effects still remain intimidating challenges. Herein, we designed and developed a novel carbohydrate-based prodrug composed of carboxymethylcellulose (CMC) polymer bioconjugated with anticancer drug doxorubicin hydrochloride (DOX) by covalent amide bonds and crosslinked with citric acid for producing advanced hydrogels. The results demonstrated the effect of CMC hydrogel network structure with distinct degree of substitution of carboxymethyl groups of the cellulose backbone regarding to the process of bioconjugation and on tailoring the DOX release kinetics in vitro and the cytotoxicity towards melanoma cancer cells in vitro. To this end, an innovative platform was developed based on polysaccharide-drug hydrogels offering promising perspectives for skin disease applications associated with topical chemotherapy of melanoma.

Topics: Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line, Tumor; Citric Acid; Cross-Linking Reagents; Doxorubicin; Drug Liberation; HEK293 Cells; Humans; Hydrogels; Melanoma; Prodrugs; Skin Neoplasms

Cells aggregate on an original cellulose substratum (CEL). This influences the signaling programs of adhering cells. CEL thus appears to be a suitable tool for studying the regulation of cell-substratum and cell-cell interactions.

Topics: Animals; Carboxymethylcellulose Sodium; Cell Adhesion; Cell Aggregation; Cell Culture Techniques; Cell Line, Tumor; Humans; Hypromellose Derivatives; Melanoma; Methylcellulose

Irregular facial contours can make radiation therapy of head and neck tumors difficult. Isodose lines become skewed, making treatment planning complex. A traditional solution to this problem is the paraffin wax box bolus. Such a bolus is made to fit the irregular surface compensating for the topology and creating an even surface. The fabrication of a wax bolus can be a difficult and time-consuming process. A method that is simple and efficient has been devised. Super Stuff bolus can be easily molded and has approximately the same effect as a similar paraffin wax bolus. This was verified by irradiating a Rando head phantom with both a paraffin wax bolus and a Super Stuff bolus. Doses to various points of interest were measured with thermoluminescent dosimetry (TLD) chips (LiF). The particular case addressed is malignant melanoma of the nasal septum, but the technique described can be useful in the treatment of other sites as well.

Topics: Carboxymethylcellulose Sodium; Face; Head and Neck Neoplasms; Humans; Melanoma; Nasal Septum; Nose Neoplasms; Paraffin; Phantoms, Imaging; Radiotherapy Dosage; Radiotherapy, Computer-Assisted; Radiotherapy, High-Energy; Surface Properties; Thermoluminescent Dosimetry; Waxes

Sixteen patients with metastatic malignant melanoma were treated with poly(I,C)-LC 5 mg/m2 twice weekly by intravenous injection. No antitumor responses occurred. Fever (frequently greater than 40 degrees C) and fatigue were dose limiting toxicities. One patient developed a fever of 42.2 degrees C when poly(I,C)-LC was given on 2 consecutive days. Interferon was consistently detected in the serum 8 h after a single injection of poly(I,C)-LC (median titer 199 U/ml). No enhancement of interferon induction was detected on the second day when poly(I,C)-LC was given on 2 consecutive days.

Topics: Adult; Aged; Antineoplastic Agents; Carboxymethylcellulose Sodium; Drug Evaluation; Fatigue; Female; Fever; Humans; Interferons; Male; Melanoma; Methylcellulose; Middle Aged; Poly I-C; Polylysine

Topics: Adjuvants, Immunologic; Animals; Carboxymethylcellulose Sodium; Hypersensitivity, Delayed; Leukemia L1210; Male; Melanoma; Methylcellulose; Mice; Mice, Inbred Strains; Peptides; Poly I-C; Polylysine; Polymers; Pyran Copolymer; Vaccines