Faculty Bibliography

With the discovery of increasing numbers of tumor antigens, there is a need to rapidly determine whether these antigens and the individual peptides they express are able to stimulate immune responses in vivo and thus, can be used to construct cancer vaccines. In this study we used the method of vaccine-induced immune response (VIIR) analysis to identify multiple immunogenic peptide epitopes derived from several melanoma associated antigens and presented by HLA-A*03, A*11 and B*07. Thirty-one patients with melanoma were immunized to a polyvalent vaccine containing multiple antigens, including MAGE-3, Melan A/MART-1, gp100 and tyrosinase. Their peripheral blood was tested for peptide-specific, vaccine-induced CD8+ T cell responses before and after immunization using an enzyme-linked immune spot (ELISPOT) assay with panels of peptides restricted by these three alleles. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*03, A*11 or B*07. Overall, 60% of the 20 peptides studied were recognized by at least one patient and 50% of the patients showed a vaccine-induced CD8+ T cell response to at least one peptide that matched their HLA specificity. We conclude that VIIR analysis is an effective strategy to directly identify immunogenic peptides that are good candidates for vaccine construction

The extent of tumor reduction from neoadjuvant chemotherapy for breast cancer correlates with outcome. We investigated whether the initial cellular responses to paclitaxel are related to the extent of tumor reduction. Eleven women with breast cancer received paclitaxel (every 2 weeks for 4 cycles) as neoadjuvant treatment. Serial fine-needle aspirations (FNA; 25-gauge, 1 pass) were obtained before treatment and at 24, 48, 72, and 96 h after the first paclitaxel dose. Microscopic counts of apoptotic and mitotic indices were performed. The change in cancer volume from treatment was determined using radiological measurements with allowance for change in the histopathological amount of cancer. Apoptotic and mitotic responses usually subsided within 4 days. The duration of the initial apoptotic response was different for women with different treatment results. Cumulative apoptotic response for the first 4 days inversely correlated with the proportion of residual cancer after neoadjuvant treatment. FNA is a versatile clinical method to obtain breast cancer cells for therapy response studies. Apoptotic response to the first dose of paclitaxel is almost complete within 4 days, implying that more frequent (weekly) paclitaxel dosing might be beneficial. The apoptotic response to the first dose of paclitaxel appeared to predict the amount of cancer reduction from this treatment. This is a promising start toward the development of an early chemopredictive assay for paclitaxel treatment of breast cancer

PURPOSE: Didemnin B is a novel marine natural product cyclic depsipeptide containing unusual amino acid moieties. This agent demonstrates promising preclinical antitumor activity, including activity against B16 melanoma and against melanoma isolates in the human tumor stem cell assay. METHODS: We conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced malignant melanoma were eligible. All patients were previously untreated with chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and 5.6 mg/m2 in cycles 2 and 3, respectively. RESULTS: Nineteen patients were entered and treated with a median of one cycle per patient. Eight of these patients went off study for toxicity including 7 with anaphylactoid reactions in the first or second cycle. One patient went off study after 3 cycles with severe myopathy, a newly described toxicity. Two were not evaluable for response and five were considered stable, including one patient with a transient PR of soft tissue disease in the first cycle. Another patient had stable disease for twelve cycles before progressing and one went off study electively after 3 cycles, for a total of 7 patients with stable disease. One patient with a measurable partial remission (PR) and went off study after three cycles due to severe myopathy, a then newly-described toxicity. No hematologic toxicity was seen. Nausea and vomiting were controlled with anti-emetics. CONCLUSIONS: This study was indeterminate with respect to the activity of Didemnin B in melanoma. Signs of activity were seen, particularly in soft tissue masses, though a large number of patients could not be evaluated fully for activity due to the occurrence of anaphylactoid reactions. This study does not preclude a clinically important level of activity for Didemnin B

Interleukin 1 alpha (IL-1 alpha) is a cytokine with pleiotropic effects, including cytotoxic-cytostatic activity against some tumor cell lines. We have conducted a phase I study of recombinant human IL-1 alpha (rhIL-1 alpha) in 17 patients with refractory malignancies to examine its toxicity and biologic activity. rhIL-1 alpha was given as a 2-h IV infusion daily for 5 days at five dose levels (0.08, 0.2, 0.8, 2.0, and 5.0 micrograms/m2). Seventeen patients with malignancies were treated, with no objective tumor responses noted. Common toxicities included: fever (100%), rigors and/or chills (96%), myalgia (54%), and headache (48%). Three patients developed grade III hypotension. The maximum tolerated dose was 2.0 micrograms/m2. rhIL-1 alpha induced a significant increase in absolute neutrophil count over baseline (p < 0.05), a delayed but significant increase in platelet count over baseline (p < 0.05), and there was a marked increase in the number of progenitors [colony-forming units (CFU)-G, CFU-M, CFU-GM, CFU-GEMM and burst-forming units (BFU-E)] observed in the peripheral blood. Nine of 12 evaluable patients showed an increase in bone marrow cellularity or myeloid:erthyroid ratio. Immunophenotyping did not demonstrate an increase in peripheral blood or bone marrow CD34+ cells. Interferon-gamma-mediated monocyte cytotoxicity (MCCTX) was significantly enhanced from baseline (p < 0.001), although an increase in direct MCCTX did not reach statistical significance. In summary, rhIL-1 alpha administration is well tolerated at a dose of 2.0 micrograms/m2 with fever, rigors, myalgia, and headache being the most frequent toxicities. Although there were no objective tumor responses, we have demonstrated significant biologic activity with increased neutrophil and platelet counts, increased peripheral blood progenitor cells, and enhanced interferon-gamma-mediated MCCTX