Biomedical subjects

Craig L Slingluff

Publications and source records attributed to Craig L Slingluff.

28 records · Page 2Linked to original sources

PubMed2003

Lymphoscintigraphy and sentinel node biopsy accurately stage melanoma in patients presenting after wide local excision.

BACKGROUND: Patients have traditionally been considered candidates for sentinel node biopsy (SNBx) only at the time of wide local excision (WLE). We hypothesized that patients with prior WLE may also be staged accurately with SNBx. METHODS: Seventy-six patients, including 18 patients from the University of Virginia and 58 from a multicenter study of SNBx led by investigators at the University of Vermont, who had previous WLE for clinically localized melanoma underwent lymphoscintigraphy with SNBx. Median follow-up time was 38 months. RESULTS: Intraoperative identification of at least 1 sentinel node was accomplished in 75 patients (98.6%). The mean number of sentinel nodes removed per patient was 2.0. Eleven patients (15%) had positive sentinel nodes. Among the 64 patients with negative SNBx, 3 (4%) developed nodal recurrences in a sentinel node-negative basin simultaneous with systemic metastasis, and 1 (1%) developed an isolated first recurrence in a lymph node. CONCLUSIONS: This multicenter study more than doubles the published experience with SNBx after WLE and provides much-needed outcome data on recurrence after SNBx in these patients. These outcomes compare favorably with the reported literature for patients with SNBx at the time of WLE, suggesting that accurate staging of the regional lymph node bed is possible in patients after WLE.

Female↗

PubMed2003

MAGE-6 encodes HLA-DRbeta1*0401-presented epitopes recognized by CD4+ T cells from patients with melanoma or renal cell carcinoma.

CD4+ T cells modulate the magnitude and durability of CTL responses in vivo and may serve as potent effector cells within the tumor microenvironment. The current study was undertaken to define novel epitopes from the broadly expressed tumor antigen MAGE-6 that are recognized by CD4+ T cells. We have combined the use of a HLA-DR4/peptide binding algorithm with the IFN-gamma enzyme-linked immunospot assay to identify four nonoverlapping sequences derived from the MAGE-6 protein that served as CD4+ T-cell epitopes in HLA-DR4+ donors. Strikingly, patients with active melanoma or renal cell carcinoma failed to secrete IFN-gamma in response to MAGE-6-derived epitopes, whereas both normal donors and cancer patients with no current evidence of disease were responsive, particularly after short-term in vitro stimulations with peptide-pulsed dendritic cells. Importantly, peptide-specific CD4+ T cells also recognized HLA-DRbeta1*0401+ tumor cells that constitutively expressed the MAGE-6 protein and autologous HLA-DRbeta1*0401+ dendritic cells transfected with MAGE-6 cDNA-elicited CD4+ T cells that reacted against individual peptide epitopes in vitro. These data suggest that MAGE-6-derived epitopes could serve as useful vaccine candidate components and may provide an immune-monitoring index of clinically important Th1-type immunity in patients with renal cell carcinoma or melanoma.

Adenoviridae↗

PubMed2002

Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase.

Antigen-presenting cells (APCs) can induce tolerance or immunity. We describe a subset of human APCs that express indoleamine 2,3-dioxygenase (IDO) and inhibit T cell proliferation in vitro. IDO-positive APCs constituted a discrete subset identified by coexpression of the cell-surface markers CD123 and CCR6. In the dendritic cell (DC) lineage, IDO-mediated suppressor activity was present in fully mature as well as immature CD123+ DCs. IDO+ DCs could also be readily detected in vivo, which suggests that these cells may represent a regulatory subset of APCs in humans.

Antigen-Presenting Cells↗

PubMed2002

Sentinel node biopsy in vulvar and vaginal melanoma: presentation of six cases and a literature review.

BACKGROUND: Urogenital melanoma is a rare neoplasm with poor prognosis. Its management in the past involved radical vulvectomy and complete bilateral inguinofemoral lymphadenectomy. Sentinel lymph node biopsy is an accurate low-morbidity procedure when used in the context of cutaneous melanoma. However, prophylactic lymphadenectomy has not been shown to improve survival of melanoma patients. We wanted to determine the feasibility of sentinel lymph node biopsy in patients with female urogenital melanoma as a staging procedure. METHODS: Six patients with vulvar or vaginal melanomas underwent preoperative lymphatic mapping with (99m)Tc-labeled sulfur colloid followed by sentinel lymphadenectomy. In addition, we reviewed the literature on the application of sentinel lymph node biopsy in urogenital tract melanomas. RESULTS: One or more sentinel nodes were identified in all six patients by lymphoscintigraphy. All patients underwent sentinel lymphadenectomy, except for one patient with a deep vaginal melanoma that drained to pelvic nodes. The five successful cases had unilateral drainage patterns. None of the sentinel lymph nodes excised had tumor invasion. Combined with five other patients from the published literature, the success rate of localizing sentinel lymph nodes in the patients with urogenital melanoma approaches 100%. CONCLUSIONS: This experience, plus reports of a small number of patients from three similar studies, supports the impression that sentinel lymph node biopsy is feasible for vulvar and vaginal melanoma.

Adult↗

PubMed2002

Problems in the interpretation of apparent "radial growth phase" malignant melanomas that metastasize.

BACKGROUND: The delineation of radial and vertical growth phases in primary cutaneous malignant melanomas has contributed to our understanding of melanoma progression and has enhanced the ability of pathologists to provide clinicians with meaningful prognostic information. Vertical growth phase (VGP) lesions have the potential to metastasize, but radial growth phase (RGP) melanomas are believed to lack competence for metastasis. METHODS: We have identified three cases in which metastasis occurred in association with lesions initially interpreted as RGP melanomas. To determine whether these cases truly represented exceptional metastasizing RGP melanomas or VGP lesions incorrectly identified as RGP lesions, careful microscopic re-review of these cases was performed. RESULTS: In one case, additional microscopic sectioning revealed a focus of vertical growth that was not evident on the original sections. In the other two cases, only radial growth was found. In one of these cases there was melanoma in situ with regressive changes, but no evidence for invasive melanoma. In the other, a RGP lesion was associated with an adjacent compound nevus with periadnexal involvement. CONCLUSIONS: These cases suggest that, while true RGP melanomas have an excellent prognosis, caution must be exercised in defining a lesion as having no metastatic potential when multiple sections of the primary lesion are unavailable, when the lesion is accompanied by regressive changes, or when there is an associated melanocytic nevus. It is possible that strictly defined RGP melanomas may metastasize in very rare cases. Our observations also suggest that metastatic potential is a function of numerous factors, and may not be evaluable on morphological grounds alone.

Adult↗

PubMedDate not supplied

Preventing the spontaneous modification of an HLA-A2-restricted peptide at an N-terminal glutamine or an internal cysteine residue enhances peptide antigenicity.

The p68-derived peptide, QIVDVCHDV, was identified by a reverse immunology approach as capable of reconstituting an epitope recognized by the melanoma-reactive cytotoxic T lymphocyte (CTL) line VMM5. The peptide has not been demonstrated definitively on the cell surface by mass spectrometry; thus, it is not yet considered appropriate for use in human melanoma vaccines. Interestingly, however, the antigenicity of this peptide was affected by spontaneous modifications at two distinct residues. Spontaneous modification of the QIVDVCHDV peptide can occur at the cysteine residue at position 6 or at the N-terminal glutamine residue, and both modifications dramatically affect CTL recognition. Avoidance of an acidic environment prevents the conversion of the N-terminal glutamine residue to pyroglutamic acid, a conversion that inhibits binding of the peptide to HLA-A2 and diminishes recognition by CTLs. Substitution of asparagine for the N-terminal glutamine and substitution of serine for the cysteine were shown to enhance the binding of the peptide to HLA-A2 and to enhance the recognition of the peptide by CTLs. These findings suggest general strategies for enhancing the antigenicity of other peptides containing similar amino acids in their sequence.

Antigens, Neoplasm↗

PubMedDate not supplied

Assessment of the toxicities of systemic low-dose interleukin-2 administered in conjunction with a melanoma peptide vaccine.

In this phase 2 study, the authors assessed the hematologic and clinical toxicities of a melanoma peptide vaccine administered in conjunction with low-dose interleukin-2 (IL-2) therapy. Forty patients were randomized to receive a weekly vaccine paired with a regimen of subcutaneous IL-2 (3 x 10(6) IU/m2/day) administered daily for 6 weeks beginning either at week 1 or at week 4 of vaccine therapy. The differences in the time course of the IL-2 between the two groups permitted assessment of the cause of the toxicities, due either to IL-2 or to vaccine components. Both treatment regimens were well tolerated in the outpatient setting. Toxicities attributable to the vaccine components were principally limited to grade 1 injection site reactions. Systemic clinical toxicities correlated with the initiation of IL-2 therapy. These toxicities coincided temporally and in magnitude with changes in circulating eosinophil counts, suggesting that systemic clinical toxicities and eosinophilia may have common etiologic pathways. Other minor toxicities attributable to this low-dose IL-2 regimen were clinically insignificant hepatic toxicity, mild anemia, and mild thrombocytosis. The hematologic effects of this therapy were delayed in time between the two treatment groups, without dramatic differences in magnitude, which suggests minimal modulation of the IL-2 toxicity by components of the vaccine.

Cancer Vaccines↗

PubMedDate not supplied

Competition among peptides in melanoma vaccines for binding to MHC molecules.

The effectiveness of peptide-based cancer vaccines depends on the ability of peptides to bind to MHC molecules on the surface of antigen-presenting cells, where they reconstitute epitopes for cytotoxic T lymphocytes (CTLs). Multivalent vaccines have advantages over single-peptide vaccines; however, peptides may compete for binding to the same MHC molecules. In particular, it is possible that peptides with high affinity for MHC molecules prevent the binding of lower-affinity peptides. However, only small numbers of peptide/MHC complexes per cell are required for CTL recognition. Thus, the authors hypothesized that competition of peptides for MHC binding would not significantly reduce CTL recognition of individual peptides within a multiple-peptide mixture, and this hypothesis was tested by a series of experiments performed in vitro. In multiple experiments, two peptides with different affinities for HLA-A*0201 molecules were mixed at various concentrations and pulsed onto HLA-A2 cells, which were then evaluated for susceptibility to lysis by HLA-A*0201-restricted CTLs. CTL recognition of the melanoma peptides gp100(154-162) (KTWGQYWQV), gp100(280-288) (YLEPGPVTA), and tyrosinase(369-377D) (YMDGTMSQV) was maintained even when target cells were co-pulsed with equimolar concentrations of peptides with comparable or higher affinity for HLA-A2. In some cases, CTL recognition was maintained even when the higher-affinity peptide was present at concentrations several orders of magnitude higher than the target peptide. In addition, CTLs generated by in vitro stimulation with a peptide mixture developed reactivity to three different peptides, at a level comparable to that obtained by stimulation with each individual peptide separately. These data suggest that CTLs can respond to multiple peptides presented on the same antigen-presenting cells and justify further investigation, in clinical trials, of multiple-peptide cancer vaccines.

Binding, Competitive↗

PubMedDate not supplied

Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2.

The purpose of this investigation was to evaluate the occurrence of autoimmune toxicities associated with the administration of low-dose IL-2 in conjunction with vaccines for melanoma. Ninety-three patients with stage IIB, III, or IV melanoma were enrolled in three clinical trials and received anti-melanoma vaccines on days 1, 8, 15, 29, 36, and 43. The vaccines comprised peptide-pulsed dendritic cells, autologous tumor cells with GM-CSF in Montanide ISA-51, or synthetic peptides with GM-CSF in Montanide ISA-51. In conjunction with the vaccines, all patients were administered 3 x 10(6) IU/m2/d IL-2 subcutaneously for 42 days, either days 8 to 49 or 29 to 70. Clinical and laboratory data from these studies were reviewed in aggregate to evaluate the occurrence of autoimmune toxicities. Of 91 evaluable patients, vitiligo was documented in 6 patients (7%). In addition, one patient experienced transient severe insulin-dependent diabetes that resolved after discontinuing IL-2, and another experienced an exacerbation of his pre-existing diabetes; these occurrences are consistent with an autoimmune insulitis. Four occurrences (4%) of transient minor ocular toxicity were documented, but no autoimmune ocular toxicities or changes in visual acuity were found. Of 55 evaluable patients, 14 experienced thyroid abnormalities (25%). These were attributed to an autoimmune thyroiditis, which was supported by findings of antithyroid antibodies in three of the seven patients evaluated. Overall, autoimmune toxicities affecting several organ systems were observed in patients receiving melanoma vaccines in conjunction with low-dose IL-2. None of these toxicities caused major long-term effects, though one was acutely life-threatening and others contributed to treatment-related morbidity. Peptide- or cell-based vaccines administered in combination with low-dose IL-2 appear to be capable of breaking tolerance to self-antigens; despite the associated toxicities, these combinations may still be useful to administer as an immunotherapy for cancer. However, careful monitoring for autoimmune toxicities should be incorporated in future clinical studies incorporating low-dose IL-2.

Adult↗

PubMedDate not supplied

Immunotherapy for melanoma.

BACKGROUND: Immunotherapy for cancers is based on the principle that the host's immune system is capable of generating immune responses against tumor cells. Currently available treatments for melanoma patients are limited by poor response rates. Interferon-a has been approved for adjuvant treatment of stage III melanoma with improved survival. New and more innovative approaches with improved efficacy are needed. METHODS: We reviewed the various new approaches and strategies for immunotherapy for the treatment of melanoma. RESULTS: Immunotherapy for melanoma includes a number of different strategies with vaccines utilizing whole cell tumors, peptides, cytokine-mediated dendritic cells, DNA and RNA, and antibodies. CONCLUSIONS: A variety of approaches can be used to enhance immune reactivity in patients with melanoma. Preclinical studies and initial clinical trials have shown promising results. Additional clinical trials are currently ongoing to evaluate the clinical efficacy and the associated toxicities of these novel treatment strategies.

Cancer Vaccines↗