Augmentation of T-cell response with a melanoma cell vaccine expressing specific HLA-A antigens.
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Antigens, Neoplasm↗
Biomedical subjects
L J Foshag
Publications and source records attributed to L J Foshag.
A preclinical model to assess the antigenicity of an HLA-A2 melanoma cell vaccine.
BACKGROUND: The authors have demonstrated that immunization with melanoma whole-cell vaccine (MCV) augments T-cell responses to melanoma and that cytotoxic T-cells (CTL) recognize allogeneic melanoma-bearing shared HLA-A antigens. A preclinical model was developed to assess CTL activation in vitro using melanoma lines as stimulators. HLA-A2 expression is predominant in melanoma patients and plays a role in HLA class I restricted CTL killing of melanomas. The authors hypothesized that a MCV consisting of allogeneic HLA-A2 melanomas may be as good as autologous melanoma MCV for HLA-A2 patients. METHODS: CTL were generated from peripheral blood lymphocytes of patients with HLA-A2 melanoma by stimulation with autologous melanoma, allogeneic melanoma (HLA-A2 or non-HLA-A2), or allogeneic MCV (mixed HLA-A2 and non-HLA-A2 melanomas). RESULTS: HLA-A2 MCV and autologous melanoma were similar and significantly better stimulators than the others. Specificity also was supported by CTL killing and mixed lymphocyte tumor reaction assays. CONCLUSIONS: These studies provide important information for the studying immunization of patients with HLA-A2 melanoma with an allogeneic HLA-A2 MCV in a Phase I clinical trial.
Antigens, Neoplasm↗
Multivariate analysis of the relationship between survival and the microstage of primary melanoma by Clark level and Breslow thickness.
BACKGROUND: The American Joint Committee on Cancer (AJCC) uses both Breslow thickness and Clark level in its staging system for malignant melanoma. Stage I corresponds to Breslow thicknesses less than 1.5 mm and Clark levels II and III. Stage II corresponds to Breslow thicknesses of at least 1.5 mm and Clark levels IV and V. However, most investigators have found Clark level to be of no prognostic significance once Breslow thickness has been taken into consideration by multivariate analysis. METHODS: The authors examined the prognostic significance of Clark level by studying patients in the large database of the John Wayne Cancer Institute. Among 5575 patients with melanoma seen during the past 20 years, complete data on microstaging by both Clark and Breslow methods were available for 3323 patients. The 5-year survival rates were as follows: Clark II, 95%; III, 81%; IV, 68%; V, 47%. The Breslow thicknesses were as follows: < 0.75 mm, 95%; 0.75-1.49 mm, 85%; 1.5-3.99 mm, 66%; > or = 4.0 mm, 46%. RESULTS: By univariate analysis, both Clark level and Breslow thickness were highly significant prognostic indicators (P < 0.0001). By multivariate analysis, Breslow thickness remained significant (P < 0.0001). However, even when Breslow thickness was included in the model, Clark level also remained highly significant (P < 0.0015). CONCLUSIONS: Decisions regarding therapy for patients with clinical Stage I melanoma should consider both Clark level and Breslow thickness of the primary lesion. When there is a discordance between the two methods of microstaging, the AJCC stage should be amended to reflect the least favorable of the two prognostic indicators.
Humans↗
Interleukin-4 plus tumor necrosis factor alpha augments the antigenicity of melanoma cells.
Immune cytokines are important regulators of the immune response to neoplastic cells. We previously reported that interleukin 4 (IL-4) and either tumor necrosis factor alpha (TNF) or interferon gamma (IFN) synergistically inhibit melanoma cell growth and induce cell differentiation. In the present study we used various combinations of IL-4, IFN and TNF to enhance the antigenicity of melanoma cells. IL-4 plus TNF significantly increased the ability of melanoma cells to stimulate cytotoxic T cells (CTL) and act as targets of these CTL; IL-4 plus IFN was somewhat less effective, while TNF plus IFN was not as effective. IL-4 plus TNF also increased the expression of HLA class I and HLA-DR antigens on melanoma cells. The CTL lines examined in this study were CD3+CD4+ and oligoclonal. These preclinical results suggest that the immune response to melanoma whole-cell vaccines might be enhanced by pretreating vaccine cells with IL-4 plus TNF.
Antigens, CD↗
Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.
PURPOSE: We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck. PATIENTS AND METHODS: Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND). RESULTS: Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND. CONCLUSION: Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.
Adolescent↗
The role of surgery in the treatment of nonregionally recurrent melanoma.
BACKGROUND: Between 1971 and 1989, 144 patients underwent 183 surgical procedures for resection of nonregional metastatic melanoma. METHODS: Thirty-six patients with subcutaneous or nodal metastases, 46 patients with pulmonary metastases, 17 patients with brain metastases, 19 with gastrointestinal metastases, and 26 patients with miscellaneous sites of metastatic involvement underwent resection. RESULTS: The overall 5- and 10-year actuarial survival rates were 20% and 14%, respectively. A single postoperative death occurred in a patient operated on for palliative treatment of gastrointestinal metastases. CONCLUSIONS: Cox regression analysis suggests that patients with a solitary metastasis confined to the subcutaneous, nonregional lymph nodes or lung are most likely to benefit from aggressive surgical intervention. Surgical intervention represents a potentially important modality in the management of selected patients with nonregional metastatic melanoma.
Adolescent↗
Interleukin 4 receptor expression and growth inhibition of gastric carcinoma cells by interleukin 4.
The expression of the interleukin 4 (IL-4) receptor (IL-4R) and effects of human recombinant IL-4 on human gastric carcinoma cell lines were studied. We demonstrated that IL-4 inhibited the growth of gastric carcinoma cells in a dose dependent manner (0.1-100 units/ml) in a [3H]thymidine incorporation proliferation assay. The gastric carcinoma cells varied in sensitivity to treatment with low dose IL-4. Treatment of cells with IL-4 altered the morphology of the cells to a "flattened" morphological shape resembling differentiation. The IL-4-mediated growth inhibition was significantly abrogated by neutralization of IL-4 with specific anti-IL-4 antibody. IL-4R expression on the cell surface was determined by assessing biotin-labeled IL-4 binding to cells using flow cytometry. IL-4R expression ranged from 5 to 85% of total cell population in the gastric carcinoma cell lines assessed. There was a positive correlation between the sensitivity to IL-4-mediated growth inhibition and IL-4R expression. By Northern blot analysis, we demonstrated that mRNA of IL-4R was expressed in the gastric carcinoma cells. Using in situ hybridization, we confirmed that IL-4R mRNA was expressed in the gastric carcinoma cell at the single cell level. By using a sensitive polymerase chain reaction technique, we demonstrated that gastric carcinoma cells expressed IL-4 mRNA, suggesting a possible autocrine loop. These studies indicate that IL-4 can significantly modulate gastric carcinoma cells that possess IL-4R. IL-4R on gastric carcinoma cells may be a potential therapeutic target site for IL-4-directed therapy.
Base Sequence↗
Technical details of intraoperative lymphatic mapping for early stage melanoma.
The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.
Adolescent↗
Induction of CD4+ cytotoxic T cells by sensitization with allogeneic melanomas bearing shared or cross-reactive HLA-A.
Human melanoma is an immunogenic neoplasm whereby enhancement of specific cell-mediated immunity can alter tumor progression. HLA-A2-restricted CTL have been demonstrated to kill allogeneic HLA-A2-matched melanoma. We investigated the ability of allogeneic melanoma cells sharing HLA-A antigens to sensitize melanoma patients' lymphocytes to induce HLA-A-restricted CTL to autologous melanoma. PBL from melanoma patients were cocultured with autologous melanoma cells in defined "cocktail medium" to generate melanoma-specific HLA-A-restricted CTL lines. CTL generated by sensitization with allogeneic melanoma bearing shared HLA-A2, A11, A24, or "cross-reactive" HLA-A antigens could kill almost as many autologous melanoma cells as CTL sensitized with autologous melanoma. There are HLA-A antigens that are immunogenically cross-reactive because they share determinant epitopes. CTL were not activated NK or LAK cells. The HLA restriction and melanoma cell specificity of the CTL were demonstrated by cold target inhibition with autologous and allogeneic melanoma and B lymphoblasts. Anti-CD3 and anti-HLA AB inhibited CTL killing of melanoma. The CTL were predominantly CD3+CD4+ TCR alpha/beta+. These studies demonstrate that melanomas being shared or cross-reactive HLA-A can be used for in vitro generation of HLA-restricted CTL that recognize melanoma-associated antigens. The findings have very important implications in human tumor immunotherapy.
CD4 Antigens↗
Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.
A new polyvalent melanoma cell vaccine (MCV) was administered to 136 stage IIIA and IV (American Joint Committee on Cancer) melanoma patients. Induction of cell-mediated and humoral immune responses to common melanoma-associated antigens present on autologous melanoma cells was observed in patients receiving the new MCV. This was accompanied by increased activation of tumor-infiltrating lymphocytes. Survival correlated significantly with delayed cutaneous hypersensitivity (p = 0.0066) and antibody responses to MCV (p = 0.0117). Of 40 patients with evaluable disease, nine (23%) had regressions (three complete). From our historical database of 126 stage IIIA and 1275 stage IV melanoma patients, there were no significant changes in the natural history of metastatic melanoma during the past 20 years. Univariate and multivariate analyses demonstrated prognostic significance for site of metastases (p = 0.0001) and immunotherapy with the new MCV (p = 0.0001). Overall our new MCV increased the median and 5-year survival of stage IIIA melanoma patients with regional soft tissue metastases twofold (p = 0.00024), and stage IV patients threefold (p = 0.0001) compared with previous immunotherapy and other treatments.
Adult↗
Prospective evaluation of the use of antigen-specific immune complexes in predicting the development of recurrent melanoma.
We previously demonstrated that the antigen-specific immune complexes captured by the monoclonal antibody MAb JSI in a sandwich enzyme-linked immunosorbent assay were associated with recurrent melanoma. To determine the potential use of antigen-specific immune complex analysis in predicting the development of recurrent melanoma, we prospectively analyzed serum obtained from patients with melanoma following surgical treatment. Two hundred fifty-three patients have been followed up for a median of 25 months (range, 17 to 29 months). Seventy-seven patients (30%) have developed recurrent melanoma. Antigen-specific immune complexes correlated with the stage of disease at time of entry into the study. The absence of antigen-specific immune complexes in postoperative serum samples is predictive of a disease-free status. Long-term follow-up will define the false-positive rate of antigen-specific immune complex analysis. Continued refinement of this approach should lead to clinically useful methodology to monitor human melanoma.
Antibodies, Monoclonal↗
Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide.
Previous studies have shown that melanoma patients develop an immune response to cell surface melanoma-associated antigens. The presence of this antibody response to cell surface antigens has been correlated with a better clinical outcome when melanoma patients are treated with an allogeneic melanoma cell vaccine (MCV) as an active immunotherapy protocol. It was hypothesized that the inability to consistently induce or enhance existing immune responses to melanoma-associated antigens was related to the downregulation by suppressor cells. Patients received treatments of MCV 3 times in a 4-week interval and then every fourth week. The biological response modifier cyclophosphamide (CYP) is an immunomodulator of suppressor T-cell function. In this study we set out to determine whether CYP given prior to MCV could reduce suppressor cell activity during vaccination. In a randomized trial stage II and III melanoma patients (n = 41) were given MCV alone or in conjunction with CYP at dosages of 300, 150, or 75 mg/m2. CYP was given 3 days prior to each MCV treatment. Suppressor cell activity in patients was monitored by a concanavalin A suppressor assay using peripheral blood lymphocytes from serial phlebotomies during a 12-week period of treatment. In each trial group there were patients who had major reduction in suppressor cell activity (greater than 50%). Overall, the greatest reduction in suppressor cell activity occurred in patients receiving 300 mg/m2 CYP compared to the other CYP dosages or MCV alone. For the first two treatments at all CYP dosages there was a greater number of patients showing reduced suppressor cell activity compared to later treatments. In a comparison of patients receiving MCV alone to MCV + CYP 300 mg/m2 phenotypic analysis of lymphocyte subsets showed significant (P = 0.03) reduction in the CD8+CD11B+ (suppressor) cells of the latter group. These studies suggest that CYP can be used at low dosages in conjunction with MCV to reduce suppressor cell activity.
Adult↗
Clarifying the role of fine-needle aspiration cytologic evaluation and frozen section examination in the operative management of thyroid cancer.
The final histologic diagnoses of 486 patients who underwent thyroidectomy at UCLA Medical Center from March 1975 to August 1988 were reviewed. There were 146 patients with a diagnosis of thyroid malignant neoplasm. All patients who had preoperative fine-needle aspiration cytologic evaluation, intraoperative frozen section analysis, or both were included in the present study. Carcinoma was diagnosed by frozen section in 87 (69%) of 126 cases. Frozen section analysis was incorrect in 39 (31%) of 126 cases. Fine-needle aspiration was performed in 62 patients. A malignant neoplasm was identified by fine-needle preoperative fine-needle aspiration and intraoperative frozen section analysis, and carcinoma was detected by both methods in 32 (57%) of 56 cases. Fine-needle aspiration cytologic evaluation is extremely valuable in the diagnosis of thyroid cancer and is at least as accurate as frozen section analysis with less morbidity and expense. When fine-needle aspiration demonstrates malignant neoplasm, thyroid resection may be planned with confidence.
Adolescent↗
Active specific immunotherapy in malignant melanoma.
We have recently initiated clinical trials of active specific immunotherapy evaluating a new polyvalent melanoma cell vaccine in patients with high-risk and/or recurrent melanoma. The vaccine has been administered alone, or in combination with low-dose cyclophosphamide, as an immunomodulator of suppressor cells. Cyclophosphamide is effective in lowering suppressor cell activity in some patients undergoing active specific immunotherapy. This is not associated with an enhanced humoral immune response to melanoma-associated antigens, nor is the clinical course of those patients receiving cyclophosphamide favorably influenced. We are hopeful that other immunomodulators, alone or in combination with lower doses of cyclophosphamide, may be effective in some patients, particularly in those patients whose suppressor cell activity remains high. The optimization of the vaccine and the use of immunomodulators will enhance humoral and cellular immune responses to antigens in the allogenic vaccine that cross react with those present in the autologous melanoma, which should more favorably influence the prognosis of melanoma patients.
Antigens, Neoplasm↗
Testosterone-secreting adrenal adenoma containing crystalloids characteristic of Leydig cells.
A 49-year-old woman with virilization demonstrated biochemical features traditionally ascribed to virilizing ovarian tumors: marked elevation of serum testosterone level with normal urinary excretion of 17-ketosteroids and normal serum dehydroepiandrosterone level. An adrenal cortical adenoma containing neoplastic cells indistinguishable from Leydig cells, including the demonstration of characteristic crystalloids of Reinke, was shown to be the source of the elevated testosterone level. A review of the literature revealed 13 cases with a similar biochemical profile, and of these, two were reported to contain crystalloids of Reinke. Taking cognizance of the fact that these characteristic crystalloids are only found in 40 percent of Leydig cell tumors of the testis, it is concluded that Leydig cells may be present in, and may be active participants in, the pathophysiology of a number of testosterone-secreting adrenal tumors.
Adenoma↗
Chronic fistula developing 2 years after nephrectomy for pyonephrosis.
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Abdominal Neoplasms↗
Effect of total portal diversion on lipid synthesis.
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Animals↗
Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms.
PURPOSE: Regional lymph node involvement is the most important prognostic indicator in patients with solid tumors. Conventional lymph node dissection has not been shown to affect survival and is often associated with considerable morbidity. Intraoperative lymphatic mapping and sentinel lymph node dissection were therefore designed as a minimally invasive alternative to routine elective lymph node dissection in patients with primary cutaneous melanoma. This study examined whether introperative lymphatic mapping and sentinel lymph node dissection were accurate in staging patients with other solid malignancies. PATIENTS AND METHODS: Between 1985 and 1998, 107 patients with breast cancer, 17 with thyroid tumors, 14 with gastrointestinal/gynecologic cancers, six with Merkel cell cancers, and five with squamous cell carcinomas of the head and neck have undergone mapping and sentinel lymph node dissection at the John Wayne Cancer Institute. RESULTS: The sentinel node was identified in 96% of patients (98% melanoma). In 36% of patients the sentinel node was the only tumor-positive node (71% melanoma). Eighteen percent of sentinel nodes were negative by hematoxylin and eosin staining but were positive by immunohistochemical staining (15% melanoma). CONCLUSION: These data suggest that many solid neoplasms have a primary lymphatic channel and lymph node to which it drains. Although sentinel lymph node dissection has been popularized in melanoma therapy, we have found it feasible for treatment of other solid malignancies. This technique may ultimately replace conventional dissection with more accurate staging.
Adult↗