Ralph C. Jones

Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: An immunologic survival model

AbstractBackground: Our polyvalent, allogeneic melanoma cell vaccine (MCV) induces immunoglobulin M (IgM) and immunoglobulin G (IgG) class antibodies to a 90-kDa glycoprotein melanoma-associated antigen (MAA). Additionally, MCV induces delayed-type hypersensitivity (DTH) responses that we previously correlated with survival. We hypothesized that early DTH responses to MCV and early humoral responses to the 90-kDa MAA expressed on MCV cells may be predictive of overall survival. We tested this hypothesis by monitoring immunologic profiles in 59 patients with melanoma who were receiving MCV after surgical resection of regional lymph node or soft-tissue metastases.nMethods: Blood was drawn before vaccine administration, biweekly for 6 weeks, and then monthly. DTH to MCV was recorded at 0, 2, 4, and 8 weeks of MCV therapy. Mean antibody titers during the first 6-week interval were calculated. Changes in DTH were calculated as the difference between peak and prevaccine values (ΔDTH).nResults: At a median follow-up of 75.6 months (range 5–138), univariate analysis assigned prognostic significance to gender (p=0.046), lymph node involvement (p=0.024), ΔDTH (p=0.044), mean anti-90-kDa MAA IgG (p=0.0009), and mean anti-90-kDa MAA IgM (p=0.0014). In multifactorial analysis, only the three immunologic variables significantly impacted survival (p=0.046, 0.0005, and 0.0053, respectively). A mathematical model based on ΔDTH and mean anti-90-kDa MAA IgG and IgM titers closely approximated the observed individual and overall survival rates.nConclusions: The correlation between overall survival and initial humoral/cellular immune responses to MCV immunotherapy may be useful in selecting patients most likely to benefit from prolonged adjuvant immunotherapy.

Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells

Tamoxifen, a synthetic antiestrogen, is known for its antitumoral action in vivo; however, it is well accepted that many tamoxifen effects are elicited via estrogen receptor‐independent routes. Previously, we reported that tamoxifen induces PKC translocation in fibroblasts. In the present study, we investigated the influence of tamoxifen, and several triphenylethylene derivatives, on protein kinase C (PKC) in MCF‐7 human breast cancer cells. As measured by Western blot analysis, tamoxifen elicited isozyme‐specific membrane association of PKC‐ϵ, which was time‐dependent (as early as 5 min post‐treatment) and dose‐dependent (5.0–20 μM). Tamoxifen did not influence translocation of α, β, γ, δ or ζ PKC isoforms. Structure‐activity relationship studies demonstrated chemical requirements for PKC‐ϵ translocation, with tamoxifen, 3‐OH‐tamoxifen and clomiphene being active. Compounds without the basic amino side chain, such as triphenylethylene, or minus a phenyl group, such as N,N‐dimethyl‐2‐[(4‐phenylmethyl)phenoxy]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent‐induced PKC‐ϵ translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. Since PKC‐ϵ has been associated with cell differentiation and cellular growth‐related processes, the antiproliferative influence of tamoxifen on MCF‐7 cells may be related to the interaction with PKC‐ϵ. Int. J. Cancer 77:928–932, 1998.© 1998 Wiley‐Liss, Inc.

Evaluation of axillary lymphadenectomy without axillary drainage for patients undergoing breast-conserving therapy.

AbstractBackground: The routine use of drainage after axillary node dissection in patients undergoing breast-conserving therapy (BCT) is being questioned. To determine the value of routine drainage, we evaluated the postoperative course of patients with primary breast carcinoma who underwent axillary dissection with or without axillary drainage.nMethods: A retrospective review of 69 patients prompted a prospective randomized trial of 46 patients undergoing BCT at our tertiary cancer center. Variables studied were age, treatment (drain or no drain), number and tumor status of excised lymph nodes, size of primary tumor, duration of drainage or aspiration, number and volume of aspirations, number of office visits, incidence of complications and degree of pain, change in arm or forearm circumference, and body mass index (BMI). Data from prospective and retrospective studies were pooled for analysis.nResults: Of 115 patients, 72 were treated with a drain (Drain group) and 43 were not (No-drain group). Overall there was no difference in the number or tumor status of excised nodes, the size of the primary tumor, or the incidence of complications between the two groups. Aspiration was required in 50% of the No-drain patients and 8.3% of the Drain patients. The incidence of drain placement or replacement postoperatively was 9.3% for the No-drain patients and 4.2% for the Drain patients. The No-drain patients had more office visits (5.1±0.4 vs. 3.6±0.1;P=.0002) and a longer interval between operation and last aspiration or drain removal (16.2±1.4 days vs. 11.3±0.6 days;P=.0040). Findings were similar in the subgroup of 46 prospectively studied patients, who included 24 Drain patients and 22 No-drain patients. In this group, pain evaluation using a scale of 0 to 10 showed a mean rating of 4.2±2.6 in Drain patients and 2.7±0.4 in No-drain patients (P=.0062).nConclusions: Axillary node dissection can be managed with or without a drain. More office visits but less pain can be expected if a drain is not used.

Tumor-associated antigen TA-90 immune complex assay predicts subclinical metastasis and survival for patients with early stage melanoma†

TA‐90 is a tumor‐associated antigen first identified in the urine and sera of patients with metastatic melanoma. In the early stages of disease, TA‐90 is present in circulating immune complexes (ICs) that may be detected with an antigen specific enzyme‐linked immunosorbent assay (ELISA). In this study, the authors evaluated the efficacy of the TA‐90 IC assay in detecting subclinical metastasis of early stage melanoma and predicting the survival of patients with this disease.

Ratio of IgG: IgM antibodies to sialyl LewisX and GM3 correlates with tumor growth after immunization with melanoma‐cell vaccine with different adjuvants in mice

Human melanoma cells (from biopsies and culture) express sialyl‐Lewisx and sialyl Lewisa, the ligands for ECAM. These ligands may facilitate tumor progression and metastasis in human cancers. To test whether the antibodies to these ligands inhibit tumor progression, IgG and IgM responses to sLex and sLea were induced in C57BL/6j mice (n = 76) by immunization with human melanoma cells, with or without adjuvants (BCG, MPL, KLH). Control mice were treated with saline or BCG. Tumor growth and antigen expression were monitored after challenge with B16 mouse melanoma cells expressing sLex, sLea and the ganglioside GM3. Tumor growth was reduced in mice immunized with BCG alone or cells with BCG or MPL, while tumors in mice receiving cells without adjuvants grew larger than in the control. Augmentation of IgM titers to sLex and GM3 after immunization with BCG, or with cells with BCG or MPL correlated with retarded tumor growth, while increased IgG titers to sLex significantly correlated with aggressive tumor growth in mice immunized with cells without adjuvants. SLex, sLea and GM3 were expressed in tumors from mice treated with saline or BCG. SLex expression, in particular, was lost in tumors growing in mice immunized with cells with or without adjuvants. Anti‐sLex antibodies may promote or prevent tumor growth by antigenic modulation or by cytotoxic killing of tumor cells. Since early anti‐sLex IgM correlated with tumor regression, in contrast to anti‐sLex IgG, it may serve as a potential early endpoint for the effectiveness of melanoma vaccines expressing the antigens. Int. J. Cancer 75:117–124, 1998.© 1998 Wiley‐Liss, Inc.

Cellular cancer vaccine induces delayed-type hypersensitivity reaction and augments antibody response to tumor-associated carbohydrate antigens (sialyl Le(a), sialyl Le(x), GD3 and GM2) better than soluble lysate cancer vaccine.

Allogenlc whole cell and lysate cancer vaccines are associated with very different clinical outcome, which could be due to different immune responses to critical tumor-associated antigens. We used a guinea pig model to evaluate the immune responses to melanoma-associated carbohydrate antigens administered in whole cell and soluble lysate vaccines produced from the same cell lines and administered with or without Bacille Calmette-Guerin (BCG). Animals immunized with whole cell vaccine developed a significantly higher delayed-type hypersensitivity (DTH) reaction. The IgG response to all tumor-associated carbohydrate antigens except GD2 was significantly higher in animals Immunized with whole cell vaccine than lysate vaccine. This study indicates that whole cell vaccine is superior to soluble or lysate vaccine because it induces a better immune response against cell-surface antigens. The addition of BCG significantly increased the antibody response, suggesting that an exogenous adjuvant may immunopotentiate antigens better in the presence of an intact cell membrane.