EDITORIAL ESPANOL:

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Hola Amigos de la red. En esta ocasión les traigo una revisión sobre el tema MELANOMA Y VACUNAS. Realmente es impresionante la cantidad de estudios que se han hecho para encontrar una vacuna contra el temido melanoma. En estas 56 referencias quedan evidenciados esos intentos por encontrar una vacuna al melanoma. Las referencias datan de los años 90 hasta el 99, incluidas hasta el 2024.

Bienvenido Dr. Jorge Alvarado (Maracay), a DERMAGIC/EXPRESS,

Saludos,,,

Dr. José Lapenta R.,,,

 EDITORIAL ENGLISH:

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Hello Friends of the net. In this occasion I bring a revision on the topic MELANOMA AND VACCINES. It is really impressive the quantity of studies that have been made to find a vaccine against the feared melanoma. In these 56 references those intents are evidenced to find a vaccine to the melanoma. The references date of the nineties up to the 99, included until 2024.

Greetings,,,

Dr. José Lapenta R. 

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MELANOMA Y VACUNAS / MELANOMA AND VACCINES

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A..- Strategies in DNA Vaccine for Melanoma Cancer.

B.- Melanoma Cancer Vaccines and Anti-Tumor T Cell Responses.

C.- Vaccimel Immunization Is Associated With Enhanced Response to Treatment With Anti-Pd-1 Monoclonal Antibodies in Cutaneous Melanoma Patients - a Case Reports Study.

D.- Melanoma Vaccines: Mixed Past, Promising Future.

E.- A Bibliometric Analysis of Melanoma Treated With Vaccinations Research From 2013 to 2023: A Comprehensive Review of the Literature.

F.- An Update of Cutaneous Melanoma Patients Treated in Adjuvancy With the Allogeneic Melanoma Vaccine VACCIMEL and Presentation of a Selected Case Report With in-Transit Metastases.

G.- A Phase I Study of an Allogeneic Cell Vaccine (VACCIMEL) With GM-CSF in Melanoma Patients.

H.- Vaccimel Immunization Is Associated With Enhanced Response to Treatment With Anti-Pd-1 Monoclonal Antibodies in Cutaneous Melanoma Patients - a Case Reports Study.

I.- Individualised Neoantigen Therapy mRNA-4157 (V940) Plus Pembrolizumab Versus Pembrolizumab Monotherapy in Resected Melanoma (KEYNOTE-942): A Randomised, Phase 2b Study.

J.- mRNA Vaccine Slows Melanoma Recurrence.

K.- Evolution and Progress of mRNA Vaccines in the Treatment of Melanoma: Future Prospects.

L.- Peptide Vaccines in Melanoma: Chemical Approaches Towards Improved Immunotherapeutic Efficacy.

M.- Peptide Nanovaccine in Melanoma Immunotherapy.

N.- Immunoinformatic Approach to Design an Efficient Multi-Epitope Peptide Vaccine Against Melanoma.

O.- Multiepitope Supramolecular Peptide Nanofibers Eliciting Coordinated Humoral and Cellular Antitumor Immune Responses.

P.- Potential Association Factors for Developing Effective Peptide-Based Cancer Vaccines.

Q.- Vaccination With Melanoma Helper Peptides Induces Antibody Responses Associated With Improved Overall Survival.

R.- Guidelines of Care for the Management of Primary Cutaneous Melanoma.

S.- Therapy With Oncolytic Viruses: Progress and Challenges.

T.- Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-Pd-1 Immunotherapy.

U.- Design and Application of Oncolytic Viruses for Cancer Immunotherapy.

V.- Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-Melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16f10-Derived Mouse Melanoma Model.1.) Active specific immunotherapy with polyvalent melanoma cell vaccine for

1.) Active specific immunotherapy with polyvalent melanoma cell vaccine for

 patients with in-transit melanoma metastases.

2.) Enhancement of complement-dependent cytotoxicity by polyvalent melanoma

cell vaccine (CancerVax): correlation with survival.

3.) Overview of melanoma vaccines: active specific immunotherapy for

melanoma patients.

4.) Correlation of specific immune responses with survival in melanoma

patients with distant metastases receiving polyvalent melanoma cell vaccine.

5.) TA90 immune complex predicts survival following surgery and adjuvant

vaccine immunotherapy for stage IV melanoma.

6.) Current status of melanoma vaccines.

7.) Vaccines and other adjuvant therapies for melanoma.

8.) Autologous hapten-modified melanoma vaccine as postsurgical adjuvant

treatment after resection of nodal metastases.

9.) Prolongation of survival in metastatic melanoma after active specific

immunotherapy with a new polyvalent melanoma vaccine.

10.) Immunotherapy and experimental approaches for metastatic melanoma.

11.) Allogeneic cells vaccine increases disease-free survival in stage III

melanoma patients. A non randomized phase II study.

12.) Relationship between immune response to melanoma vaccine immunization

and clinical outcome in stage II malignant melanoma.

13.) Increased effectiveness of interferon alfa-2b following active

specific immunotherapy for melanoma.

14.) Active-specific immunotherapy for melanoma.

15.) Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in

association with histocompatibility leukocyte antigen DR11.

16.) A 15-year follow-up of AJCC stage III malignant melanoma patients

treated postsurgically with newcastle disease virus (NDV) oncolysate and

determination of alterations in the CD8 T cell repertoire.

17.) IgM anti-ganglioside antibodies induced by melanoma cell vaccine

correlate with survival of melanoma patients.

18.) Changes in the fine specificity of gp100(209-217)-reactive T cells in

patients following vaccination with a peptide modified at an HLA-A2.1

anchor residue.

19.) Improved efficacy of dendritic cell vaccines and successful

immunization with tumor antigen peptide-pulsed peripheral blood mononuclear

cells by coadministration of recombinant murine interleukin-12.

20.) Development of herpes simplex virus replication-defective multigene

vectors for combination gene therapy applications.

21.) Developing recombinant and synthetic vaccines for the treatment of

melanoma.

22.) New trends in the development of cancer vaccines.

23.) A new mouse model of experimental melanoma for vaccine and lymphokine

therapy. 

24.) Dinitrophenyl-modified autologous melanoma vaccine induces a T cell

response to hapten-modified, melanoma peptides. 

25.) Stimulation of CD8+ T cell responses to MAGE-3 and Melan A/MART-1 by

immunization to a polyvalent melanoma vaccine. 

26.) Double-copy bicistronic retroviral vector platform for gene therapy

and tissue engineering: application to melanoma vaccine development. 

27.) Favorable clinical responses in subsets of patients from a randomized,

multi-institutional melanoma vaccine trial. 

28.) Increased survival of patients treated with a vaccinia melanoma

oncolysate vaccine: second interim analysis of data from a phase III,

multi-institutional trial. 

29.) Active specific immunotherapy with hapten-modified autologous melanoma

cell vaccine. 

30.) IgM anti-ganglioside antibodies induced by melanoma cell vaccine

correlate with survival of melanoma patients. 

31.) Cancer vaccines.

32.) Active specific immunotherapy of metastatic melanoma with an

antiidiotype vaccine: a phase I/II trial of I-Mel-2 plus SAF-m. 

33.) Allogeneic murine melanoma cell vaccine: a model for the development

of human allogeneic cancer vaccine. 

34.) Immune response to polyvalent melanoma cell vaccine in AJCC stage III

melanoma: an immunologic survival model. 

35.) Immunization with a tumor-cell-lysate-loaded

autologous-antigen-presenting-cell-based vaccine in melanoma. 

36.) Augmentation of IgM antibody to gp43 tumor-associated antigen peptide

by melanoma cell vaccine. 

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1.) Active specific immunotherapy with polyvalent melanoma cell vaccine for

patients with in-transit melanoma metastases.

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Cancer 1999 May 15;85(10):2160-9 

Hsueh EC, Nathanson L, Foshag LJ, Essner R, Nizze JA, Stern SL, Morton DL

Roy E. Coats Research Laboratories, John Wayne Cancer Institute at Saint

John's Health Center, Santa Monica, California 90404, USA. 

BACKGROUND: This study was conducted to document the rate, duration, and

type of objective response to active specific immunotherapy with a

polyvalent melanoma cell vaccine (PMCV) for patients with in-transit

melanoma metastases and to identify any acute or chronic toxic effects of

PMCV treatment. METHODS: An analysis was conducted of all in-transit

melanoma patients seen at the John Wayne Cancer Institute in Santa Monica,

California, during the period 1985-1997 who were enrolled in prospective

PMCV protocols in the absence of other therapies with possible antitumor

activity (n = 54). Clinical response to PMCV was assessed by standard

criteria. Survival curves were estimated by the Kaplan-Meier method.

Toxicity was graded according to the Eastern Cooperative Oncology Group

standard. RESULTS: PMCV produced a 17% (9 of 54 patients) objective

response rate with a 13% rate (7 of 54 patients) of complete remission

(CR). The median duration of CR was >22 months. Complete response lasting

more than 1 year was observed in 4 patients (7.2%); 1 patient remained in

remission over 9 years. Median survival was >53 months (i.e., not reached)

for responders, 42 months for nonresponders, and 53 months overall. Salvage

interventions allowed reinduction with PMCV in 23 of 25 patients, who

subsequently remained clinically free of disease for a median of 14 months.

Overall toxicity was mild, easily tolerable, and did not significantly

change the quality of life. There were no toxic deaths. CONCLUSIONS: PMCV

can cause objective complete regression of measurable intransit metastatic

melanoma with minimal toxicity, and may prolong patients' median survival. 

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2.) Enhancement of complement-dependent cytotoxicity by polyvalent melanoma

cell vaccine (CancerVax): correlation with survival.

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Ann Surg Oncol 1998 Oct-Nov;5(7):595-602 

Hsueh EC, Famatiga E, Gupta RK, Qi K, Morton DL

Sonya Valley Ghidossi Vaccine Laboratory, John Wayne Cancer Institute at

Saint John's Health Center, Santa Monica, California 90404, USA. 

BACKGROUND: Case control studies have demonstrated that administration of

CancerVax, a polyvalent melanoma cell vaccine (PMCV), after complete

resection of melanoma metastases produces a significant improvement in

disease-free survival (DFS). Because PMCV has no direct cytotoxic effect on

melanoma cells, the authors hypothesized that it prolongs survival by

enhancing antibody-mediated antimelanoma cytotoxicity. METHODS: One hundred

melanoma patients participating in a trial of PMCV adjuvant therapy

following complete resection of regional node metastases were randomly

selected for study. Serum samples obtained immediately before (T0) and 4,

8, 12, and 16 weeks after initiation of PMCV adjuvant therapy were adsorbed

with L-14 lymphoblastoid cells and then tested for in vitro

complement-dependent cytotoxicity (CDC) against M-14 cells, a melanoma cell

line not used in PMCV. CDC was expressed as percentage of total cells (n =

10,000) killed. Survival curves were estimated by the Kaplan-Meier method.

Statistical analysis was performed by the signed rank sum test, Spearman

test, log-rank test, and Cox proportional hazard regression. RESULTS:

Median CDC at T0 was 4.5% (range, 0% to 40%). Within 16 weeks after

initiation of PMCV therapy, CDC had increased in 82 (82%) patients. The

median increase of 7.5% (range, -9% to 39%) represented a highly

significant change (signed rank sum test; P = .0001). At a median follow-up

of 29 months (range, 6 to 92 months), the maximum increase in CDC

(deltaCDC) as a continuous variable was significantly correlated with DFS

(P = .0001). Median survival and 5-year DFS were more than 54 months and

less than 54%, respectively, for patients with deltaCDC > or =10% (n = 44)

but only 7 months and 14%, respectively, for those with deltaCDC <10% (n =

56; P = .0001). Multivariate analysis confirmed deltaCDC as the most

significant independent variable associated with DFS following initiation

of PMCV therapy (P = .0001). CONCLUSION: PMCV therapy greatly enhances

serum CDC against melanoma cells. This enhancement is directly correlated

with DFS following initiation of vaccine therapy. 

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3.) Overview of melanoma vaccines: active specific immunotherapy for

melanoma patients.

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Semin Surg Oncol 1998 Jun;14(4):328-36 

Ollila DW, Kelley MC, Gammon G, Morton DL

The Roy E. Coats Research Laboratories, John Wayne Cancer Institute at

Saint John's Health Center, Santa Monica, California 90404, USA. 

Although a phase III trial has yet to show a statistically significant

improvement in the disease-free or overall survival of melanoma patients

receiving vaccine therapy, several phase II trials have shown enhanced

disease-free and overall survival of patients who develop a humoral and/or

cellular response to a melanoma vaccine. The challenge of active specific

immunotherapy research is to determine which combination of humoral and

cellular immune responses optimizes clinical outcome and how to monitor the

immune response effectively. This review identifies key components of a

successful melanoma vaccine, discusses new ways to modulate and stimulate

the immune system, and summarizes some of the important clinical trials of

active specific immunotherapy for patients with melanoma. 

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4.) Correlation of specific immune responses with survival in melanoma

patients with distant metastases receiving polyvalent melanoma cell vaccine.

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J Clin Oncol 1998 Sep;16(9):2913-20 

Hsueh EC, Gupta RK, Qi K, Morton DL

Sonya Valley Ghidossi Vaccine Laboratory of the Roy E. Coats Research

Laboratories of the John Wayne Cancer Institute at Saint John's Health

Center, Santa Monica, CA 90404, USA. 

PURPOSE: The mechanisms that underlie the clinical efficacy of melanoma

vaccines are not well understood. We hypothesized that the type and

strength of the immune response generated by CancerVax (John Wayne Cancer

Institute, Santa Monica, CA), a polyvalent melanoma cell vaccine (PMCV),

might be correlated with its effect on overall survival (OS). PATIENTS AND

METHODS: Seventy-seven patients began PMCV therapy after complete surgical

resection of distant metastatic melanoma. During the first two treatments,

PMCV was administered with bacille Calmette-Guerin (BCG). Blood was drawn

at 0, 2, 4, 8, and 12 weeks to measure serum titers of immunoglobulin G

(IgG) and IgM antibodies against a tumor-associated 90-kd glycoprotein

antigen (TA90) expressed on most melanoma cells, including those of PMCV.

Cellular immune response to PMCV was assessed by delayed-type

hypersensitivity (DTH). General immune competence was assessed by skin

tests to purified protein derivative (PPD), mumps, and candida. RESULTS:

Median follow-up time was 31.5 months. Within the first 12 weeks of PMCV

immunotherapy, there was a significant increase in the anti-TA90 IgM

(P=.0001) and IgG titers (P=.0001), and in the DTH response to PMCV

(P=.0001). Univariate analysis showed that high anti-TA90 IgM titer and

strong PMCV-DTH were associated with improved survival (P=.051 and .0173,

respectively), whereas elevated anti-TA90 IgG was correlated with decreased

survival (P=.0119). Multivariate analysis considering clinical variables

and PMCV immune responses identified anti-TA90 IgM, anti-TA90 IgG, and

PMCV-DTH as significant independent variables influencing survival

following PMCV immunotherapy (P=.0342, .0105, and .0082, respectively).

These responses to PMCV were not correlated with immune responses to BCG

and therefore were not a manifestation of general immune competence for

responses to unrelated antigens. The median survival time and 5-year

survival rate were more than 76 months and 75%, respectively, if both

anti-TA90 IgM and PMCV-DTH responses were strong (> or = 800 and > or = 7

mm, respectively; n=29); 32 months and 36%, respectively, if only one

response was strong (n=35); and 19 months and 8%, respectively, if neither

was strong (n=13) (P < .0001). CONCLUSION: PMCV induces both humoral and

cell-mediated immune responses to melanoma-associated tumor antigens, the

type and strength of which appear to be directly related to its therapeutic

efficacy. 

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5.) TA90 immune complex predicts survival following surgery and adjuvant

vaccine immunotherapy for stage IV melanoma.

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Cancer J Sci Am 1997 Nov-Dec;3(6):364-70 

Hsueh EC, Gupta RK, Qi K, Yee R, Leopoldo ZC, Morton DL

Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint

John's Health Center, Santa Monica, California, USA. 

PURPOSE: Although prognosis remains poor for patients with distant

metastatic melanoma, we have observed significantly prolonged survival in

patients receiving our polyvalent melanoma cell vaccine (PMCV) following

complete metastasectomy for American Joint Committee on Cancer (AJCC) stage

IV melanoma. Clinical prognostic factors specific to this stage IV subgroup

have not been well characterized. We previously reported that the serum

immune complex (IC) level of a 90-kD glycoprotein antigen (TA90) was an

objective predictor of survival and recurrence in patients with early-stage

melanoma. In the present study we correlated the postoperative TA90-IC

level of AJCC stage IV patients prior to adjuvant PMCV therapy with their

duration of subsequent survival. PATIENTS AND METHODS: From October 1,

1984, to December 31, 1995, 125 stage IV patients began PMCV after complete

resection of distant melanoma metastases. One blood sample was obtained

immediately prior to vaccine therapy, and the serum TA90-IC level was

assessed as positive or negative using our double-determinant ELISA.

Disease-free and overall survival were recorded prospectively from the

start of vaccine therapy. The correlation between prevaccine TA90-IC level

and survival was assessed by the log-rank test and Cox proportional hazards

model. RESULTS: Median follow-up after PMCV therapy was 36.5 months, with a

minimum of 12 months. Univariate analysis demonstrated that TA90-IC level

is significant for both overall survival and disease-free survival. Median

overall survival, median disease-free survival, and rate of 5-year survival

were higher for patients with negative TA90-IC levels than for those with

positive TA90-IC level (58 vs 19 months, 7 vs 4 months, and 49% vs 27%,

respectively). Multivariate analysis established TA90-IC as an independent

prognostic indicator for both overall and disease-free survival following

adjuvant PMCV therapy for AJCC stage IV melanoma. CONCLUSION: Prevaccine

TA90-IC level correlated strongly with overall and disease-free survival in

our stage IV melanoma patients receiving postoperative PMCV immunotherapy.

This is the first serum marker shown to have importance in predicting the

survival of melanoma patients receiving adjuvant immunotherapy after

complete resection of distant metastases. 

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6.) Current status of melanoma vaccines.

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Dermatol Surg 1997 Aug;23(8):649-54; discussion 654-5 

Kuhn CA, Hanke CW

Department of Dermatology, Indiana University School of Medicine,

Indianapolis, USA. 

BACKGROUND: Malignant melanoma is increasing worldwide faster than any

other cancer and the American lifetime risk is estimated to reach 1 in 75

by the year 2000. Active specific immunotherapy with vaccines is evolving

as a promising new modality in the treatment of malignant melanoma.

OBJECTIVE: To present a concise and understandable summary of the key

molecular and clinical concepts of melanoma vaccines currently under

investigation, the history that led to their development, and their

anticipated clinical response. METHODS: The recent advances in the field of

melanoma immunobiology and the newest experiment vaccines are reviewed.

RESULTS: There is no effective melanoma vaccine that successfully treats or

prevents melanoma. However, their use has been associated with regression

or delayed disease progression in some cases. The minority of patients who

do have a major clinical response to vaccine therapy experience an

improvement in survival. Even in those patients in whom melanoma vaccines

cannot improve survival, the paucity of severe side effects has provided a

quality of life superior to standard multiagent chemotherapy. CONCLUSION:

Melanoma vaccines are relatively safe immunotherapeutic modalities for the

management of malignant melanoma. The clinical effectiveness of melanoma

vaccines is unclear and adequately controlled studies need yet to be

performed. Current melanoma vaccines manipulate antigen presentation

networks and combine the best cellular and antibody antitumor immune

response effective in mediating tumor protective immunity; these

combination vaccines hold the most promise. The ideal melanoma vaccine will

ultimately prevent melanoma. 

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7.) Vaccines and other adjuvant therapies for melanoma.

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Hematol Oncol Clin North Am 1998 Aug;12(4):835-48, vii 

Wolchok JD, Livingston PO, Houghton AN

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,

New York, USA. 

Patients with thick primary melanomas or regional lymph node involvement

are at high risk of relapse. Investigations of adjuvant therapy over the

past 30 years show only one significantly positive trial employing high

dose interferon-alpha-2b. This is a potentially toxic regimen, therefore,

other better-tolerated forms of adjuvant immunotherapy are being studied.

Recent advances in basic science have led to a better understanding of the

T-cell response to human cancer. This article discusses the background and

current clinical trials of active specific immunotherapies for melanoma,

including peptide and ganglioside vaccines. 

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8.) Autologous hapten-modified melanoma vaccine as postsurgical adjuvant

treatment after resection of nodal metastases.

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J Clin Oncol 1997 Jun;15(6):2359-70 

Berd D, Maguire HC Jr, Schuchter LM, Hamilton R, Hauck WW, Sato T,

Mastrangelo MJ

Department of Medicine, Thomas Jefferson University, Philadelphia, PA

19107, USA. d_berd@lac.jci.tju.edu 

PURPOSE: To determine whether treatment with an autologous whole-cell

vaccine modified with the hapten dinitrophenyl (DNP vaccine) is an

effective postsurgical adjuvant treatment for melanoma patients with

clinically evident nodal metastases. PATIENTS AND METHODS: Eligible

patients had regional nodal metastases that were large enough (> or = 3 cm

diameter) to prepare vaccine. Following standard lymphadenectomy, patients

were treated with DNP vaccine on a monthly or weekly schedule. RESULTS: Of

62 patients with metastasis in a single lymph node bed (stage III), 36 are

alive after a median follow-up time of 55 months (range, 29 to 76); the

projected 5-year relapse-free and overall survival rates are 45% and 58%,

respectively. Of 15 patients with metastases in two nodal sites, five are

alive with a median follow-up time of 73 months. An unexpected finding was

the significantly better survival of older patients; the projected 5-year

survival of patients greater than 50 versus < or = 50 years was 71% and

47%, respectively (P = .011, log-rank test). The development of a positive

delayed-type hypersensitivity (DTH) response to unmodified autologous

melanoma cells was associated with significantly longer 5-year survival

(71% v 49%; P = .031). Finally, the median survival time from date of first

recurrence was significantly longer for patients whose subcutaneous

recurrence exhibited an inflammatory response (> 19.4 v 5.9 months; P <

.001). CONCLUSION: Postsurgical adjuvant therapy with autologous

DNP-modified vaccine appears to produce survival rates that are markedly

higher than have been reported with surgery alone. Moreover, this approach

has some intriguing immunobiologic features that might provide insights

into the human tumor-host relationship. 

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9.) Prolongation of survival in metastatic melanoma after active specific

immunotherapy with a new polyvalent melanoma vaccine.

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Ann Surg 1992 Oct;216(4):463-82 

Published erratum appears in Ann Surg 1993 Mar;217(3):309 

Morton DL, Foshag LJ, Hoon DS, Nizze JA, Famatiga E, Wanek LA, Chang C,

Davtyan DG, Gupta RK, Elashoff R, et al

John Wayne Cancer Institute, Santa Monica, CA 90404. 

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. 

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10.) Immunotherapy and experimental approaches for metastatic melanoma.

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Hematol Oncol Clin North Am 1998 Aug;12(4):877-902, viii 

Atkins MB

Melanoma Program, Beth Israel Deaconess Medical Center, Boston,

Massachusetts, USA. 

This article reviews the clinical investigations involving recombinant

cytokines (either alone or in combination with adoptive immunotherapy,

toxicity reduction agents, or cytotoxic chemotherapy), vaccines, monoclonal

antibodies or antibody conjugates, and gene therapy. These various

approaches are reviewed for their current and potential roles in curing

metastatic melanoma. 

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11.) Allogeneic cells vaccine increases disease-free survival in stage III

melanoma patients. A non randomized phase II study.

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Medicina (B Aires) 1997;57(4):421-7 

Mordoh J, Kairiyama C, Bover L, Solarolo E

Instituto de Investigaciones Bioquimicas Fundacion Campomar, Buenos Aires,

Argentina. 

The incidence of melanoma is increasing rapidly, and in many cases the

primary tumor is excised after metastatic spreading. In 80% of the cases,

the first metastatic site is in regional lymph nodes (AJCC Stage III).

After excision of these nodes, the patient is clinically disease-free, but

the chances of recurrency vary between 40-80%. Thirty patients with stage

III melanoma were treated in a non-randomized Phase II adjuvant trial with

a vaccine consisting of a mixture of three allogeneic cell lines:

IIB-MEL-J, IIB-MEL-LES and IIB-MEL-IAN (5 x 10(6) cells each). The cells

were irradiated (5,000 cGy) and BCG was used as nonspecific stimulant.

Before each vaccination (72 hr) the patients received cyclophosphamide (300

mg/sqm). The untreated control group was composed of 24 Stage III melanoma

patients. Vaccination started within 60 days after surgery, and patients

received 4 vaccinations, one every 21 days and then 1 every two months

during the 1st year; 1 every three months during the 2nd year, and 1 every

6 months during the 3rd, 4th and 5th years. The treated group was composed

by 19 men (63.3%) and 11 women (36.7%); average age: 47.6 +/- 14.1 years

(range: 16-70 yr). The control group was composed by 18 men (75%) and 6

women (25%); average age 49.8 +/- 14.2 yr (range: 26-73 yr). The median

disease free survival (DFS) calculated according to Kaplan-Meier was 7.0

months in the control group vs 20.0 months in the treated group (p <

0.001). The results of this clinical trial suggest that treatment with

allogeneic cell vaccines increases DFS in stage III melanoma patients. 

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12.) Relationship between immune response to melanoma vaccine immunization

and clinical outcome in stage II malignant melanoma.

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Cancer 1992 Mar 1;69(5):1157-64 

Bystryn JC, Oratz R, Roses D, Harris M, Henn M, Lew R

Department of Dermatology, New York University School of Medicine, NY 10016. 

The authors investigated whether there was a relationship between the

induction of a delayed-type hypersensitivity (DTH) response to melanoma

vaccine immunization and disease recurrence. They studied prospectively 94

evaluable patients with surgically resected Stage II malignant melanoma who

were immunized to a partially purified, polyvalent, melanoma antigen

vaccine. The DTH response to skin tests to the vaccine was measured before

treatment and at the fourth vaccine immunization. Vaccine treatment induced

a strong DTH response in 29 (31%) patients, an intermediate response in 24

(25%), and no response in 41 (44%). The median disease-free survival (DFS)

of patients with a strong, intermediate, and no DTH response to vaccine

immunization was more than 72 months, 24 months, and 15 months,

respectively. The relationship between an increase in the DTH response and

a prolonged DFS was statistically significant (P = 0.02); clinically

meaningful (the median DFS of patients with a strong DTH response was 4.7

years longer than that of nonresponders); and, by multivariate analysis,

independent of disease severity or overall immune competence. These

findings suggest, but do not prove, that vaccine treatment can slow the

progression of melanoma in some patients. 

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13.) Increased effectiveness of interferon alfa-2b following active

specific immunotherapy for melanoma.

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J Clin Oncol 1994 Feb;12(2):402-11 

Mitchell MS, Jakowatz J, Harel W, Dean G, Stevenson L, Boswell WD, Groshen S

Department of Medicine, Norris Comprehensive Cancer Center, University of

South California School of Medicine, Los Angeles 90033. 

PURPOSE: To determine whether interferon alfa-2b (IFN-alfa; intron-A,

Schering Corp, Kenilworth, NJ) can induce a remission in patients

previously treated with active specific immunotherapy (therapeutic melanoma

vaccine) without response. PATIENTS AND METHODS: Eighteen patients with

disseminated melanoma who had failed to respond to at least five injections

of Melacine therapeutic melanoma vaccine (Ribi ImmunoChem Research, Inc,

Hamilton, MT) were then treated IFN-alfa after a 4-week interval. IFN-alfa

5 or 6 x 10(6) U/m2 was self-administered three times a week subcutaneously

by melanoma patients for at least 2 months. Computed tomographic (CT) scans

of the chest, abdomen, and pelvis and magnetic resonance imaging of the

brain were performed within 4 weeks before treatment as a baseline, and

then at 2-month intervals during treatment to evaluate response. All 18

patients were HLA-typed before treatment. The frequency of cytolytic T-cell

precursors (pCTL) in the blood had been measured weekly in 13 of the

patients during treatment with Melacine. RESULTS: Eight of 18 patients

(44.4%) had a major objective clinical response induced by IFN-alfa,

including site-specific complete remissions in five. Responses lasted a

median of 11 months. The median survival duration of the responders has not

been reached, and exceeds 32 months. The group as a whole had a median

survival duration of 10.1 months, and nonresponders lived 7.3 months.

Cytolytic T-cell precursors had been increased by immunization in all five

responding patients tested, but also in five of eight nonresponders. There

was no association of response to IFN-alfa with specific HLA phenotypes, in

contrast to our previous results with melanoma theraccine alone.

CONCLUSION: These data suggest an additive effect of active specific

immunotherapy and IFN-alfa on the objective response rate, perhaps through

upregulation of HLA molecules and tumor-associated antigens on the tumor

cell by IFN-alfa, after immunization of the patient by Melacine. This

treatment may have improved survival over that expected in metastatic

melanoma. 

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14.) Active-specific immunotherapy for melanoma.

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J Clin Oncol 1990 May;8(5):856-69 

Mitchell MS, Harel W, Kempf RA, Hu E, Kan-Mitchell J, Boswell WD, Dean G,

Stevenson L

Department of Medicine, University of Southern California School of

Medicine, Los Angeles. 

Twenty-five patients with metastatic melanoma were treated with a

therapeutic vaccine ("theraccine") consisting of allogeneic melanoma

lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc,

Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor

cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical

responses included one complete remission, three partial remissions, and a

long-term (17-month) stability. Two other patients had mixed responses,

with partial remissions of numerous subcutaneous nodules. Sites of

responsive disease included primarily the skin, but ileal, breast, and a

liver metastasis also responded. Removal of residual lesions in patients

with partial remissions, whose other lesions had disappeared during

treatment, led to long disease-free survivals. The median duration of

remission was 17 months, with four of the five responders alive for at

least 24 months after treatment. An increase in precursors of cytolytic T

cells (CTLs) correlated with clinical outcome, when complete, partial, and

mixed responses and long-term stability were considered. The CTLs

recognized melanoma-associated antigens on many cell lines, but not other

types of tumor or normal lymphocytes. Skin-test reactivity to melanoma

antigens and serum antibodies against the melanoma cells was unrelated to

clinical response. Toxicity was minimal, restricted largely to minor

soreness at the site of injection. Only five patients, four of whom were

treated with repeated courses, developed severe granulomas. These results

confirm that active-specific immunization with allogeneic lysates of

melanoma administered with the adjuvant DETOX can induce immunity to

melanoma, and can induce regressions of disease in a proportion of patients

with metastatic disease with little toxicity. 

=====================================================================

15.) Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in

association with histocompatibility leukocyte antigen DR11.

=====================================================================

J Exp Med 1999 Mar 1;189(5):871-6 

Manici S, Sturniolo T, Imro MA, Hammer J, Sinigaglia F, Noppen C, Spagnoli

G, Mazzi B, Bellone M, Dellabona P, Protti MP

Laboratory of Tumor Immunology, Department of Biology and Technology

(DIBIT), Scientific Institute H. San Raffaele, 20132 Milan, Italy. 

In this study we used TEPITOPE, a new epitope prediction software, to

identify sequence segments on the MAGE-3 protein with promiscuous binding

to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic

peptides corresponding to the identified sequences were synthesized and

used to propagate CD4(+) T cells from the blood of a healthy donor. CD4(+)

T cells strongly recognized MAGE-3281-295 and, to a lesser extent,

MAGE-3141-155 and MAGE-3146-160. Moreover, CD4(+) T cells proliferated in

the presence of recombinant MAGE-3 after processing and presentation by

autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes

recognized are naturally processed. CD4(+) T cells, mostly of the T helper

1 type, showed specific lytic activity against HLA-DR11/MAGE-3-positive

melanoma cells. Cold target inhibition experiments demonstrated indeed that

the CD4(+) T cells recognized MAGE-3281-295 in association with HLA-DR11 on

melanoma cells. This is the first evidence that a tumor-specific shared

antigen forms CD4(+) T cell epitopes. Furthermore, we validated the use of

algorithms for the prediction of promiscuous CD4(+) T cell epitopes, thus

opening the possibility of wide application to other tumor-associated

antigens. These results have direct implications for cancer immunotherapy

in the design of peptide-based vaccines with tumor-specific CD4(+) T cell

epitopes. 

=====================================================================

16.) A 15-year follow-up of AJCC stage III malignant melanoma patients

treated postsurgically with newcastle disease virus (NDV) oncolysate and

determination of alterations in the CD8 T cell repertoire.

=====================================================================

Mol Med 1998 Dec;4(12):783-94 

Batliwalla FM, Bateman BA, Serrano D, Murray D, Macphail S, Maino VC, Ansel

JC, Gregersen PK, Armstrong CA

North Shore University Hospital-NYU School of Medicine, 350 Community

Drive, Manhasset, New York, USA. 

[Medline record in process]

Background: The development of effective adjuvant therapies for the

treatment of high-risk melanoma patients is critical for the prevention of

metastatic disease and improvement of patient survival. Active specific

immunotherapy has been tested as an adjuvant treatment in numerous clinical

trials with overall limited, but occasionally promising, success rates.

Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive

immunotherapeutic agent in the postsurgical management of these patients. A

phase II study initiated in 1975 using adjuvant vaccine therapy composed of

allogeneic and autologous human melanoma cells infected with live NDV (NDV

oncolysate) in patients with AJCC stage III melanoma following therapeutic

lymph node dissection has shown >60% survival rate at 10 years with no

adverse effects. Continued long-term analysis of trials with promising

early results as well as assessment of immunologic responses generated in

these patients may result in improved therapeutic decisions for clinical

trials in the future. Materials and Methods: We analyzed the 15-year

survival of patients treated postsurgically with NDV oncolysate in the

phase II study described above. In an attempt to understand the

immunological effects of this treatment, we have also carried out a

comprehensive analysis of the peripheral blood T cell repertoire in these

patients. Results: The overall 15-year survival of this group of patients

is 55%. Previous studies have suggested that improved outcome in patients

undergoing immunotherapy is correlated with increased numbers of

CD8(+)CD57(+) cells. In surviving patients, we observed a striking

oligoclonality in the CD8(+) T cell population in peripheral blood, which

reflects clonal expansions in the CD8(+)CD57(+) subset. Conclusions: The

data suggest that adjuvant vaccination with NDV oncolysates is associated

with prolonged survival of patients with lymph node-positive malignant

melanoma and that CD8(+) T cells may be an important component of

therapeutic efficacy. 

=====================================================================

17.) IgM anti-ganglioside antibodies induced by melanoma cell vaccine

correlate with survival of melanoma patients.

=====================================================================

J Invest Dermatol 1999 Feb;112(2):205-9 

Takahashi T, Johnson TD, Nishinaka Y, Morton DL, Irie RF

Department of Biotechnology Sciences, John Wayne Cancer Institute, Santa

Monica, California 90404, USA. 

Melanoma cells express ganglioside antigens GM3, GD3, GM2, and GD2 on their

surface. This study examined whether immunization with a melanoma cell

vaccine induced anti-ganglioside antibody responses in melanoma patients

and whether these responses were correlated with survival. Sixty-six

patients who had received melanoma cell vaccine immunotherapy after

surgical removal of regional metastatic melanoma were identified.

Cryopreserved serum samples from these patients were used in an

enzyme-linked immunsorbent assay to determine the IgM antibody levels to

GM2, GD2, GM3, and GD3 prior to melanoma cell vaccine treatment and 4 wk

after the first melanoma cell vaccine immunization. All antibody levels

significantly increased by week 4 (p < 0.001 for all four antibodies) and

all increases were significantly associated with survival (anti-GD2, p <

0.001; anti-GM2, p = 0.001; anti-GD3, p < 0.001; anti-GM3, p < 0.001).

Anti-tumor activity of these antibodies was proved using five

representative antibody-positive sera in a complement-dependent

cytotoxicity assay with cultured melanoma cell lines. These studies suggest

that GM2, GD2, GM2, and GD3 expressed by melanoma cells can induce specific

IgM antibodies and that high levels of these antibodies might have a

beneficial impact on survival. 

=====================================================================

18.) Changes in the fine specificity of gp100(209-217)-reactive T cells in

patients following vaccination with a peptide modified at an HLA-A2.1

anchor residue.

=====================================================================

J Immunol 1999 Feb 1;162(3):1749-55 

Clay TM, Custer MC, McKee MD, Parkhurst M, Robbins PF, Kerstann K,

Wunderlich J, Rosenberg SA, Nishimura MI

Surgery Branch, National Cancer Institute, National Institutes of Health,

Bethesda, MD 20892, USA. 

In a recent clinical trial, HLA-A2+ melanoma patients were vaccinated with

a peptide derived from the melanoma Ag gp100, which had been modified at

the second position (g9-209 2M) to enhance MHC binding affinity.

Vaccination led to a significant increase in lymphocyte precursors in 10 of

11 patients but did not result in objective cancer responses. We observed

that some postvaccination PBMC cultures were less reactive with tumor cells

than they were with g9-209 peptide-pulsed T2 cells. In contrast,

g9-209-reactive tumor-infiltrating lymphocyte cultures generally reacted

equally with tumor cells and g9-209 peptide-pulsed T2 cells. To investigate

this difference in T cell reactivity, T cell cloids derived from the PBMC

of three patients vaccinated with g9-209 2M were compared with T cell

cloids isolated from g9-209-reactive TIL cultures. All of the T cell cloids

obtained from TIL reacted with HLA-A2+, gp100+ melanoma cell lines as well

as with g9-209 and g9-209 2M peptide-pulsed targets. In contrast, only 3 of

20 PBMC-derived T cell cloids reacted with melanoma cell lines in addition

to g9-209 and to g9-209 2M peptide-pulsed targets. Twelve of twenty

PBMC-derived cloids reacted with g9-209 and g9-209 2M peptide-pulsed

targets but not with melanoma cell lines. And 5 of 20 PBMC-derived cloids

recognized only the g9-209 2M-modified peptide-pulsed targets. These

results suggest that immunizing patients with the modified peptide affected

the T cell repertoire by expanding an array of T cells with different fine

specificities, only some of which recognized melanoma cells. 

=====================================================================

19.) Improved efficacy of dendritic cell vaccines and successful

immunization with tumor antigen peptide-pulsed peripheral blood mononuclear

cells by coadministration of recombinant murine interleukin-12.

=====================================================================

Int J Cancer 1999 Jan 18;80(2):324-33 

Fallarino F, Uyttenhove C, Boon T, Gajewski TF

Department of Pathology, University of Chicago, IL, USA. 

The well-characterized P815 tumor model was used to optimize anti-tumor

immunization approaches in mice. Tumor peptides derived from antigens P198

or P1A were targeted to antigen-presenting cells (APC) by ex vivo pulsing.

Initial experiments with irradiated pulsed splenic dendritic cells (sDC)

injected weekly in the hind footpads for 3 weeks demonstrated cytolytic T

lymphocyte (CTL) generation in 10-20% of mice. Because of the importance of

interleukin-12 (IL-12) in tumor rejection responses, pulsed sDCs also were

given together with recombinant murine IL-12 (rmIL-12). This strategy

induced peptide-specific CTL in 100% of the mice. The IL-12 had to be

injected in the footpads on days 0, 1 and 2 of each immunization week to

achieve an optimal effect. The improvement seen with the addition of IL-12

prompted examination of other sources of APC. Purified resting B cells,

lipopolysaccharide (LPS) blasts and nonfractionated splenocytes or

peripheral blood mononuclear cells (PBMC) were pulsed with peptide and

administered with the same schedule of rmIL-12. Because these cell types

appeared to bind peptides less avidly than did DC, increasing peptide doses

were used during pulsing. Interestingly, immunization with each of these

APC also induced specific CTL in 100% of mice, provided rmIL-12 was

coadministered. CTLs were detected both in the spleen and in the peripheral

blood. Immunization with irradiated, P1A-pulsed PBMC plus rmIL-12 resulted

in protection against challenge with tumors expressing the specific antigen

in all mice. The ease by which human patient PBMCs can be prepared provides

a straightforward vaccination approach to be used in clinical trials of

peptide-based immunization in melanoma. 

=====================================================================

20.) Development of herpes simplex virus replication-defective multigene

vectors for combination gene therapy applications.

=====================================================================

Gene Ther 1998 Nov;5(11):1517-30 

Krisky DM, Marconi PC, Oligino TJ, Rouse RJ, Fink DJ, Cohen JB, Watkins SC,

Glorioso JC

Department of Molecular Genetics and Biochemistry, University of Pittsburgh

School of Medicine, PA 15261, USA. 

Some gene therapy applications will require simultaneous expression of

multiple gene products to achieve a therapeutic effect. In this study we

describe the generation and characterization of replication incompetent

herpes simplex virus type 1 (HSV-1) vectors (HX86Z or HX86G) carrying

distinct and independently regulated expression cassettes for five

transgenes (hIL-2, hGM-CSF, hB7.1, HSV-tk and lacZ or hIFN gamma). The

transgenes, representing 12 kb of DNA sequence, were recombined into

separate loci of a single mutant virus vector deleted for 11.6 kb of vector

sequences representing portions of nine viral genes, ICP4, ICP22, ICP27,

ICP47, UL24, UL41, UL44, US10 and US11. Deletion of the immediate--early

genes ICP4, ICP22 and ICP27 substantially reduced vector cytotoxicity,

prevented early and late viral gene expression and left intact MHC class I

antigen expression. Simultaneous expression of multiple transgenes was

obtained for up to 7 days in primary human melanoma cells with peak

expression at 2-3 days after infection. The transgenes were chosen for

their potential to function synergistically in tumor destruction and

vaccine gene therapy applications, but the method and vector employed could

be applied to other multigene therapy strategies. This study demonstrates

the potential for engineering large transgene capacity DNA viruses such as

HSV-1 for expression of multiple transgenes. 

=====================================================================

21.) Developing recombinant and synthetic vaccines for the treatment of

melanoma.

=====================================================================

Curr Opin Oncol 1999 Jan;11(1):50-7 

Restifo NP, Rosenberg SA

National Cancer Institute, National Institutes of Health, Bethesda, MD

20892-1502, USA. 

To develop new vaccines for the treatment of patients with cancer, target

antigens presented on tumor cell surfaces have been cloned. Many of these

antigens are non-mutated differentiation antigens and are expressed by

virtually all melanomas, making them attractive components for a widely

efficacious melanoma vaccine. These antigens are also expressed by

melanocytes, however, and are likely to be subject to immune tolerance. A

central challenge for tumor immunologists has thus been the breaking of

tolerance to cancer antigens. We review recent clinical trials using

experimental cancer vaccines, including recent evidence that therapeutic

vaccines can induce objective responses in patients with metastatic

malignant melanoma. We focus on the foundations of these approaches in new

experimental animal models designed to test novel vaccines and report on

what these new models predict for the future development of therapeutic

vaccines for cancer. 

=====================================================================

22.) New trends in the development of cancer vaccines.

=====================================================================

In Vivo 1998 Nov-Dec;12(6):629-38 

Minev BR, Chavez FL, Mitchell MS

Center for Biological Therapy and Melanoma Research, University of

California, San Diego, La Jolla 92093, USA. bminev@ucsd.edu 

Recent advances in understanding of the molecular mechanisms of antigen

processing and presentation, and the identification of tumor-associated

antigens in melanoma and other cancers, have stimulated the development of

a new generation cancer vaccines. This review summarizes the most recent

approaches for the design of safe and more effective vaccines for cancer.

Peptide-based vaccines are safe and can be synthesized with high purity and

reproducibility. Recombinant viruses encoding tumor-associated antigens

allow efficient delivery and precise control over the form and the quantity

of the delivered antigens. DNA-based vaccines induce long-lasting immune

responses and are considered very safe. Antigen-loaded dendritic cells, and

the use of newly developed adjuvants are also very promising new

approaches. In this review, we also discuss the possible clinical

applications and future directions for vaccine development. 

=====================================================================

23.) A new mouse model of experimental melanoma for vaccine and lymphokine

therapy. 

=====================================================================

Author 

Shrayer DP; Bogaars H; Wolf SF; Hearing VJ; Wanebo HJ 

Address 

Surgical Oncology Research Laboratory, Roger Williams Medical Center,

Providence, RI 02908, USA. 

Source 

Int J Oncol, 13(2):361-74 1998 Aug 

Abstract 

The annual incidence of malignant melanoma is estimated at 10-12 per

100,000 inhabitants in countries of central Europe and the United States,

and alarmingly there has been a dramatic upward trend in that estimate. The

B16 murine melanoma is a rapidly growing metastatic tumor of spontaneous

origin, as are human malignant melanomas. Melanoma cells produce specific

antigens which are uniquely different from normal cellular antigens, and

the expression of such antigens is the cornerstone for preparation of

anti-melanoma vaccines. One major problem in evaluating the effectiveness

of vaccination and other biologic therapies is the variability of

experimental tumor models. A new metastatic model of experimental melanoma

which was developed in our laboratory imitates the major clinical stages of

malignant metastatic melanoma: stage I, primary (local) tumor growth and

bone marrow invasion; stage II, regional lymph node involvement; and stage

III, metastasis to distant organs, such as the lungs. This model has been

used successfully for screening vaccines constructed in our laboratory.

Immunization with formalinized vaccines (of extracellular antigens, intact

melanoma cells, or B700 antigen) or irradiated vaccines (of intact melanoma

cells) partially inhibit primary melanoma tumor growth, reduce metastasis

to regional lymph nodes and lungs, and significantly increase mean survival

time. These anti-tumor effects were improved when polyvalent and monovalent

vaccines were combined with IL-2 therapy. We also compared the immunogenic

activity of vaccines made from B16 melanoma cells transfected with genes

encoding murine IL-2 or GM-CSF, and effects on tumor bearing mice were

compared with or without therapy using the corresponding lymphokines. In

sum, comparison of antibody production, growth of primary melanoma tumors,

number of surviving mice, mean survival time, and percent of mice with lung

metastases, showed that the best course of immunotherapy involves

vaccination of mice with irradiated B16 melanoma cells transfected to

secrete GM-CSF, coupled with GM-CSF therapy. 

=====================================================================

24.) Dinitrophenyl-modified autologous melanoma vaccine induces a T cell

response to hapten-modified, melanoma peptides. 

=====================================================================

Author 

Sato T; Bullock TN; Eisenlohr LC; Mastrangelo MJ; Berd D 

Address 

Department of Medicine, Thomas Jefferson University, Philadelphia,

Pennsylvania 19107-5099, USA. 

Source 

Clin Immunol Immunopathol, 85(3):265-72 1997 Dec 

Abstract 

Active specific immunotherapy with dinitrophenyl (DNP)-modified autologous

melanoma vaccine elicits inflammatory responses in metastatic tumor sites.

Postsurgical adjuvant immunotherapy with this vaccine prolongs survival in

stage III melanoma patients. We have reported that, after administration of

DNP-modified melanoma vaccine, T cell responses to DNP-modified autologous

tumor cells are demonstrable in vivo and in vitro. These responses are

hapten specific and MHC restricted. To elucidate this phenomenon, we

investigated the immune response to DNP-modified peptides eluted from

autologous cells. Short peptides were extracted from DNP-modified and

unmodified autologous melanoma cells by an acid elution technique and HPLC

fractionation. Peptides were also extracted from DNP-modified and

unmodified, EB virus-transformed, autologous B lymphoblasts. These various

peptide fractions were loaded onto autologous B lymphoblasts and tested for

ability to elicit a response by a DNP-specific T cell line as measured by

IFN-gamma production. Unexpectedly, stimulatory activity of peptides from

DNP-modified melanoma cells was confined to a single HPLC fraction.

Spectrometric analysis of this fraction confirmed modification of peptides

with DNP. A weaker T cell response was observed to a single HPLC fraction

of DNP-modified peptides from the patient's B lymphoblasts. No T cell

response was elicited by corresponding fractions of peptides eluted from

unmodified melanoma cells or B lymphoblasts. These findings demonstrate the

human T cell response to DNP-modified autologous melanoma cells is mediated

by hapten-modified, MHC-associated peptides. Further investigation of these

peptides could lead to a new strategy for peptide-based cancer 

=====================================================================

25.) Stimulation of CD8+ T cell responses to MAGE-3 and Melan A/MART-1 by

immunization to a polyvalent melanoma vaccine. 

=====================================================================

Author 

Reynolds SR; Oratz R; Shapiro RL; Hao P; Yun Z; Fotino M; Vukmanovi´c S;

Bystryn JC 

Address 

Ronald O. Perelman Department of Dermatology, New York University Medical

Center, New York 10016, USA. 

Source 

Int J Cancer, 72(6):972-6 1997 Sep 17 

Abstract 

A critical requirement for cancer vaccines is that they stimulate CD8+ T

cell responses. In this study, we tested the ability of a polyvalent

melanoma vaccine to induce CD8+ T cell responses to the melanoma associated

antigens MAGE-3 and Melan A/MART-1. Fifteen HLA-A2+ patients with resected

malignant melanoma were immunized with the vaccine s.c. every 2-3 weeks.

CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on

MAGE-3 (FLWGPRALV) and Melan A/MART-1/(AAGIGILTV) were quantitated using a

filter spot assay at baseline and following 4 immunizations. Vaccine

immunization induced CD8+ T cells reacting to one or both of these peptides

in 9 of the 15 (60%) patients. These cells were CD8+ and HLA-A2 restricted,

as reactivity was abrogated by monoclonal antibodies (MAbs) to CD8 and

class I HLA, but not by anti-CD4. All responding patients remained

recurrence-free for at least 12 months (median 15 months, range 12 to >21

months), whereas melanoma recurred within 3-5 months in non-responders. The

differences in outcome were unrelated to differences in disease severity or

overall immunological competence between responders and non-responders. Our

results demonstrate directly that MAGE-3 and Melan A/MART-1 can stimulate

CD8+ T cell responses in humans, and suggest that these responses are

protective and surrogate markers of vaccine efficacy. 

=====================================================================

26.) Double-copy bicistronic retroviral vector platform for gene therapy

and tissue engineering: application to melanoma vaccine development. 

=====================================================================

Author 

Wiznerowicz M; Fong AZ; Mackiewicz A; Hawley RG 

Address 

Department of Cancer Immunology, Great Poland Cancer Center, Poznan, Poland. 

Source 

Gene Ther, 4(10):1061-8 1997 Oct 

Abstract 

The efficient genetic modification of solid tumors in situ to stimulate

therapeutic immune responses against them is currently under active

investigation, but is not yet possible using existing gene transfer

technologies. Thus, ex vivo/in vivo vaccination strategies have been

proposed in which the patient's tumor is surgically excised, single cell

suspensions are prepared, the therapeutic genes are introduced and then the

gene-modified cells, after being gamma-irradiated, are injected back into

the patient. However, even with high-efficiency gene delivery systems, this

is a labor-intensive process. Moreover, it is often difficult to obtain

sufficient numbers of gene-modified primary tumor cells during short-term

culturing. On the other hand, extended in vitro passaging of primary tumor

explants may alter their immunophenotypic properties. One approach to

overcome these limitations would be to design universal vaccines consisting

of standardized gene-transduced neoplastic cell lines or mixtures of

gene-transduced cell lines to be combined with autologous tumor samples if

available. Melanoma, which is notable for being one of the most immunogenic

human malignancies, represents a cancer where shared tumor-associated

antigens have been identified. We developed and analyzed several different

retroviral vectors for their ability to stably express exogenous genes at

high levels in a panel of melanoma cell lines. All vectors contained a

reporter gene (nlslacZ) encoding beta-galactosidase with a nuclear

localization signal and the neomycin phosphotransferase (neo) gene as

selectable marker. One vector, DCCMV, which carried a bicistronic

nlslacZ-neo transcriptional unit under the control of the human

cytomegalovirus immediate-early promoter in the U3 region of its 3' LTR,

was found to perform consistently better than the other vectors. The DCCMV

vector, which is an extreme example of the double-copy class of retroviral

vectors, was subsequently used to generate melanoma cell lines

constitutively secreting human interleukin-6 or a soluble form of the human

interleukin-6 receptor for potential use in a phase II clinical vaccine

trial for the treatment of melanoma patients. The DCCMV vector design may

also be useful in gene therapy applications where the intent is to implant

polymer-encapsulated cell lines genetically engineered to stably express

high levels of bioactive proteins. 

=====================================================================

27.) Favorable clinical responses in subsets of patients from a randomized,

multi-institutional melanoma vaccine trial. 

=====================================================================

Author 

Wallack MK; Sivanandham M; Whooley B; Ditaranto K; Bartolucci AA 

Address 

St. Vincent's Hospital, Department of Surgery, New York, NY, USA. 

Source 

Ann Surg Oncol, 3(2):110-7 1996 Mar 

Abstract 

BACKGROUND: A phase III, randomized, double-blind, multi-institutional

trial was performed evaluating active specific immunotherapy using vaccinia

melanoma oncolysate (VMO) in the surgical adjuvant setting in patients with

stage II melanoma (UICC staging). The first interim analysis showed no

significant difference in disease-free and overall survival. The data were

further analyzed to identify subsets of patients with improved outcome when

treated with VMO. METHODS: Patients received either VMO or placebo of live

vaccinia vaccine virus (V), once a week for 13 weeks and then once every 2

weeks for an additional 39 weeks or until recurrence. Having stratified

patients according to sex, age, number of positive nodes, tumor thickness,

and clinical stage, data were analyzed for disease-free survival and

overall survival. RESULTS: Male patients showed a 17% difference in overall

survival at 4 years when treated with VMO (p = 0.19). A subset of male

patients < 57 years of age with one to five positive nodes showed a 30%

difference at 4 years with VMO (p = 0.06). Patients with clinical stage I

but pathological stage II disease (both male and female), who had undergone

prophylactic node dissection, showed a 23% difference in survival at 3

years with VMO (p = 0.11). CONCLUSIONS: This subset analysis shows

encouraging survival benefit in certain subsets of patients and an

increasing trend in overall survival. Further follow-up of this phase III

trial from a second interim analysis will be forthcoming. 

=====================================================================

28.) Increased survival of patients treated with a vaccinia melanoma

oncolysate vaccine: second interim analysis of data from a phase III,

multi-institutional trial. 

=====================================================================

Author 

Wallack MK; Sivanandham M; Ditaranto K; Shaw P; Balch CM; Urist MM; Bland

KI; Murray D; Robinson WA; Flaherty L; Richards JM; Rosen L; Bartolucci AA 

Address 

St. Vincent's Hospital and Medical Center/New York Medical College, New

York 10011, USA. 

Source 

Ann Surg, 226(2):198-206 1997 Aug 

Abstract 

OBJECTIVE: The efficacy of vaccinia melanoma oncolysate (VMO) vaccine to

increase overall survival and disease-free survival of patients with

surgically resected International Union Against Cancer (UICC) stage II

melanoma was studied in a phase III, randomized, multi-institutional trial.

SUMMARY BACKGROUND DATA: Phase I and II trials with VMO showed minimal

toxicity and clinical efficacy in patients with melanoma. In a recently

completed phase III VMO trial, the first interim analysis performed in

April 1994 showed an increasing trend in the survival of patients treated

with VMO. The second interim analysis was performed in April 1995. METHODS:

Patients with surgically resected stage II (UICC) melanoma were treated

with VMO (N = 104) or placebo vaccinia vaccine virus (V) (N = 113) once a

week for 13 weeks and then once every 2 weeks for a total of 12 months.

Patients' clinical data were collected as of May 1995 and analyzed for

survival. RESULTS: In this second interim analysis, the mean follow-up time

is 42.28 months. No survival difference was observed between VMO and V

treatments. However, in a retrospective subset analysis, a subset of males

between the ages of 44 and 57 years and having one to five positive nodes

(at 2-, 3-, and 5-year intervals, 13.6%, 15.9%, and 20.3% difference

insurvival in favor of VMO [N = 20] when compared to V [N = 18] [p =

0.037]) and another subset of patients with clinical stage I (at 3- and

5-year intervals, 30% and 7% difference in survival in favor of VMO [N =

20] when compared to V [N = 23], [p = 0.05]) showed significant survival

advantage with VMO. CONCLUSIONS: Although VMO vaccine therapy in surgical

adjuvant setting did not produce a significant survival benefit to all

patients with melanoma, patients from the above two subsets had significant

survival benefit. 

=====================================================================

29.) Active specific immunotherapy with hapten-modified autologous melanoma

cell vaccine. 

=====================================================================

Author 

Sato T 

Address 

Department of Medicine, Jefferson Medical College, Thomas Jefferson

University, Philadelphia, PA 19107-5099, USA. t_sato@lac.jci.tju.edu 

Source 

Cancer Immunol Immunother, 43(3):174-9 1996 Nov 

Abstract 

We have developed a novel approach to cancer immunotherapy-an autologous

whole-cell vaccine modified with the hapten dinitrophenyl (DNP). This

approach elicits significant inflammatory responses in metastatic sites and

some objective tumor responses. Post-surgical adjuvant immunotherapy with

DNP-modified melanoma vaccine in a setting of micrometastatic disease

produces significant survival prolongation in stage III melanoma patients.

Histologically, the inflammatory responses of the tumor consist of

infiltration by lymphocytes, the majority of which are CD8+, HLA-DR+ T

cells. T cells from these lesions tend to have mRNA for interferon gamma. T

cell receptor analysis suggests that the tumor-infiltrating T cells are

clonally expanded. DNP-modified vaccine also induces T cells in the

peripheral blood, which respond to DNP-modified autologous cells in a

hapten-specific, MHC-restricted manner. Moreover, a T cell line generated

from these lymphocytes responded to only a single HPLC fraction of

MHC-associated, DNP-modified tumor peptides. Since inflammatory responses

in metastases were not consistently associated with dramatic tumor

regression, we considered the possibility of immunosuppression at the tumor

site. We found that mRNA for the anti-inflammatory cytokine, interleukin-10

(IL-10) is expressed in most metastatic melanoma tissues and subsequently

demonstrated that IL-10 protein is produced by melanoma cells. Thus the

efficacy of DNP vaccine could be further enhanced by inhibition of IL-10

production or binding. Finally, we expect these results obtained with

melanoma to be applicable to other human cancers. 

=====================================================================

30.) IgM anti-ganglioside antibodies induced by melanoma cell vaccine

correlate with survival of melanoma patients. 

=====================================================================

Author 

Takahashi T; Johnson TD; Nishinaka Y; Morton DL; Irie RF 

Address 

Department of Biotechnology Sciences, John Wayne Cancer Institute, Santa

Monica, California 90404, USA. 

Source 

J Invest Dermatol, 112(2):205-9 1999 Feb 

Abstract 

Melanoma cells express ganglioside antigens GM3, GD3, GM2, and GD2 on their

surface. This study examined whether immunization with a melanoma cell

vaccine induced anti-ganglioside antibody responses in melanoma patients

and whether these responses were correlated with survival. Sixty-six

patients who had received melanoma cell vaccine immunotherapy after

surgical removal of regional metastatic melanoma were identified.

Cryopreserved serum samples from these patients were used in an

enzyme-linked immunsorbent assay to determine the IgM antibody levels to

GM2, GD2, GM3, and GD3 prior to melanoma cell vaccine treatment and 4 wk

after the first melanoma cell vaccine immunization. All antibody levels

significantly increased by week 4 (p < 0.001 for all four antibodies) and

all increases were significantly associated with survival (anti-GD2, p <

0.001; anti-GM2, p = 0.001; anti-GD3, p < 0.001; anti-GM3, p < 0.001).

Anti-tumor activity of these antibodies was proved using five

representative antibody-positive sera in a complement-dependent

cytotoxicity assay with cultured melanoma cell lines. These studies suggest

that GM2, GD2, GM2, and GD3 expressed by melanoma cells can induce specific

IgM antibodies and that high levels of these antibodies might have a

beneficial impact on survival. 

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31.) Cancer vaccines.

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AU: Durrant-LG

AD: CRC Department of Clinical Oncology, University of Nottingham, City

Hospital, UK.

SO: Anticancer-Drugs. 1997 Sep; 8(8): 727-33

ISSN: 0959-4973

PY: 1997

LA: ENGLISH

CP: ENGLAND

AB: A better understanding of immune recognition of cells has led to

identification of potential new targets on tumor cells. Noticeable

successes in melanoma have been immunization with the GM2 ganglioside

vaccine, and the identification of novel antigens such as MAGE, BAGE and

GAGE recognized by T cells cloned from cancer patients with regressing

disease. However, the unexpected finding that other antigens recognized by

these T cells were overexpressed normal differentiation antigens such as

tyrosinase. Pmel 17 and Melan A have led to vaccines developed against

differentiation antigens expressed in other solid tumors. Monoclonal

antibody, anti-idiotype and antigen based vaccines for colorectal target

antigens 17-1A, CEA and 791Tgp72 are all in clinical development. Similarly

HER2/neu and mucin overexpression in breast cancer represent promising

targets. Mutations in tumor oncogenes or suppressor genes which lead to

malignant transformation can also present tumor-specific antigens. The most

effective vaccines against infectious disease are live viruses. The

development of DNA vaccines which act like viruses in entering cells and

show continuous production of antigens offers great potential for the future.

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32.) Active specific immunotherapy of metastatic melanoma with an

antiidiotype vaccine: a phase I/II trial of I-Mel-2 plus SAF-m. 

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Author 

Quan WD Jr; Dean GE; Spears L; Spears CP; Groshen S; Merritt JA; Mitchell MS 

Address 

Center for Biological Therapy and Melanoma Research, University of

California, San Diego, La Jolla 92093-0061, USA. 

Source 

J Clin Oncol, 15(5):2103-10 1997 May 

Abstract 

PURPOSE: To determine the toxicity and immunologic activity of an

antiidiotype melanoma vaccine that consists of monoclonal antibody I-Mel-2

(MELIMMUNE-2, IDEC Pharmaceuticals, La Jolla, CA) and an immunologic

adjuvant SAF-m. PATIENTS AND METHODS: Twenty-six patients with metastatic

melanoma, 17 of whom had previously received chemotherapy, were given 2 mg

of I-Mel-2 and either 100 micrograms (n = 6) or 250 micrograms (n = 20) of

SAF-m. Antiidiotype vaccine was given intramuscularly (IM) biweekly for 4

weeks, and then bimonthly until disease progression. Human antimurine

antibodies (HAMA), anti-I-Mel-2 antibodies, and specific antibody (Ab)3

against the melanoma epitope mimicked by the vaccine were titrated before

treatment, biweekly from weeks 4 to 12, and every 4 to 8 weeks thereafter.

Computed tomographic (CT) scans of the chest, abdomen, and pelvis and

magnetic resonance imaging (MRI) of the brain were obtained before and

bimonthly during treatment to evaluate responses. RESULTS: Elevated titers

of human antimouse antibodies and anti-I-Mel-2 antibodies were associated

with clinical antitumor effect (P = .02 and P = .05, respectively). Ab3 was

absent in most patients, but was found in the best clinical responder.

Fever, myalgias/arthralgias, fatigue, nausea, and headaches were the most

common toxicities. Grade III myalgias/arthralgias and headaches required

dose reduction of SAF-m in eight patients at the 250-microgram dose. No

treatment-related death occurred. Six patients had an antitumor effect: one

complete response in liver and lung, two minor responses, and three stable

disease. The patient with a complete response has survived nearly 5 years.

CONCLUSION: I-Mel-2 antiidiotype vaccine was safe, tolerated best at the

100-microgram dose of SAF-m, and had immunologic and clinical activity. 

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33.) Allogeneic murine melanoma cell vaccine: a model for the development

of human allogeneic cancer vaccine. 

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Author 

Knight BC; Souberbielle BE; Rizzardi GP; Ball SE; Dalgleish AG 

Address 

Division of Oncology, St George's Hospital Medical School, Tooting, London,

UK. 

Source 

Melanoma Res, 6(4):299-306 1996 Aug 

Abstract 

In an attempt to induce an immune response against tumour antigens, several

groups are transfecting cytokine and other genes into autologous tumour

cells which are given to the patient as a vaccine. This process is

labour-intensive, time-consuming and expensive. Allogeneic cells would

offer a more convenient vehicle for the delivery of cytokines and other

molecules. However, current dogma suggests that MHC-matched cells are a

prerequisite for an effective immune response. Using murine melanoma models

we compared allogeneic and autologous vaccination and showed that the

survival of C56BL/6 mice (H-2b) was prolonged with some degree of

protection achieved against an autologous B15-F10 (H-2b) cell challenge

when the mice were vaccinated with allogeneic K1735-M2 (H-2k) cells but not

when immunized with autologous B16-F10 cells. Both vaccination with live

and irradiated allogeneic cells induced an anti-tumour effect using only

one immunization and no boost or adjuvant. Protection was not observed

after vaccination with another melanoma (S91; H-2d) or with a carcinoma

(A9HT; H-2k). Allogeneic vaccination promoted a cytotoxic cellular response

against both the allogeneic and the syngeneic melanomas. This allogeneic

vaccination model will be useful for studying the underlying mechanisms of

protection, in both pre- and post-challenge settings, as well as for

developing whole cell vaccination systems using genetically modified

allogeneic tumour cells. 

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34.) Immune response to polyvalent melanoma cell vaccine in AJCC stage III

melanoma: an immunologic survival model. 

=====================================================================

Author 

Jones RC; Kelley M; Gupta RK; Nizze JA; Yee R; Leopoldo Z; Qi K; Stern S;

Morton DL 

Address 

Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint

John's Hospital and Health Center, Santa Monica, California, USA. 

Source 

Ann Surg Oncol, 3(5):437-45 1996 Sep 

Abstract 

BACKGROUND: 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.

METHODS: 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 (delta DTH). RESULTS: 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), delta DTH (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 delta DTH and mean anti-90-kDa

MAA IgG and IgM titers closely approximated the observed individual and

overall survival rates. CONCLUSIONS: 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. 

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35.) Immunization with a tumor-cell-lysate-loaded

autologous-antigen-presenting-cell-based vaccine in melanoma. 

=====================================================================

Author 

Chakraborty NG; Sporn JR; Tortora AF; Kurtzman SH; Yamase H; Ergin MT;

Mukherji B 

Address 

Department of Medicine, University of Connecticut School of Medicine,

Farmington 06030, USA. 

Source 

Cancer Immunol Immunother, 47(1):58-64 1998 Sep 

Abstract 

The discoveries of human melanoma-associated antigens in molecular terms

have renewed interest in peptide- or peptide- and antigen-presenting-cell

(APC)-based cancer vaccines. Considering the limited scope of immunization

using defined peptides, we have studied an alternative approach of specific

immunization with tumor-lysate-loaded autologous APC (adherent peripheral

mononuclear cells cultured in 1000 U

granulocyte/macrophage-colony-stimulating factor for 14 days) as a

surrogate vaccine. Seventeen patients (11 with active metastatic disease)

were intradermally immunized with the vaccine in a phased dose escalation

(10(5)-10(7) cells/injection) monthly for 4 months. Thirteen patients

completed all four immunizations showing no toxicity (3 patients had to be

taken off study because of progressive disease and 1 patient went off study

as a result of myocardial infarction due to multi-vessel coronary artery

disease). None has shown any immediate or delayed toxicity attributable to

the immunization and none has shown any evidence of autoimmunity. One

patient showed a partial regression of a subcutaneous nodule. Thirteen

patients are alive after 4+ months to 30+ months (17-month median survival

for the group). Nine patients showed evidence of delayed-type

hypersensitivity at the vaccine sites. Monitoring of biological response in

conventional natural killer or cytolytic T lymphocyte assays with pre- and

post-immune peripheral blood lymphocytes revealed no consistent

differences. The vaccine-infiltrating lymphocytes (VIL) from nine specimens

were adequately expanded following in vitro stimulation with the respective

autologous-lysate-loaded APC for phenotypic and functional analyses. Five

of the nine ex vivo expanded VIL were predominantly CD8+. Evidence of an

antigen-specific CD8+ T cell response (cytotoxicity and/or tumor necrosis

factor production) was detected in three of the five CD8+ VIL. These

observations suggest that this type of vaccine is feasible, that it has

biological activity, and that the approach may be improved through

additional strategic manipulations. 

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36.) Augmentation of IgM antibody to gp43 tumor-associated antigen peptide

by melanoma cell vaccine. 

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Author 

Takahashi T; Conforti A; Kikumoto Y; Hoon DS; Morton DL; Irie RF 

Address 

Department of Biotechnology Sciences, John Wayne Cancer Institute, Santa

Monica, California. 

Source 

J Clin Immunol, 18(4):299-305 1998 Jul 

Abstract 

We previously reported that gp43 tumor-associated antigen peptide

(DLTMKYQIF; designated 810 antigen) on human melanoma cells is recognized

by IgM human monoclonal antibody L92 and by cytotoxic T lymphocytes (CTL).

In this study, we retrospectively tested sera of 44 patients with regional

metastatic melanoma (22 who recurred within 1 year and 22 who survived

longer than 5 years) to determine if antibody responses to 810 antigen

could be induced by immunization with an allogeneic melanoma cell vaccine

that contained 810 peptide. IgM and IgG antibodies were assessed by

enzyme-linked immunosorbent assay using a synthetic 810 nonamer peptide. A

significant augmentation of IgM antibody was demonstrated 4 weeks after

initiation of vaccine therapy, and the IgM level was significantly higher

in patients who survived more than 5 years. The antigen epitope recognized

by antibodies was located within TMKYQI. Of this epitope sequence, K

appears to play a central role in antigenicity. The 810 antigen recognized

by antibody and CTL may have clinical relevance as a potential source of

melanoma vaccine. 

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DATA-MÉDICOS/DERMAGIC-EXPRESS No (60) 09/06/99 DR. JOSE LAPENTA R. 

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Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

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