Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chung, M. H.
Right arrow Articles by Morton, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chung, M. H.
Right arrow Articles by Morton, D. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
Journal of Clinical Oncology, Vol 21, Issue 2 (January), 2003: 313-319
© 2003 American Society for Clinical Oncology

Humoral Immune Response to a Therapeutic Polyvalent Cancer Vaccine After Complete Resection of Thick Primary Melanoma and Sentinel Lymphadenectomy

Mathew H. Chung, Rishab K. Gupta, Eddy Hsueh, Richard Essner, Wei Ye, Reynold Yee, Donald L. Morton

From the 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.

Address reprint requests to Donald L. Morton, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; email: mortond{at}jwci.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: A therapeutic polyvalent cancer vaccine (Canvaxin vaccine; CancerVax Corp, Carlsbad, CA) induces antibodies to a glycoprotein tumor-associated antigen (TA90). However, endogenous immune responses to TA90 have also been reported. This study examined anti-TA90 antibody responses with respect to the survival of patients who received adjuvant vaccine immunotherapy after resection of thick (>= 4 mm) primary cutaneous melanoma.

Patients and Methods: Serum specimens were obtained from 54 patients immediately before and then 1, 2, 4, and 6 months after wide local excision of thick primary cutaneous melanoma and sentinel lymphadenectomy. All patients were offered adjuvant therapies with the vaccine, high-dose interferon, or other agents. An enzyme-linked immunosorbent assay was used to determine serial serum titers of immunoglobulin G (IgG) and IgM antibodies against TA90. These titers were correlated with clinical course.

Results: Forty-three patients chose vaccine therapy, and 11 patients chose postoperative observation. Preoperative anti-TA90 IgG and IgM titers were similar for vaccine and observation groups (P = .184). At a median follow-up of 26 months, univariate analysis of Cox regression showed that disease-free survival and overall survival of vaccine patients were significantly correlated with maximal IgM response (P = .0006 and .006, respectively) but not with maximal IgG response (P = .73 and .95, respectively). Neither response predicted survival in the observation group.

Conclusion: Postoperative vaccine therapy may enhance IgG and IgM immune responses to TA90 after surgical resection, but only the IgM response is correlated with improved survival. These findings may become useful to guide selection of patients for postoperative adjuvant therapy of high-risk melanoma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ALTHOUGH ADJUVANT therapy is often used after complete surgical resection of regional or distant metastatic melanoma, its administration after resection of high-risk primary melanoma is far from standard. Toxicity and questionable efficacy render many of the currently available chemotherapeutic and biochemotherapeutic regimens even less desirable in patients who have no clinical evidence of metastasis.1,2 Still, the generally high rates of recurrence for patients with thick primary cutaneous melanomas indicate the need for postoperative adjuvant therapy, particularly when the sentinel lymph node shows histologic evidence of regional metastasis.3–7

Active specific immunotherapy against melanoma has great appeal not only because melanoma is responsive to immune modulation, but also because cancer vaccines lack the toxicity of more conventional chemotherapeutic or biotherapeutic regimens.8–13 The vaccine developed at the John Wayne Cancer Institute (Canvaxin therapeutic polyvalent cancer vaccine; CancerVax Corp, Carlsbad, CA) is composed of three viable irradiated allogeneic melanoma cell lines that express high levels of immunogenic melanoma-associated and tumor-associated antigens (Table 1Go).10,12,14–38 We have demonstrated objective clinical responses and prolonged survival of patients receiving the vaccine during treatment of regional or distant metastases.9–11 The survival benefit is highest among patients who have undergone complete resection of metastatic disease before vaccine therapy. Tafra et al39 showed that resection of pulmonary metastases and postoperative adjuvant immunotherapy with the vaccine were independent predictors of survival by multivariate analysis (P < .0001). Recent matched-pair analyses based on prognostic factors have confirmed the prolonged survival associated with postoperative vaccine immunotherapy for patients with stage III and stage IV melanoma.40,41


View this table:
[in this window]
[in a new window]
  		Table 1. Immunogenic Antigens Present in Canvaxin Therapeutic Polyvalent Cancer Vaccine
 
Because this cancer vaccine has no direct cytotoxic effect on tumor cells, its therapeutic efficacy may depend on the ability of its tumor-associated and melanoma-associated antigens to induce immune responses against cross-reactive antigens on the patient’s residual melanoma cells after surgical resection.42 TA90, a 90-kDa glycoprotein tumor-associated antigen, is one such cross-reactive antigen that has been extensively studied.10,12 Immunization with the vaccine can elevate immunoglobulin G (IgG) and IgM antibody titers to TA90.10,12,14 However, an endogenous immune response to TA90 has also been demonstrated in patients who did not receive the vaccine.43 In that study of 64 patients undergoing complete resection of metastatic melanoma, elevated postoperative anti-TA90 IgM titers were significantly associated with improved overall survival (P = .0001).

This study was undertaken to determine whether adjuvant administration of Canvaxin therapeutic polyvalent cancer vaccine could increase the humoral immune response to TA90, and whether such an enhanced immune response would be correlated with improved survival after resection of thick (>= 4 mm) primary cutaneous melanoma and surgical management of regional nodes guided by the results of sentinel lymphadenectomy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
The patient population consisted of individuals who underwent treatment for primary cutaneous melanomas >= 4 mm thick at the John Wayne Cancer Institute between 1985 and 1999. Excluded were patients in whom complete physical examination and chest radiography revealed metastatic disease and patients who were lost to follow-up. All study patients underwent wide local excision of the primary tumor with at least a 2-cm margin. During the same procedure, lymphatic mapping and sentinel lymphadenectomy (LM-SL) was performed as previously described.44,45 Patients entering the study before 1992 underwent complete lymphadenectomy immediately after LM-SL, regardless of the tumor status of the sentinel node (SN), because LM-SL was still in its developmental stages. Patients entering the study after that time underwent complete lymphadenectomy only if the SN contained tumor.

Because the study population represented a high-risk melanoma group, all patients were offered adjuvant therapy with Canvaxin therapeutic polyvalent cancer vaccine, high-dose interferon alfa, or other agents. All protocols for vaccine adjuvant therapy were in accordance with the ethical standards of the joint Saint John’s Health Center and John Wayne Cancer Institute institutional review board, in compliance with the Helsinki Declaration, and instituted only after the patient’s informed consent. The decision to receive adjuvant therapy and the selection of the type of adjuvant therapy rested with each patient.

Each patient’s clinical status was recorded prospectively until the time of recurrence, death, or the end of the study period on October 30, 1999. Institutional review board approval was obtained for collection of serum samples before surgical resection and at 1, 2, 4, and 6 months after resection. These serum samples were processed, coded, and stored at -35°C until the time of analysis, at which point they were thawed and tested in a blinded fashion. The coded sample results were given to the statisticians for analysis and correlation with survival.

Vaccine Preparation and Administration
The preparation and administration of the vaccine have been described previously.8,12 Briefly, melanoma cells from the M10-V, M24-V, and M101-V cell lines were cultured in tissue medium, then harvested, washed, and pooled to obtain 24 x 106 total cells (8 x 106 cells per line). The cells were then irradiated with 150 Gy and cryopreserved in liquid nitrogen until they were thawed in preparation for administration. Each injection consisted of 24 x 106 cells. The vaccine was given intradermally every 2 weeks for four cycles, then monthly for the remainder of the first year. Subsequently, the vaccine was administered every 3 months for three cycles and thereafter at 6-month intervals. During the first two treatments, vaccine was administered in conjunction with the Tice strain of bacille Calmette-Guerin at a dose of 3 to 8 x 106 total organisms per treatment.

Anti-TA90 IgG and IgM Assay
Humoral immune responses to TA90 were measured by an enzyme-linked immunosorbent assay (ELISA).12 Purified TA90 was used as a target in the ELISA assay, as described previously.46 Briefly, TA90 was adsorbed to polystyrene wells of ELISA plates at 15 ng/well. Serum samples at dilutions of 1:100, 1:200, 1:400, 1:800, and 1:1,600 were added to the wells (100 µL of each dilution). Subsequently, the bound immunoglobulins were reacted with an alkaline phosphatase-conjugated antigen-binding fragment (Fab) of goat antihuman IgG at a 1:500 dilution or goat antihuman IgM at a 1:1,000 dilution (Sigma Chemical Co, St Louis, MO). The unreacted conjugate was washed off and p-nitrophenyl phosphate (1 mg/mL) in 10% diethanolamine buffer was added. Then, absorbance at 405 nm was assessed using the microtiter plate reader (Titertek Multiscan; Dynatech, Alexandria, VA). Controls on each ELISA plate consisted of nonspecific binding of goat antihuman IgG or IgM to TA90, as well as nonspecific binding of a patient’s immunoglobulins and the goat antihuman IgG or IgM to the polystyrene plate. The antibody titer was defined as the reciprocal of the highest dilution that resulted in an absorbance of 0.05 optical density at 405 nm after the absorbance value of the control was subtracted.

Statistical Analysis
Disease-free survival (DFS) was the period between surgical resection and recurrence; overall survival (OS) was the period between surgical resection and death or last follow-up. Survival curves were estimated by the Kaplan-Meier method, and the log-rank test was used for univariate analysis of categorical variables to determine differences between curves. Both univariate and multivariate analyses were performed using the Cox proportional hazards regression method to analyze the survival impact of potential prognostic factors such as age, sex, primary tumor location, ulceration, SN status, and humoral immune responses to TA90. On the basis of our previous studies, important cutoff points for anti-TA90 IgG and IgM titers were defined as 1:400 and 1:800, respectively.10,12 The difference in the baseline (preoperative) and maximal anti-TA90 IgG and IgM titers between treatment groups was determined with the Wilcoxon signed rank sum test. A P value less than .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient characteristics are listed in Table 2Go. Of the 54 total patients, 43 patients chose adjuvant treatment with the therapeutic polyvalent cancer vaccine, and 11 patients chose close observation instead of adjuvant therapy. The median age of the patients was 51.1 years (range, 19 to 82 years), and the median Breslow thickness of the primary tumors was 5.5 mm (range, 4 to 15 mm). Complete resection of macroscopic tumor was confirmed in all cases by clinical examination and by computed tomography of the chest, abdomen, pelvis, brain, and/or positron emission tomography. SN metastasis had been identified in 22 of the patients (51%) who chose adjuvant therapy with vaccine and in two of the patients (18%) who chose observation instead of adjuvant therapy. All nodal metastases were microscopic.


View this table:
[in this window]
[in a new window]
  		Table 2. Clinicopathologic Characteristics of the Study Population
 
During follow-up, melanoma recurred in 10 (23%) of the 43 vaccine patients and seven (64%) of the 11 observation patients. Seven patients underwent complete resection of recurrent disease and were offered postoperative adjuvant therapy as described in Methods. These patients invariably chose vaccine therapy or observation; no patient elected adjuvant therapy with interferon. When vaccine therapy was restarted, the first dose of the vaccine was administered with a booster dose of bacille Calmette-Guerin. Four patients with recurrent disease had bulky hepatic metastases or other surgically inaccessible disease; these patients chose first-line treatment with biochemotherapy.47 The remaining six patients had unresectable brain metastases that required either whole-brain or gamma-knife irradiation.

The median baseline anti-TA90 IgM titer was 1:100 (range, 1:100 to 1:800) for the entire cohort. As expected, baseline anti-TA90 IgM titers were similarly low in the vaccine and observation groups; 40 (93%) of 43 vaccine patients and nine (82%) of 11 observation patients had baseline IgM titers less than 1:800 (P = .7214). The range of increase for anti-TA90 IgM titers was 0 to 1:3,000 in the 54 patients. Anti-TA90 IgM antibody titers increased at least two-fold in 25 patients (46%) and at least four-fold in 19 patients (35%). Most of these elevations occurred in patients receiving vaccine; 25 vaccine patients (58%) but no observation patients had at least a four-fold increase in anti-TA90 titers. Furthermore, maximal anti-TA90 IgM titers were significantly greater in the vaccine group than in the observation group (P = .0022).

The anti-TA90 IgG response followed a similar pattern. The median baseline anti-TA90 IgG titer was 1:200 (range, 1:100 to 1:2,400) for the entire cohort and was not significantly different between the two groups (P = .1843). Five (45%) of the 11 observation patients and 26 (60%) of the 43 vaccine patients had baseline IgG titers less than 1:400. The range of increase for anti-TA90 IgG titers was 0 to 1:2,400. Again, most of these increases occurred in the vaccine group; 20 vaccine patients (47%) but no observation patients had a four-fold increase in titer. However, maximal anti-TA90 IgG titers were not significantly different between the two groups (P = .1035).

A maximal anti-TA90 IgM titer >= 1:800 was associated with improved DFS (Fig 1Go) and OS (Fig 2Go) by log-rank test. Estimated 5-year OS was 78% for patients who had a maximal anti-TA90 IgM titer >= 1:800 versus 44% for patients who had a maximal anti-TA90 IgM titer less than 1:800 (P = .0008). Similarly, estimated 5-year DFS was 68% for patients who had a maximal anti-TA90 IgM titer >= 1:800 versus only 30% in patients who had maximal titer less than 1:800 (P = .001).



View larger version (14K):
[in this window]
[in a new window]
  		Fig 1. Comparison of disease-free survival between patients with anti-TA90 immunoglobulin M < 800 versus >= 800.

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig 2. Comparison of overall survival between patients with anti-TA90 immunoglobulin M < 800 versus >= 800.

 
Neither a baseline anti-TA90 IgG titer less than 1:400 nor a maximal anti-TA90 IgG titer >= 1:400 correlated with improved DFS (Fig 3Go) or OS (Fig 4Go). Estimated 5-year DFS was similar when anti-TA90 IgG titer was less than 400 and >= 1:400 (40% and 50%, respectively; P = .678). Although estimated 5-year OS was higher when anti-TA90 IgG was less than 400 versus >= 1:400, the difference was not significant (75% and 58%, respectively; P = .982).



View larger version (13K):
[in this window]
[in a new window]
  		Fig 3. Comparison of disease-free survival between patients with anti-TA90 immunoglobulin G < 400 versus >= 400.

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig 4. Comparison of overall survival between patients with anti-TA90 immunoglobulin G < 400 versus >= 400.

 
Tables 3Go and 4Go examine the prognostic significance of conventional and immunologic factors in the entire study population. None of the conventional prognostic factors was significant for DFS on univariate or multivariate analysis. The tumor status of the SN was significant for OS on univariate analysis (P = .023). With respect to anti-TA90 immunoglobulin responses, only a maximal anti-TA90 IgM >= 1:800 was significant for DFS and OS (P = .001 and P = .003, respectively).


View this table:
[in this window]
[in a new window]
  		Table 3. Prognostic Factors for DFS Using Cox Regression (54 patients)
 

View this table:
[in this window]
[in a new window]
  		Table 4. Prognostic Factors for OS Using Cox Regression (54 patients)
 
Table 5Go compares the prognostic significance of conventional and immunologic factors in the vaccine and observation groups. The tumor status of the SN correlated with OS in the vaccine group (P = .026) but not in the observation group. DFS was not affected by the tumor status of the SN. In the vaccine group but not in the observation group, there was a significant correlation between survival and anti-TA90 titers; patients with a preoperative anti-TA90 IgG titer less than 1:400 and/or a maximal anti-TA90 IgM titer >= 1:800 had a significantly longer DFS (P = .041 and P = .0006, respectively) and OS (P = .032 and P = .006, respectively).


View this table:
[in this window]
[in a new window]
  		Table 5. Univariate Analysis of Prognostic Factors for Vaccine (n = 43) and Observation (n = 11) Groups Using Cox Regression
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because active specific immunotherapy is believed to improve survival by enhancing the patient’s immunity against autologous tumor cells, specific immune responses to a vaccine should reflect overall clinical response. Although the cellular immune response to the vaccine can be measured via a delayed-type hypersensitivity skin test and has been correlated with improved clinical outcome of patients with American Joint Committee on Cancer stage IV melanoma,12,41 it was not associated with significantly improved DFS or OS in a recent study of patients with American Joint Committee on Cancer stage II melanoma.48 In that study, 5-year OS was 60% when the delayed-type hypersensitivity skin test was less than 4 mm, compared with 75% when the skin test was >= 4 mm (P = .4607). It is possible that the cellular immune response may not play as critical a role in the destruction of tumor cells when the tumor burden is low; that is, in earlier stage melanoma or in patients rendered free of disease by surgery.

As expected, preoperative anti-TA90 IgG and IgM titers were similar between vaccine and observation groups (P = .1843 and P = .7214, respectively). The majority of patients had preoperative IgG titers less than 400 (57% of patients) and preoperative IgM titers less than 800 (91% of patients). Interestingly, low preoperative anti-TA90 IgG titer was associated with improved DFS and OS (P = .041 and P = .032, respectively) in the vaccine group (Table 5Go) but not in the observation group. This finding is in accordance with our previous reports.10,12

All patients had detectable anti-TA90 IgG and IgM titers at baseline, which suggests the endogenous induction of a low-level humoral immune response to TA90 expressed by the patient’s (autologous) melanoma cells. Furthermore, adjuvant therapy with the vaccine elicited a stronger anti-TA90 humoral immune response than did surgery alone. Twenty vaccine patients (47%) but no observation patients had a four-fold elevation of the anti-TA90 IgG titer. Likewise, 25 vaccine patients (58%) but no observation patients had a four-fold elevation of anti-TA90 IgM titer. However, maximal anti-TA90 IgG titers were not significantly different between the two groups (P = .1035), whereas the maximal anti-TA90 IgM titers were significantly different (P = .0022).

IgM titers that increased to at least 800 correlated with improved survival (Figs 1Go and 2Go). The estimated 5-year DFS and OS rates were 68% and 78%, respectively, for patients in the vaccine group who had an enhanced anti-TA90 IgM response. In comparison, TA90 IgM nonresponders (titers < 800) had 5-year DFS and OS rates of 30% and 44%, respectively. A similar beneficial effect has been reported for enhanced IgM antibody responses to gangliosides GM3, GD3, GM2, and GD2 on melanoma cells.49 Interestingly, only the TA90 IgM responders in the vaccine group, not in the observation group, had an improved outcome. This is most likely because a marked increase in anti-TA90 IgM titer (more than four-fold elevation from preoperative titer) was seen only in patients receiving active specific immunotherapy. In addition, the sample size might have been too small to realize a beneficial effect of endogenously elevated anti-TA90 IgM titer.

It is more difficult to induce active immunity against tumor antigens than viral or bacterial antigens because most tumor antigens identified to date are normal or mutated autoantigens.50 Therefore, various vaccine adjuvants have been tested to maximize the benefit from active specific immunotherapy. In a study by Basalp et al,51 purified IgM-type monoclonal antibody against hepatitis B virus (HBv) vaccine was complexed to commercially available HBv vaccine. When compared with HBv vaccine alone, the HBv vaccine-IgM complex enhanced the immune response at all doses, and antibody levels increased with increasing concentrations of HBv antigens in the vaccine’s formulation. In our study, we hypothesize that the improved survival of patients with an enhanced anti-TA90 IgM response to the vaccine might reflect an adjuvant effect: formation of a vaccine-IgM complex that could elicit a clinically stronger anti-TA90 immune response. The antitumor activity of IgM antibody has been correlated with improved survival in nonmelanoma malignancies.52,53

In conclusion, we have demonstrated that adjuvant therapy with a therapeutic polyvalent cancer vaccine induces a stronger humoral immune response to TA90 than does surgery alone. Almost 60% of our vaccine patients but none of the observation patients had a four-fold elevation of anti-TA90 immunoglobulin titers. Enhanced titers of anti-TA90 IgM but not anti-TA90 IgG correlated with improved DFS and OS. Conversely, nonresponders to the vaccine (no enhancement of anti-TA90 IgM) did not have improved outcome when compared with observation patients. Because most vaccine therapy is administered over a protracted period that often exceeds 12 months, changes in the humoral response to TA90 during vaccine therapy might be used to determine whether the vaccine should be continued or replaced with alternate therapies such as interferon alfa-2b.

Because most systemic treatment regimens for melanoma are associated with significant toxicity, adjuvant active specific immunotherapy with a nontoxic preparation, such as Canvaxin therapeutic polyvalent cancer vaccine, should be investigated after surgical resection of high-risk cutaneous melanomas. In addition, future investigations should focus on enhancing the IgM response to TA90 and other selected immunogenic proteins that are commonly expressed by human melanoma cells.


   ACKNOWLEDGMENTS
 
Canvaxin and CancerVax are trademarks of CancerVax Corporation.


   NOTES
 
Supported in part by grant nos. CA12582 and CA29605 from the National Cancer Institute, Bethesda, MD, and by funding from the Wayne and Gladys Valley Foundation, Oakland, CA, and the Harold McAlister Charitable Foundation, Los Angeles, CA.

Presented at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 15–19, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Flaherty LE: Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma. Cancer J Sci Am6:S15–S20, 2000

2. McDermott DF, Mier JW, Lawrence DP, et al: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2b in patients with metastatic melanoma. Clin Cancer Res6:2201–2208, 2000[Abstract/Free Full Text]

3. Balch CM, Murad TM, Soong SJ, et al: A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg 188:732–742, 1978[Medline]

4. Balch CM: The role of elective lymph node dissection in melanoma: Rationale, results, and controversies. J Clin Oncol 6:163–172, 1988[Abstract]

5. Coit D, Sauven P, Brennan M: Prognosis of thick cutaneous melanoma of the trunk and extremity. Arch Surg 125:322–326, 1990[Abstract/Free Full Text]

6. Kim SH, Garcia C, Rodriguez J, et al: Prognosis of thick cutaneous melanoma. J Am Coll Surg 188:241–247, 1999[CrossRef][Medline]

7. Gershenwald JE, Mansfield PF, Lee JE, et al: Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (>=4 mm) primary melanoma. Ann Surg Oncol 7:160–165, 2000[CrossRef][Medline]

8. Morton DL, Foshag LJ, Hoon DS, et al: Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 216:463–482, 1992[Medline]

9. Morton DL, Hoon DS, Nizze JA, et al: Polyvalent melanoma vaccine improves survival of patients with metastatic melanoma. Ann N Y Acad Sci 690:120–134, 1993[Medline]

10. Jones RC, Kelley M, Gupta RK, et al: Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: An immunologic survival model. Ann Surg Oncol 3:437–445, 1996[CrossRef][Medline]

11. Hsueh EC, Nathanson L, Foshag LJ, et al: Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases. Cancer 85:2160–2169, 1999[CrossRef][Medline]

12. Hsueh EC, Gupta RK, Qi K, et al: Correlation of specific immune responses with survival in melanoma patients with distant metastases receiving polyvalent melanoma cell vaccine. J Clin Oncol 16:2913–2920, 1998[Abstract/Free Full Text]

13. Chan AD, Morton DL: Active immunotherapy with allogeneic tumor cell vaccines: Present status. Semin Oncol 25:611–622, 1998[Medline]

14. Euhus DM, Gupta RK, Morton DL: Induction of antibodies to a tumor-associated antigen by immunization with a whole melanoma cell vaccine. Cancer Immunol Immunother 29:247–254, 1989[CrossRef][Medline]

15. Chi DD, Merchant RE, Rand R, et al: Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 150:2143–2152, 1997[Abstract]

16. Gupta RK, Morton DL: Studies of a melanoma tumor-associated antigen detected in the spent culture medium of a human melanoma cell line by allogeneic antibody: III. Physicochemical properties. J Natl Cancer Inst 72:83–92, 1984[Medline]

17. Gupta RK, Morton DL: Studies of a melanoma tumor-associated antigen detected in the spent culture medium of a human melanoma cell line by allogeneic antibody: II. Immunobiologic characterization. J Natl Cancer Inst 72:75–82, 1984[Medline]

18. Gupta RK, Morton DL: Studies of a melanoma tumor-associated antigen detected in the spent culture medium of a human melanoma cell line by allogeneic antibody: I. Purification and development of a radioimmunoassay. J Natl Cancer Inst 72:67–74, 1984[Medline]

19. Hoon DS, Yuzuki D, Hayashida M, et al: Melanoma patients immunized with melanoma cell vaccine induce antibody responses to recombinant MAGE-1 antigen. J Immunol 154:730–737, 1995[Abstract]

20. Huang SK, Okamoto T, Morton DL, et al: Antibody responses to melanoma/melanocyte autoantigens in melanoma patients. J Invest Dermatol 111:662–667, 1998[CrossRef][Medline]

21. Nishinaka Y, Ravindranath MH, Irie RF: Development of a human monoclonal antibody to ganglioside G(M2) with potential for cancer treatment. Cancer Res 56:5666–5671, 1996[Abstract/Free Full Text]

22. Ravindranath MH, Morton DL, Irie RF: An epitope common to gangliosides O-acetyl-GD3 and GD3 recognized by antibodies in melanoma patients after active specific immunotherapy. Cancer Res 49:3891–3897, 1989[Abstract/Free Full Text]

23. Ravindranath MH, Tsuchida T, Morton DL, et al: Ganglioside GM3:GD3 ratio as an index for the management of melanoma. Cancer 67:3029–3035, 1991[CrossRef][Medline]

24. Ravindranath MH, Amiri AA, Bauer PM, et al: Endothelial-selectin ligands sialyl Lewis(x) and sialyl Lewis(a) are differentiation antigens immunogenic in human melanoma. Cancer 79:1686–1697, 1997[CrossRef][Medline]

25. Sarantou T, Chi DD, Garrison DA, et al: Melanoma-associated antigens as messenger RNA detection markers for melanoma. Cancer Res 57:1371–1376, 1997[Abstract/Free Full Text]

26. Tai T, Cahan LD, Tsuchida T, et al: Immunogenicity of melanoma-associated gangliosides in cancer patients. Int J Cancer 35:607–612, 1985[Medline]

27. Tai T, Paulson JC, Cahan LD, et al: Ganglioside GM2 as a human tumor antigen (OFA-I-1). Proc Natl Acad Sci U S A 80:5392–5396, 1983[Abstract/Free Full Text]

28. Tsuchida T, Saxton RE, Morton DL, et al: Gangliosides of human melanoma. J Natl Cancer Inst 78:45–54, 1987[Medline]

29. Okamoto T, Irie RF, Fujii S, et al: Anti-tyrosinase-related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol 111:1034–1039, 1998[CrossRef][Medline]

30. Morioka N, Kikumoto Y, Hoon DS, et al: A decapeptide (Gln-Asp-Leu-Thr-Met-Lys-Tyr-Gln-Ile-Phe) from human melanoma is recognized by cytotoxic T lymphocytes in melanoma patients. J Immunol 153:5650–5658, 1994[Abstract]

31. Takahashi T, Conforti A, Kikumoto Y, et al: Augmentation of IgM antibody to gp43 tumor-associated antigen-peptide by polyvalent melanoma cell vaccine. J Clin Immunol 18:299–305, 1998[CrossRef][Medline]

32. Tsuchida T, Saxton RE, Morton DL, et al: Gangliosides of human melanoma. Cancer 63:1166–1174, 1989[CrossRef][Medline]

33. Gupta RK, Morton DL: Immunochemical characterization of fetal antigen isolated from spent medium of a human melanoma cell line. J Natl Cancer Inst 70:993–1004, 1983[Medline]

34. Wong JH, Gupta RK, Morton DL: Recovery of a cell surface fetal antigen and antibody in stage I melanoma patients. Cancer Immunol Immunother 27:142–146, 1988[Medline]

35. Wong JH, Xu SH, Gupta RK, et al: Tumor associated antigen immune complexes. Arch Surg 125:187–191, 1990[Abstract/Free Full Text]

36. Doi F, Chi DDJ, Charuworn BB, et al: Detection of beta-human chorionic gonadotropin mRNA as a marker for cutaneous malignant melanoma. Int J Cancer 65:454–459, 1996[CrossRef][Medline]

37. Cheresh DA, Reisfeld RA, Varki AP: O-acetylation of disialoganglioside GD3 by human melanoma cells creates a unique antigenic determinant. Science 225:844–846, 1984[Abstract/Free Full Text]

38. Wilson BS, Imai K, Natali PG, et al: Distribution and molecular characterization of a cell-surface and a cytoplasmic antigen detectable in human melanoma cells with monoclonal antibodies. Int J Cancer 28:293–300, 1981[Medline]

39. Tafra L, Dale PS, Wanek LA, et al: Resection and adjuvant immunotherapy for melanoma metastatic to the lung and thorax. J Thorac Cardiovasc Surg 110:119–129, 1995[Abstract/Free Full Text]

40. Morton DL, Hsueh EC, Essner R, et al: Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes. Ann Surg 236:438–449, 2002[CrossRef][Medline]

41. Hsueh EC, Essner R, Foshag LJ, et al: Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine. J Clin Oncol 20:4549–4554, 2002[Abstract/Free Full Text]

42. Morton DL, Barth A: Vaccine therapy for malignant melanoma. CA Cancer J Clin 46:225–244, 1996[Medline]

43. Hsueh EC, Gupta RK, Yee R, et al: Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma? Ann Surg Oncol 7:232–238, 2000[CrossRef][Medline]

44. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early-stage melanoma. Arch Surg 127:392–399, 1992[Abstract/Free Full Text]

45. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: Multicenter trial. Ann Surg 230:453–465, 1999[CrossRef][Medline]

46. Euhus DM, Gupta RK, Morton DL: Detection of a tumor-associated glycoprotein antigen in serum and urine of melanoma patients by murine monoclonal antibody (AD1-40F4) in enzyme immunoassay. J Clin Lab Anal 3:184–190, 1989[Medline]

47. O’Day SJ, Gammon G, Boasberg PD, et al: Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma. J Clin Oncol 17:2752–2761, 1999[Abstract/Free Full Text]

48. DiFronzo LA, Gupta RK, Essner R, et al: Enchanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer Stage II melanoma patients receiving adjuvant polyvalent vaccine. J Clin Oncol 20:3242–3248, 2002[Abstract/Free Full Text]

49. Takahashi T, Johnson TD, Nishinaka Y, et al: IgM anti-ganglioside antibodies induced by melanoma cell vaccine correlate with survival of melanoma patients. J Invest Dermatol 112:205–209, 1999[CrossRef][Medline]

50. Kim SK, Ragupathi G, Cappello S, et al: Effect of immunological adjuvant combinations on the antibody and T-cell response to vaccination with MUC1-KLH and GD3-KLH conjugates. Vaccine 19:530–537, 2001

51. Basalp A, Cirakoglu B, Bermek E: Enhancement of the immune response to hepatitis B virus vaccine by antigen specific IgM. Immunol Lett 73:1–6, 2000[Medline]

52. Ollert MW, David K, Schmitt C, et al: Normal human serum contains a natural IgM antibody cytotoxic for human neuroblastoma cells. Proc Natl Acad Sci U S A 93:4498–4503, 1996[Abstract/Free Full Text]

53. MacLean GD, Reddish MA, Koganty RR, et al: Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother 19:59–68, 1996[Medline]

Submitted October 12, 2001; accepted September 24, 2002.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
M. Lotem, A. Machlenkin, T. Hamburger, A. Nissan, L. Kadouri, S. Frankenburg, Z. Gimmon, O. Elias, I. B. David, A. Kuznetz, et al.
Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells
Clin. Cancer Res., August 1, 2009; 15(15): 4968 - 4977.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chung, M. H.
Right arrow Articles by Morton, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chung, M. H.
Right arrow Articles by Morton, D. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online