| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
EDITORIALS |
From the Division of Surgical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan.
Correspondence: Address correspondence to: Vernon K. Sondak, MD, University of Michigan Medical Center, Division of Surgical Oncology, 3306 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0932; Fax: 734-647-9647; E-mail: vsondak{at}umich.edu
The cellular immune system recognizes antigenic protein fragments that are presented on the surface of target cells bound to human leukocyte antigen (HLA) class I and class II molecules. These HLA molecules act like keys, allowing different cellular subsets of the immune system to respond to antigens. An interesting corollary of this fact is the possibility that immune responses to the same antigen can vary from person to person. That could have several possible implications for antitumor immunity: an individual patient may be more or less able to defend against a developing tumor, and an immunologic intervention, such as a vaccine, designed to augment the antitumor immune response may not work equally well in all patients. Dr. Lee and his colleagues, in the July issue of the Annals of Surgical Oncology, present results from their pioneering studies on HLA class II expression and outcome in patients with clinically localized melanoma. Previously, they had shown that a particular class II allele, HLA-DQB*0301, was an independent predictor of melanoma recurrence. In their current study, they again find that this allele is associated with decreased 5-year disease-free survival (66% vs. 77% for patients not expressing this allele; P = .022) and also show a similar adverse impact of HLA-DRB1*1011 (53% vs. 70%; P = .007). Expression of these alleles was not associated with any differences in recognized melanoma prognostic factors, such as Breslow thickness, presence of ulceration, etc.1
In isolation, these findings are interesting but of limited clinical relevance. However, Dr. Lee’s group has been able to further dissect the phenomenon and provide a potential explanation. In doing so, they find that expression of the HLA-DRB1*1011 allele was associated with elevated levels of interferon 
in the serum, itself a poor prognostic factor. There is certainly ample precedent for cytokine production varying based on HLA expression. Still, the idea that elevated levels of interferon would be a bad thing is not intuitively obvious and merits further discussion.
Interferon is a potent immunomodulatory cytokine with lots of desirable actions that could serve to stimulate an antitumor immune response. Yet despite that, interferon has not shown clinically significant antitumor activity when given to patients with advanced melanoma2 or when used as an adjuvant after complete resection for patients with localized or node-positive melanoma.3 In fact, there was even a suggestion that the administration of interferon might actually be harmful,4 a finding that was not borne out in another trial.5 So it remains a mystery why higher levels of interferon in the serum should be a poor prognostic factor. It must be noted that there is a very broad range of values for interferon in the serum of normal individuals, so the finding of an elevated level is a relative one, not an indication of an actual abnormality of interferon production. The variability of interferon levels also makes the actual predictive value small.
The observations Dr. Lee and his group have made result from a painstaking and methodical series of scientific experiments, truly exemplifying translational research in the best sense. But the best scientific experiments generate hypotheses for further testing. The hypothesized relationship of class II antigen expression and interferon secretion, and the link of both to outcome, now needs to be tested in the ultimate clinical experiment, the randomized clinical trial. Coincidentally, so too does another intriguing hypothesis: that HLA class I antigen expression can be used to select patients for adjuvant therapy with an allogeneic melanoma vaccine.
In an initial observation in 1992, the clinical benefit of an allogeneic polyvalent melanoma cell lysate (Melacine, Corixa Corporation, Seattle WA) in patients with stage IV melanoma was strongly associated with HLA class I expression, with HLA-A2 and HLA-C3 expression as predominant factors.6 This observation led to the hypothesis that the same HLA antigens might predict benefit when the same vaccine was administered as an adjuvant after resection of clinically node-negative melanomas. Indeed, HLA-A2 and/or HLA-C3 antigen expression did correlate with improved disease-free survival after vaccination but not in unvaccinated controls.7 In an updated analysis, the same antigen expression pattern was shown to predict improved overall survival as well, the first prospective trial to demonstrate improved survival for a subset of melanoma patients treated with an adjuvant vaccine therapy.8 This observation also needs direct confirmation in a planned randomized controlled trial in melanoma patients who all express the desired HLA antigens. If the line of scientific inquiry Dr. Lee has started can be pursued in the context of this prospective trial, it would afford the unique opportunity to study two complementary interactions between HLA expression and antitumor immunity and provide important clues on how to use HLA status to identify patients who are at highest risk of recurrence and who also have the greatest chance to benefit from treatment.
Received for publication July 1, 2002. Accepted for publication July 15, 2002.
REFERENCES
levels and disease recurrence in melanoma patients. Ann Surg Oncol 2002; 9: 587–93. versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J Natl Cancer Inst 1995; 87: 1710–13. detrimental? Results of a Southwest Oncology Group randomized trial of adjuvant human interferon- versus observation in malignant melanoma. In: Salmon SE, ed. Adjuvant Therapy of Cancer VIII. Philadelphia: Lippincott-Raven, 1997: 259–72.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
