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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2250-2251 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7826
Combining a Peptide Vaccine With High-Dose Interleukin-2Melanoma/Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY High-dose interleukin-2 (IL-2) is a US Food and Drug Administration–approved treatment for metastatic melanoma. It was originally developed at the National Cancer Institute (NCI) Surgery Branch and represents one of the few examples in which antitumor effects seen in mice correctly predicted antitumor effects in patients. The initial clinical report, which used recombinant IL-2 plus lymphokine-activated killer cells (now known to be mostly natural killer cells), reported a 44% response rate.1 This caught everybody's attention. Subsequently, over the next 9 years, as more patients were treated with IL-2 alone, the NCI Surgery Branch reported progressively lower response rates from 31%2 to 24%3 and finally to 17%.4 Consistent with this, a pooled analysis of seven NCI-sponsored trials, representing 270 patients, reported a response rate of 16% with IL-2.5 It is this number, 16%, that is most commonly cited as the response rate for high-dose IL-2. However, the substage of metastatic melanoma is an important predictor of response to IL-2. Durable responses are more common in patients with either M1a disease (subcutaneous sites only) or M1b disease (lung metastases) and much less common in patients with M1c disease.5,6 The importance of this will be discussed further in this editorial. Subsequent efforts by the NCI Surgery Branch to improve the response rate to high-dose IL-2 led to combining IL-2 with either lymphokine-activated killer cells or tumor-infiltrating lymphocytes.7 Initial studies in small cohorts of patients reported response rates of 44% and 60%, respectively, which seemed to represent an improvement over IL-2 alone. However, subsequent reports in larger numbers of patients did not reproduce these high response rates.2,3,8,9 The most likely explanation is that the patient populations were different and that the addition of lymphokine-activated killer or tumor-infiltrating lymphocyte cells did not have a significant effect on response. Another strategy to improve the response rate to high-dose IL-2 was to combine it with a vaccine. The NCI group used a heteroclitic peptide vaccine against gp100, which, although relatively inactive by itself, was associated with a 42% response rate in 31 patients when administered with high-dose IL-2.10 Again, this was higher then the historical experience with high-dose IL-2 alone. The authors were careful to point out that a randomized trial would be needed to determine whether the addition of gp100 vaccine really did improve the response proportion to high-dose IL-2. It was this observation that a group of experienced investigators from the Cytokine Working Group sought to clarify in the article published in this issue.11 They carried out parallel phase II trials combining the gp100 peptide vaccine with high-dose IL-2 using three different treatment schedules. Their plan was to select the best regimen to go forward into a phase III trial. To be worthy of consideration for a phase III trial, the regimen had to have at least a 30% response rate. As it turns out, they observed only a 16.5% overall response rate, and none of the three treatment arms achieved a response rate of 30%. Thus, these are three negative parallel phase II trials. As someone who was not a primary reviewer of the report, I was asked to address the following questions. What happened? Why did they observe a response rate of 16.5%, which is the same as the expected response rate to IL-2 alone, when the NCI reported a response rate of 42%? First, was it reasonable to expect a peptide vaccine, with little activity of its own, to enhance the effect of high-dose IL-2? Initially, the hope was that IL-2 would serve as an immune adjuvant to enhance the specific T-cell response induced by the vaccine. However, the data from the NCI in fact showed just the opposite. Although the peptide vaccine was fairly immunogenic when administered alone (there was a detectable T-cell response to gp100 in > 90% of patients immunized), in patients immunized with the vaccine and IL-2, only 16% of patients developed a detectable T-cell response. This suggested that the addition of IL-2 decreased the immunogenicity of the vaccine, which is consistent with the fact that we now know that IL-2 induces expansion of regulatory T cells that suppress T-cell responses.12 Because the patients treated with IL-2 and vaccine had a substantial response rate with few detectable T-cell responses to gp100, there was suspicion at the time that the responses were a result of IL-2 and not the peptide vaccine. There were other concerns with the NCI report, in that it was a retrospective analysis of several trials with a mixture of patients whose characteristics were not well described. Therefore, going in to the current trial, there was some skepticism as to whether the NCI data really indicated that the gp100 vaccine enhanced the effect of IL-2.
Second, did the Cytokine Working Group study reproduce the NCI approach? They used a 17% lower dose of IL-2 but delivered more doses than did the NCI. Whether this is critical is difficult to say. Probably more important is the effect of patient selection. In the current study, 67% of the patients had M1c disease, which, as noted earlier, is associated with a low incidence of response to IL-2. The NCI report does not provide much information about the patients treated, although the vast majority of the responders (10 of 13 patients) had M1a or M1b disease.10 If the NCI patient cohort was enriched for M1a or M1b patients, then this alone could explain the difference in response rates between the two studies. There is another, less obvious source of patient selection. Patients who make it to the NCI with adequate performance status despite experiencing progression after multiple courses of therapy (82% of the NCI patients had had Let me turn to the trial itself, which consisted of three parallel phase II trials with 39 to 42 patients in each. It is not stated how patients were assigned to a treatment cohort, though it was not randomized. This could have been a problem had there been one treatment cohort that stood out as superior (which, of course, was the hope at the beginning). As it turns out, it is unlikely that patient imbalance led to the negative result, but it points to the fact that the trial was adequately designed to be negative but not adequately designed to be positive.
The investigators collected lymphocytes before treatment and on week 12 to assess effects on T-cell subsets and TCR- What can we conclude? I would conclude that the 16.5% response rate seen in this trial is the same as the response rate expected with IL-2 alone and that these data do not support the hypothesis that the gp100 vaccine enhances the effect of high-dose IL-2. Although the authors’ statement that "This set of phase II trials cannot definitively establish whether or not vaccine adds to the benefit of IL-2" is technically correct, they later concede that the addition of gp100 vaccine and IL-2 "does not seem to represent a significant advance."11 Despite this, they report that a phase III trial is underway that, understandably, they fear will be underpowered. It is not clear to me what justifies such a trial. Surely, there are more novel and encouraging strategies that investigators in the melanoma field could be pursuing. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492, 1985[Abstract] 2. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-897, 1987[Abstract] 3. Rosenberg S, Lotze M, Yang J, et al: Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474-484, 1989[Medline] 4. Rosenberg SA, Yang JC, Topalian SL, et al: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271:907-913, 1994 5. Atkins MB, Lotze MT, Dutcher JP, et al: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105-2116, 1999 6. Phan GQ, Attia P, Steinberg SM, et al: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477-3482, 2001 7. Rosenberg SA, Packard BS, Aebersold PM, et al: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma: A preliminary report. N Engl J Med 319:1676-1680, 1988[Abstract] 8. Dutcher J, Creekmore S, Weiss G, et al: A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol 7:477-485, 1989[Abstract] 9. Rosenberg SA, Yannelli JR, Yang JC, et al: Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86:1159-1166, 1994 10. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321-327, 1998[CrossRef][Medline] 11. Sosman JA, Carrillo C, Urba WJ, et al: Three phase II Cytokine Working Group trials of gp100 (210M) peptide plus high-dose interleukin-2 in HLA-A2–positive advanced melanoma patients. J Clin Oncol 26:2292-2298, 2008 12. Ahmadzadeh M, Rosenberg SA: IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 107:2409-2414, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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two prior therapies) and still have no brain metastases (an exclusion criterion) are likely to be biologically different than the patients treated by the Cytokine Working Group, who presumably were treated soon after developing stage IV melanoma because most had received no prior therapy. 
loss (they did not measure T-cell responses to gp100, perhaps because of the technical challenges of enzyme-linked immunosorbent spot assays at the time) but were only able to collect specimens on less than 50% of patients, an indication of the logistical difficulties of sample collection in multicenter trials even among highly experienced and motivated investigators. It is not clear what efforts were made to validate these assays (variability, robustness, sensitivity, and so on) to know whether an effect might be seen. As it turns out, this was a large effort that, sadly, did not provide much information. 
