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Interleukin-2 Effects Deserve Further Study: A Need for Better Understanding of Biology and of Optimal Dose Regimens

Division of Surgical Oncology, Human Immune Therapy Center, University of Virginia, Charlottesville, VA

Galina Yamshchikov

IBT Reference Laboratory, Lenexa, KS

To the Editor:

The letter by Andersen et al raises several interesting and relevant questions about the effects of interleukin-2 (IL-2) on immune responses to tumor antigens in humans. These issues are presented in the context of (1) our recent article on a randomized clinical trial of peptide vaccination for melanoma, in the adjuvant setting, combined with low-dose daily IL-2 applied upfront or on a delayed schedule¹ and (2) their studies with electrochemotherapy and low-dose subcutaneous IL-2.² Their studies in patients with advanced melanoma have tracked spontaneous T-cell responses against several defined melanoma-associated peptides from survivin, tyrosinase-related protein 2 (trp-2), Mart-1/MelanA, and gp100, after intralesional treatment of cutaneous melanoma lesions with bleomycin and high-voltage electric pulses (electrochemotherapy) and low-dose IL-2 administration. Interestingly, they found that spontaneous T-cell responses to these antigens decreased after electrochemotherapy during a period of several weeks, during which time low-dose IL-2 was being administered, only to reappear after a 2-week period without IL-2. These changes in T-cell reactivity were not associated with changes in reactivity to Epstein-Barr virus antigens, suggesting that the effect may have been tumor-antigen specific. These changes were observed in a small series of just eight patients, and although observed in several cases, they were not universally observed. In one patient, there was evidence of accumulation of antigen-specific T cells in a tumor deposit. These observations do raise the possibility that in some circumstances, low-dose IL-2 given daily may cause egress of antigen-specific T cells from the blood, possibly with selective accumulation in tumor deposits.

Andersen et al suggest that measures of T-cell responses in the blood may not reflect the relevant changes in T-cell responses in the patient. We certainly agree that T-cell biology cannot be assessed without consideration of the compartments in which the T cells are measured, and the time course of the responses. Further, we agree that optimal clinical trial design should include measures of the T-cell response in tumor deposits, in blood, and in vaccine-draining lymph nodes (sentinel immunized nodes). Unfortunately, harvest of tumor often is not feasible, and the ideal goal of monitoring T-cell responses in tumor at multiple intervals is particularly complex and cumbersome. Even in the studies by Andersen et al, evaluation of T cells infiltrating tumor was reported in only one of eight patients in their study, and only at one time point. While the findings of those authors are provocative, it is very difficult to make definitive conclusions about T-cell trafficking from the periphery to tumor in the setting of IL-2 based on this one tumor biopsy. In the future, studies that require tumor biopsies before treatment, during treatment, and after treatment, in a substantial patient sample should be encouraged. Evaluation of homing receptors on tumor-reactive lymphocytes detected in different compartments may bring some clarity to the issue of lymphocyte trafficking. We are currently initiating, through the Eastern Cooperative Oncology Group, a clinical trial of peptide vaccination in patients with advanced melanoma (E1602) in which the protocol prospectively encourages pretreatment and post-treatment tumor biopsies in addition to evaluation of T-cell responses in blood and nodes.

The studies by Andersen et al were based on treatment regimens very different than ours, and differed in the status of tumor in the patients studied. In our trial, we observed a decrease in the T-cell response to vaccine peptides in patients treated with low-dose IL-2 on an upfront schedule compared with what was observed in patients who received IL-2 on a delayed schedule. The finding of decreased immunogenicity in the upfront IL-2 group was based on concordant studies of peripheral blood lymphocytes and sentinel immunized node lymphocytes, in what is, to date, the largest published study with measures of both T-cell compartments. The trial was powered to detect that change, both in the blood and in sentinel immunized nodes, and we observed the difference between groups in immune responses in both compartments.

We could not measure T cells in tumor deposits in our trial because it was performed in patients who were clinically free of disease. Thus, tumor was not available during the vaccine regimen. However, there was a trend toward a poorer clinical outcome for patients with upfront IL-2. Though this study was not powered to detect differences in clinical outcome, these findings are concordant with the T-cell response data.

It is possible that some patients had microscopic tumor during the vaccine sequence; however, almost 50% of patients remained clinically disease-free for 2 years, and we would expect approximately 25% to remain disease-free long-term. Thus, a large proportion of patients had vanishingly small tumor burden or no tumor burden, so the changes seen in this study are difficult to ascribe to trafficking of T cells to tumor deposits.

Furthermore, even in patients with IL-2 administered beginning 7 days after the first vaccine (upfront IL-2), T-cell responses to vaccine peptides were detected in 55% of patients; so the majority of patients did experience induction of T-cell responses in the presence of low-dose IL-2, which is inconsistent with the finding of Andersen et al. Our data were based on a reasonable data set of 20 patients per arm.

Seeking explanations for the results of our trial, we have found that the cytokine environment in patients receiving IL-2 may be less conducive for generation of T-cell responses.³ We also wonder whether low-dose IL-2 given with vaccines may drive T cells into activation-induced cell death or may activate CD25⁺ regulatory T cells. These and other effects of IL-2 may have contributed to the findings in our study. We thank Andersen et al for their letter, because their findings deserve further investigation. However, we find it difficult to explain the findings of our study as a result of T-cell trafficking to tumor induced by IL-2.

In summary, IL-2 is a biologically active agent, whose effects remain incompletely understood. There is a great deal more to learn about the effects of IL-2 on T-cell activation, activation-induced cell death, secondary cytokine cascades, T-cell trafficking, and changes in the tumor microenvironment. The dramatic clinical regressions in some patients with advanced melanoma treated with high-dose IL-2 demonstrate the clinical value of this agent, but its effects are probably modulated by other host factors and counter-regulatory mechanisms. Greater understanding of the biology of IL-2 is needed. It is hoped that further laboratory and clinical studies will help to define dose regimens of IL-2 that may be useful for augmentation of specific T-cell responses and for optimal tumor control.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Craig L. Slingluff Jr Chiron (A) Berlex (C); Chiron (C) Galina Yamshchikov Kim Chianese-Bullock

Dollar Amount Codes (A) <$10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Slingluff CL Jr, Petroni GR, Yamshchikov GV, et al: Immunologic and clinical outcomes of vaccination with a multiepitope melanoma peptide vaccine plus low dose interleukin-2 administered either concurrently or on a delayed schedule. J Clin Oncol 22:4474-4485, 2004[Abstract/Free Full Text]

2. Andersen MH, Gehl J, Reker S, et al: Dynamic changes of specific T cell responses to melanoma correlate with IL-2 administration. Semin Cancer Biol 13:449-459, 2003[CrossRef][Medline]

3. Cragun WC, Yamshchikov GV, Bissonette EA, et al: Low-dose IL-2 induces cytokine cascade, eosinophilia, and a transient Th2 shift in melanoma patients. Cancer Immunol Immunother, May 12, 2005 (epub ahead of print)

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