It is now generally accepted that immunotherapy has a role in the treatment of advanced melanoma. This is based on the durable clinical activity of interleukin-2 (IL-2) in a subset of metastatic melanoma patients and the ability of interferon alfa to prolong the disease-free survival of patients in the adjuvant setting.^1,2 Enthusiasm for both of these therapies is limited by the relatively small number of patients who derive lasting clinical benefits and by a well-characterized panel of toxicities.

Paths to Improved Immunotherapies

Research has therefore been focused on the development of immunotherapies that may benefit a larger number of patients. The accompanying article by Dr. Steven A. Rosenberg describes the efforts of his group at NCI to develop adoptive T cell therapy for melanoma. Another area of recent research interest is immunologic checkpoint blockade; the best-known therapeutics in this new field are antibodies that block CTLA-4.

Anti-CTLA-4 Therapy

CTLA-4 is best characterized as a ‘brake’ that binds to costimulatory molecules on antigen-presenting cells, preventing their interaction with CD28 on T cells and also generating an overtly inhibitory signal constraining further T cell activation. Teleologically, CTLA-4 is necessary to prevent hyperstimulation of T cells that could lead to harmful autoimmunity or activation-induced cell death of T cells. The functional role of CTLA-4 is best demonstrated by the lethal autoimmunity observed in CTLA-4 knockout mice. However, temporary inhibition of CTLA-4 has been hypothesized to allow for more robust T cell activation. The first anti-CTLA-4 antibody was made by Dr. Jim Allison in an attempt to provide a limited release of this immunologic braking mechanism, in the hope of permitting the immune system to recognize targets on tumor cells more effectively. Initial laboratory experiments demonstrated that anti-CTLA-4 antibodies used as monotherapies could indeed mediate rejection of some mouse tumors. For the well-known B16 mouse melanoma, anti-CTLA-4 therapy could provide long-term protection from tumor challenge, but only when combined with a GM-CSF-secreting tumor cell vaccine.

Ipilimumab and Tremelimumab

To date, two human monoclonal antibodies designed to block CTLA-4 have been used in clinical trials in melanoma. Ipilimumab is an IgG1 antibody being jointly developed for use in melanoma by Medarex and Bristol-Myers Squibb. Tremelimumab is an IgG2a antibody developed by Pfizer. Both products have shown clinical activity as single agents in patients with advanced refractory metastatic melanoma. Clinical trials for ipilimumab and tremelimumab have also revealed a unique panel of mechanism-based immune-related adverse events. The vast majority of the immunerelated adverse events are low-grade pruritus and diarrhea, while some cases of more serious colitis, hepatitis and hypophysitis also have been described. These side effects are medically manageable, usually with corticosteroids, assisted by simple algorithms.

In phase II trials reported at ASCO this year, ~270 patients were treated with the optimal dose (10 mg/kg) of ipilimumab in the secondline setting. At week 12 after starting, 6-11% of patients had an objective response by WHO criteria. However, 20-30% had disease control (partial response, complete response, and stable disease) at week 24.

The clinical responses seen with these anti- CTLA-4 antibodies have been difficult to categorize using standard response criteria; the very meaning of ‘response’ for such biologics is emerging in a different way than for conventional cytotoxic therapies. Some patients certainly demonstrate classic partial and complete responses (PR, CR) using modified World Health Organization criteria. For ipilimumab, the number of such patients ranges from six to 15 percent when tumor assessments are made at week 12 after beginning therapy. However, the biologic processes leading to tumor regression by T cell activation are complex and heterogeneous between patients; some on ipilimumab have delayed responses, which may occur after long periods (>6 months) of stable disease, while others manifest overt progression of disease at week 12 before eventually having clinical benefit with no additional therapy.

Even more intriguing is the description of new lesions occurring in the context of response in baseline tumors. Such patients would be categorized as having progression of disease by standard response criteria. However, at least a subset of such patients will have eventual regression of the new lesions, albeit later than the target lesions.

To date, the best hypothesis for these varying delayed responses is that the immune system may require time to sculpt responses to different tumors with potentially different antigens. There is also inherent biologic variation in the threshold for induction of an immune response.

Responses to ipilimumab have been generally durable, with some patients from the initial trials surviving >5 years.

How To Gauge Benefits

These novel patterns of clinical response have led to much discourse about how to quantify the clinical benefit of anti-CTLA-4 therapy. Investigators have proposed a series of immune-related response criteria, which take into consideration the appearance of new lesions.^3,4 These criteria are currently being evaluated in several clinical trials of ipilimumab. From initial studies, it seems that patients who are identified as having clinical benefit by the various immune-related response criteria have similar overall survival to patients categorized as responders using standard criteria. Until the immune-related response criteria can be prospectively validated, overall survival will obviously remain the gold standard for judging clinical benefit of these and other novel biotherapies.

In the Wings

As of September, 2008, a phase III trial of ipilimumab for first-line therapy of melanoma is ongoing but closed to accrual. We in the field eagerly await the overall survival data from this randomized comparison of dacarbazine +/- ipilimumab. In the interim, other ongoing studies are focusing on the use of ipilimumab in patients with brain metastases, as some anecdotal reports of activity in brain lesions have been noted. A phase III trial of tremelimumab versus dacarbazine/ temozolomide was reported at ASCO in 2008, with no survival advantage detectable.⁵ It is unknown at this time whether further trials of tremelimumab in melanoma are planned.

Conclusion

The development of anti-CTLA-4 antibodies is of great interest to those engaged in the treatment of melanoma patients. The observation of durable responses in refractory disease using a simple intravenous infusion to administer outpatient therapy is of obvious importance. We need to focus on how to categorize the responses to this therapy more accurately and to emphasize the need for close communication between patient and clinician to diagnose immunerelated adverse events early, when they can be easily treated. Researchers have high hopes that the coming year will bring us closer to approval of a new immunotherapy for metastatic melanoma. Further hope can be gained from the early clinical trials of other immunomodulatory antibodies, such as anti-CD137, anti-CD40 and anti-PD1.

References

1. 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 Jul 1999; 17(7):2105-2116.

2. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14(1):7-17.

3. Hodi FS, Hoos A, Ibrahim R, Chin K, Pehamberger H, Harmankaya K, O’Day S, Hamid O, Humphrey R, Wolchok J. Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. J Clin Oncol 2008; 26(May 20 suppl; abstr 3008).

4. Saenger YM,Wolchok JD. The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun 2008;8:1.

5. Ribas A, Hauschild A, Kefford R, Punt CJ, Haanen JB, Marmol M, Garbe C, Gomez-Navarro J, Pavlov D, Marshall M. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma. J Clin Oncol 2008; 26(May 20 suppl; abstr LBA9011).