The Antitumor Immunity of Ipilimumab: (T-Cell) Memories to Last a Lifetime?

Published OnlineFirst February 15, 2012; DOI: 10.1158/1078-0432.CCR-12-0409

Clinical Cancer CCR Translations Research Commentary on Prieto et al., p. 2039

The Antitumor Immunity of Ipilimumab: (T-cell) Memories to Last a Lifetime?

Michael A. Postow1,3, Margaret K. Callahan1,3, and Jedd D. Wolchok1,2,3,4

Ipilimumab has shown an overall survival beneﬁt in 2 randomized phase III studies. A minority of patients achieve long-term disease control, highlighting the potential of this immunotherapeutic approach. In ongoing efforts, investigators are continuing to characterize these patients’ unique clinical courses and correlate their responses with underlying mechanisms of antitumor immunity. Clin Cancer Res; 18(7); 1821–3. 2012 AACR.

In this issue of Clinical Cancer Research, Prieto and col- Prieto and colleagues have assembled findings from the leagues (1) report long-term follow-up data for 177 patients largest reported long-term clinical experience with ipilimu- treated with ipilimumab in some of the earliest trials in its mab. They provide updated data from 3 previously development. Their results underscore the remarkable, published studies that examined ipilimumab with gp100 durable benefits a subset of patients with melanoma achieve vaccination [protocol 1 (6)]; ipilimumab with concomitant from ipilimumab, hint at the promise of combining ipili- IL-2 [protocol 2 (7)]; and ipilimumab via a strategy of mumab with interleukin 2 (IL-2), and raise the provocative intrapatient dose escalation ( gp100) until occurrence of question of whether, in some patients, metastatic melano- response or intolerable side effects [protocol 3 (8)]. The ma can be cured. authors evaluate a total of 177 patients treated with ipili- Ipilimumab (Yervoy; Bristol-Myers Squibb) is a fully mumab, with a median follow-up of 92, 84, and 71 months, human monoclonal antibody that blocks cytotoxic respectively. The clinical and correlative implications of the T-lymphocyte antigen 4 (CTLA-4). Following T-cell acti- data presented are profound and stress several important vation, CTLA-4 is recruited to the plasma membrane, themes that have arisen during the development of ipili- where it functions in an autoregulatory role, attenuating mumab, and especially highlight the exceptional durability T-cell activation and proliferation through several of responses. mechanisms (2). Although CTLA-4 plays an essential role The authors offer robust data to support the finding that in maintaining immunologic tolerance, in the setting of patients who achieve a response after treatment with ipili- malignancy, CTLA-4 may restrain effective antitumor mumab are likely to be alive many years later. In their study immunity. As shown in Fig. 1, antibodies that block population, a total of 15 patients ultimately achieved a CTLA-4, such as ipilimumab, release T cells from this complete response (CR). The durability of responses among immunologic checkpoint and may enable them to exert patients who attained a CR is remarkable: All except one their full antitumor effect. are ongoing, with the longest lasting 99þ months (median, Ipilimumab was shown to confer an overall survival 83 months). Although it is tempting to consider these benefit in 2 phase III trials (3, 4). The objective response patients "cured," such a view should be approached with rate was modest [10% (3)], but a portion of patients in caution, because one patient did relapse after a CR lasting these trials achieved durable disease control. Although 42 months. The question of how this patient’s tumor ipilimumab is distinct in its mechanism of action and escaped after induction of a seemingly effective antitumor side-effect profile, the pattern of durable responses induced immune response underscores the complex relationship by this agent is similar to that described for a subset of between tumor and host immunity. Did the patient’s patients who received IL-2 (5). immune response select for tumor cells with reduced immunogenicity? Did the tumor microenvironment shift in favor of immune suppression? Do patients ever achieve tumor eradication, or is an ongoing memory response Authors' Affiliations: Department of 1Medicine and 2Immunology Pro- required to hold microscopic disease in check? Cases gram, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Ketter- ing Cancer Center; 3Weill Cornell Medical College, Cornell University; of durable partial response (PR) may support the notion 4Ludwig Institute for Cancer Research, New York, New York that an ongoing active immune response continues to Corresponding Author: Jedd D. Wolchok, 1275 York Avenue, Z-1462, control disease for years. In long-term follow-up, 9 patients Memorial Sloan-Kettering Cancer Center, New York, NY 10065. Phone: with PR are still alive years after initiation of treatment, with 646-888-2395; Fax: 646-422-0453; E-mail: [email protected] 3 patients maintaining a stable PR without further treat- doi: 10.1158/1078-0432.CCR-12-0409 ment and the remainder benefiting from subsequent 2012 American Association for Cancer Research. treatments.

www.aacrjournals.org 1821

Postow et al.

ABC

T cell T cell T cell

Figure 1. A, T-cell activation requires 2 signals (arrow). One signal involves the TCR recognizing a peptide antigen bound to an MHC on the surface of an APC. The second signal involves costimulation through the interaction of CD28 on T cells with B7 (B7-1/CD80, B7-2/ CD86) molecules on APCs. B, upon T-cell activation, CTLA-4 is recruited to the plasma APC APC APC membrane and functions in an inhibitory role, binding with higher afﬁnity than CD28 to B7. Through several mechanisms, this binding results in inhibition of T-cell activation and function. C, ipilimumab binds to CTLA-4 TCR CD28 CTLA-4 T-cell inhibition and blocks its inhibitory role. By disabling the inhibitory functions of CTLA-4, ipilimumab enhances T-cell activity. APC, antigen-presenting cell; TCR, Peptide/MHC B7 Ipilimumab T-cell activation T-cell receptor.

Delayed response kinetics is a hallmark of ipilimumab, lymphocyte count after the first ipilimumab dose was and Prieto and colleagues provide a more robust description associated with response (1). HLA status did not seem to of this phenomenon than was previously available. Among distinguish patients who benefited, because there was no the 15 patients who ultimately achieved a CR, an average 30 difference in the rate of response to ipilimumab between months was required to reach this endpoint. In one case, a HLA-A201–positive and HLA-A201–negative patients. patient achieved a CR at 70 months, nearly 6 years after This is consistent with our retrospective analysis and in starting treatment. These observations emphasize the var- line with ipilimumab’s proposed HLA-independent mech- iability of response patterns and the wide window of time anism of action (11). for ipilimumab to affect tumor burden. These responses Although ipilimumab confers impressively durable dis- may be best evaluated with the use of immune-related ease control for those who respond, a majority of patients response criteria, an adaptation of the World Health do not respond. Ongoing efforts to increase the number of Organization criteria, which were designed to accommo- patients who benefit from ipilimumab are focused on date the delayed kinetics and variability of responses to combining ipilimumab with chemotherapy, targeted ther- ipilimumab (9). apy, or other immunotherapies. Prieto and colleagues An important consideration in interpreting these findings report on a long-term follow-up of patients treated with is the fact that many of the patients who achieved CR ipilimumab in combination with IL-2. The high objective- received >4 doses of ipilimumab (range, 3–11), the dosing response rate of 25% (CR, 17%) achieved with this com- currently approved by the U.S. Food and Drug Administra- bination approach is intriguing, but it may have been tion for commercial use. The influence of this additional influenced by the selected patient population. Ultimately, ipilimumab on the accomplishment of a CR or the likeli- the attempt to weigh the benefits of this combination hood of a delayed response requires further study. against the toxicities of receiving both agents will require Unfortunately, only a subset of patients experience long- a randomized trial, as the authors suggest. Of note, the term disease control from ipilimumab, and identifying typical immune-related adverse events observed with ipili- which patients are likely to benefit is an ongoing effort. mumab do not seem to occur more commonly with this The absolute lymphocyte count was previously reported to combination, although in this study many patients received be associated with benefit from ipilimumab treatment (10), lower doses of ipilimumab (<3 mg/kg). Groups of patients and Prieto and colleagues’ results are consistent with who had been treated in protocols 1 and 3 (without IL-2) that observation. They found that an increase in absolute and were previously treated with IL-2 showed rates of

1822 Clin Cancer Res; 18(7) April 1, 2012 Clinical Cancer Research

(T cell) Memories to Last a Lifetime?

response to ipilimumab similar to those observed in popu- Ipilimumab has set a new standard of care for patients lations that had not previously received IL-2. This implies with melanoma. This important long-term analysis of that tumors that are resistant to IL-2 can retain sensitivity to patients treated in some of the earliest trials in ipilimumab’s ipilimumab, and may suggest a complementary mechanism development shows the true promise of ipilimumab for of action. engendering long-lasting antitumor responses. For a subset Four patients who progressed on ipilimumab achieved of patients, ipilimumab seems tantalizingly close to a cure. CRs after undergoing adoptive cell transfer (12). The pos- Understanding the immunologic features that identify sible benefit these patients received from prior ipilimumab patients who are most likely to benefit, and finding com- treatment, and whether such a benefit contributed to the plementary therapies that can enhance the activity of ipi- subsequent success of the adoptive cell transfer, is unclear. limumab, are important next steps in expanding the num- Nonetheless, because the persistence of infused cells is ber of patients who will be able to benefit from this important in adoptive cell transfer, and ipilimumab may promising therapy. have a role in potentiating the longevity of such cells, additional research will continue to evaluate this combina- Disclosure of Potential Conflicts of Interest tion approach. One study is already underway (Clinical- J. Wolchok is a consultant to Bristol-Myers Squibb. No potential conflicts of interest were disclosed by the other authors. Trials.gov Identifier: NCT00871481). Finally, the authors observed no significant benefit from Grant Support combining ipilimumab with a vaccine comprised of 2 Bristol-Myers Squibb (J. Wolchok and M.K. Callahan). gp100 peptides emulsified in Montanide ISA-51, in simi- Received February 6, 2012; accepted February 9, 2012; published larity to results from the separate large, randomized phase OnlineFirst February 15, 2012. III trial (3).

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www.aacrjournals.org Clin Cancer Res; 18(7) April 1, 2012 1823

The Antitumor Immunity of Ipilimumab: (T-cell) Memories to Last a Lifetime?

Michael A. Postow, Margaret K. Callahan and Jedd D. Wolchok

Clin Cancer Res 2012;18:1821-1823. Published OnlineFirst February 15, 2012.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-12-0409

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