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e d i t o r i a l s

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Treating Cancer by Targeting the Immune SystemPatrick Hwu, M.D.

There is currently great interest in the targeted therapy of cancer. Antibodies that target specific antigens on the surface of cancer cells — such as rituximab, which binds to CD20 on lymphoid tumors, and trastuzumab, which blocks HER2 on breast-cancer cells — were early successes. However, a novel method of using antibodies to stimulate an antitumor response was pioneered in the mid-1990s by James Allison and colleagues.1 Because the body’s immune response, if left un-checked, can result in autoimmunity, we have evolved a number of immune “checkpoints” that work as braking mechanisms to counterbalance immune activation. Studies in animals have shown that inhibition of these checkpoints — such as with an antibody against the cytotoxic T-lympho-cyte–associated antigen 4 (CTLA-4) molecule,2 an inhibitory membrane protein that is expressed after T-cell activation — enhances immune activa-tion against cancer cells, resulting in significant antitumor effects.

In this issue of the Journal, Hodi et al. report the results of the first randomized clinical trial to show an overall survival benefit with this ap-proach among cancer patients.3 In this multi-center study, patients with metastatic melanoma were randomly assigned to receive either an anti–CTLA-4 agent (ipilimumab), a vaccine based on a melanoma antigen, or a combination of the anti–CTLA-4 agent and the vaccine. An improvement in overall survival, as well as an improvement in progression-free survival and best overall response rate, was seen in the patients who received anti–CTLA-4 therapy, as compared with the patients who received the vaccine only. These results are especially important, since metastatic melanoma has historically been resistant to treatment. Al-

though primary cutaneous melanoma is curable in its early stages with surgical resection, patients with metastatic melanoma have a median surviv-al of less than 1 year. Until now, the only agents approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma have been dacarbazine and interleukin-2, and no randomized studies to date have shown a clear survival benefit with any agent or combination of agents.

Although immune-based therapies have led to progress in the treatment of metastatic mela-noma, instances of toxic effects have been seen. Symptoms related to autoimmunity develop in some patients, since host defenses that are sub-jected to checkpoint blockade appear to lose the ability to discriminate between self and nonself. Since tumors derive from self tissues, the appear-ance of immune-related adverse effects, such as colitis, hepatitis, and hypophysitis (inflammation of the pituitary gland), has been correlated with clinical response from ipilimumab therapy.4 How-ever, treatment of these toxic effects requires prompt medical attention, and in rare circum-stances, the events can be fatal.

A nonconventional aspect of the study by Hodi et al. is that the control group was not a dacar-bazine-treated group or an observation or place-bo group, as was the case in previous phase 3 clinical trials involving patients with stage IV melanoma, but instead was a vaccine-treated group. It could be argued that the vaccine could have been harmful, thereby bringing into ques-tion the benefits of the anti–CTLA-4 therapy. Indeed the best overall response rate was higher in the anti–CTLA-4 group than in the group that received both the anti–CTLA-4 agent and the

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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vaccine. However, the combination group did fare better than the group that received the vaccine alone. In addition, a similar peptide-based vac-cine was recently reported to have doubled the clinical response rate when it was used in com-bination with interleukin-2, as compared with interleukin-2 alone,5 suggesting that it is unlikely that the vaccine was overtly harmful in the study by Hodi et al.

Although the difference in median survival in the anti–CTLA-4 groups as compared with the vaccine-alone group was only 4 months, and the best overall response rate was only 6 to 11% in the groups that received the anti–CTLA-4 agent, the true importance of this drug lies in the long-term benefit that was seen in a subgroup of patients. Follow-up from the earliest cohort of patients that received the anti–CTLA-4 drug shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years.6 This long-term survival in patients with metastatic melanoma is important, and it will be critical to determine biomarkers that will predict this outcome, so that the therapy can be personalized to the proper patient population. To date, long-term survival among patients with metastatic melanoma is primarily seen only in a subgroup of patients who have been treated with immune interventions, including adoptive T-cell transfer7 and interleukin-2–based regimens. It will be interesting to determine whether there is an overlap between the subgroup of patients who have long-term survival after anti–CTLA-4 ther-apy and those who have long-term survival after other immune-based therapies.

It is important to note that the classic re-sponse criteria developed for chemotherapy, such as the criteria of the World Health Organization and the Response Evaluation Criteria in Solid Tumors (RECIST), may need to be reevaluated for immunologic agents. The development of im-mune responses against self-antigens, such as those expressed by tumors, can take time, and the clinical experience with anti–CTLA-4 drugs clearly shows that clinical responses can take months to develop, even after an initial period of tumor growth that occurs when lymphocytes in-filtrate the tumor nodules. Therefore, new crite-ria have been proposed8 to take into account these unique tumor response kinetics after im-mune therapies.

Because of these results, anti–CTLA-4 therapy

is an important option for patients with meta-static melanoma. The current work is perhaps most significant because it provides validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer. Despite this advance, the ultimate role of anti–CTLA-4 drugs in the therapy of patients with metastatic melanoma is still unclear, since the field is changing rapidly. After a period of more than 10 years in which there was no FDA approv-al of a new drug for metastatic melanoma, this area is undergoing a renaissance, with promis-ing new trials of immunotherapy as well as tar-geted therapy. For example, 50% of metastatic melanomas express a mutated BRAF gene, and the use of BRAF inhibitors to treat patients who have this mutated gene has resulted in clinical re-sponse rates higher than 50%.9 Along with the therapy in the study by Hodi et al., a number of other immune therapies have shown promise in patients with metastatic melanoma, including adoptive T-cell transfer,7 vaccines in combination with interleukin-2,5 and antibodies against other checkpoints, such as PD-1.10

Despite dramatic effects in a subgroup of pa-tients receiving the anti–CTLA-4 drug, the major-ity of patients with metastatic melanoma do not respond to this agent, and further work is vital to improve these results. Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. In-stead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevat-ing the “tail” of the survival curve. It should be possible to realize this goal if there is adequate synergy and cooperation among academia, regu-latory agencies, and the pharmaceutical industry.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the University of Texas M.D. Anderson Cancer Center, Houston.

Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-medi-1. ated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immu-nol 2001;19:565-94.

Waterhouse P, Penninger JM, Timms E, et al. Lymphoprolif-2. erative disorders with early lethality in mice deficient in CTLA-4. Science 1995;270:985-8.

Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival 3. with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.

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editorials

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Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates 4. with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043-53.

Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III 5. multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 com-pared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol 2009;27:Suppl:18s. abstract.

Prieto PA, Yang JC, Sherry RM, et al. Cytotoxic T lympho-6. cyte-associated antigen 4 blockade with ipilimumab: long-term follow-up of 179 patients with metastatic melanoma. J Clin On-col 2010;28:Suppl:15s. abstract.

Rosenberg SA, Dudley ME. Adoptive cell therapy for the 7.

treatment of patients with metastatic melanoma. Curr Opin Im-munol 2009;21:233-40.

Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evalu-8. ation of immune therapy activity in solid tumors: immune-relat-ed response criteria. Clin Cancer Res 2009;15:7412-20.

Flaherty K, Puzanov I, Sosman J, et al. Phase I study of PLX4032: 9. proof of concept for V600E BRAF mutation as a therapeutic tar-get in human cancer. J Clin Oncol 2009;27:Suppl:461s. abstract.

Sznol M, Powderly JD, Smith DC, et al. Safety and antitumor 10. activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies. J Clin Oncol 2010;28:Suppl. abstract. (Accessed July 28, 2010, at http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/2506.)Copyright © 2010 Massachusetts Medical Society.

Palliative Care — A Shifting ParadigmAmy S. Kelley, M.D., M.S.H.S., and Diane E. Meier, M.D.

Palliative care focuses on relieving suffering and achieving the best possible quality of life for pa-tients and their family caregivers. It involves the assessment and treatment of symptoms; support for decision making and assistance in matching treatments to informed patient and family goals; practical aid for patients and their family care-givers; mobilization of community resources to ensure a secure and safe living environment; and collaborative and seamless models of care across a range of care settings (i.e., hospital, home, nurs-ing home, and hospice). Palliative care is provided both within the Medicare hospice benefit (hos-pice palliative care) and outside it (nonhospice palliative care). Nonhospice palliative care is offered simultaneously with life-prolonging and curative therapies for persons living with seri-ous, complex, and life-threatening illness. Hos-pice palliative care becomes appropriate when curative treatments are no longer beneficial, when the burdens of these treatments exceed their benefits, or when patients are entering the last weeks to months of life.1

Comprehensive palliative care services inte-grate the expertise of a team of providers from different disciplines to address the complex needs of seriously ill patients and their families. Mem-bers of a palliative care team typically include professionals from medicine, nursing, and social work, with additional support from chaplaincy and professionals in nutrition, rehabilitation, pharmacy, and other professional disciplines, as needed. These programs are now available at more than 80% of large U.S. hospitals (those

with more than 300 beds), where most Ameri-cans receive their care during complex and ad-vanced illness.2

Despite the increasing availability of pallia-tive care services in U.S. hospitals and the body of evidence showing the great distress to patients caused by symptoms of the illness,3 the burdens on family caregivers,4 and the overuse of costly, ineffective therapies during advanced chronic illness,5 the use of palliative care services by physicians for their patients remains low. Physi-cians tend to perceive palliative care as the al-ternative to life-prolonging or curative care — what we do when there is nothing more that we can do — rather than as a simultaneously deliv-ered adjunct to disease-focused treatment.6

In this issue of the Journal, Temel and col-leagues challenge this prevailing notion of pal-liative care by presenting the results of a ran-domized, controlled trial of early palliative care in addition to standard oncologic care for pa-tients with newly diagnosed metastatic non–small-cell lung cancer.7 A total of 151 subjects were recruited and enrolled in the study at a sin-gle academic thoracic oncology practice. Health-related quality of life and mood were measured at baseline and at 12 weeks. In addition to stan-dard oncologic care, patients in the intervention group met with a palliative care clinician at the time of enrollment and at least monthly there-after. As compared with the standard care group, the intervention group had better quality of life, lower rates of depression, and a 2.7-month sur-vival benefit.

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