The concept of cancer immunotherapyâ€” using the patientâ€™s immune system to target and eradicate cancerâ€”has evolved over more than a century of research.
Jedd D. Wolchok, MD, PhD
The concept of cancer immunotherapy using the patient’s immune system to target and eradicate cancer—has evolved over more than a century of research. Only in the past 5 years, however, has immunotherapy been refined to the extent that the approach can now be integrated into the treatment of cancer.1In particular, an understanding of molecular mechanisms involved in T-cell activation and regulatory checkpoints, or braking mechanisms, has aided in the development of novel therapies to more effectively harness the immune system as a targeted cancer therapy.1Ipilimumab is a monoclonal antibody targeting the cytotoxic T-lymphocyte antigen 4 (CTLA-4) on T lymphocytes, an essential immune regulatory checkpoint.1CTLA-4 inhibition with ipilimumab has been shown to prolong survival in patients with advanced melanoma, a therapeutic area of significant unmet need.1,2Similarly, antibody-mediated inhibition of programmed death 1 (PD-1) receptor, another immune system checkpoint for activated T lymphocytes, has been associated with durable responses in a number of tumors, including advanced melanoma.3
Jedd D. Wolchok, MD, PhD, is chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center in New York City. Wolchok’s research has focused on the treatment of melanoma, particularly in developing novel ways to use the immune system in cancer treatment.Targeted Therapiesrecently spoke to Wolchok regarding the use of immunotherapy in advanced melanoma and other cancers.
Question: Does some degree of tumor immunity already exist from, for example, the use of chemotherapy or other treatments?Wolchok:We imagine that most patients are already somewhat “primed” naturally by the tumor. As these tumors grow, they create a sort of nontherapeutic inflammation. Certainly, prior therapies may help to some extent by causing antigen release and immune activation. However, whatever low-level immune response is mounted to the tumor, it is clearly not effective. The use of immunotherapies allows us to kind of up the ante, so to speak, by releasing this important molecular braking mechanism.
Question: What were the findings that provided critical proof of concept for the application of immunotherapy in advanced melanoma?Wolchok:In 2010, Hodi and colleagues published results from a phase III study in theNew England Journal of Medicinein which patients with advanced (unresectable phase III or IV) melanoma were randomly assigned to treatment with ipilimumab alone or in combination with the gp100 peptide vaccine.2A total of 676 patients were randomized, 403 to ipilimumab plus gp100, 137 to ipilimumab alone, and 136 to gp100 alone. Patients in the ipilimumab/gp100 group had a median overall survival (OS) of 10.0 months versus 6.4 months in the gp100-alone (control) group (hazard ratio [HR] for death = 0.68;P<.001). A similar significant difference was noted between the ipilimumab-alone group (median OS 10.1 months) and the gp100 group (HR = 0.66;P= .03).2Accordingly, treatment with ipilimumab, with or without gp100, was associated with a relative reduction in the risk for death of between 32% and 34% in this population of advanced melanoma patients who had had one or more prior therapies, and this was a major advance in improving survival.
Question: How has the advent of immunotherapy changed clinical practice for advanced melanoma?
Wolchok:Until these immunotherapies became available, the prognosis of patients with advanced melanoma was universally poor. Dacarbazine was the only approved therapy for advanced melanoma, and although well tolerated, very few individuals benefited from the therapy (~5%-12%), and if they did, only temporarily.1Other strategies included interleukin-2 therapy, but this was not widely applicable to all patients nor could it be easily administered; indeed, prior to 2011, no treatment for advanced melanoma had been proven to improve OS.1With this in mind, the approval of both ipilimumab and another therapy, vemurafenib, an inhibitor of the BRAF pathway, represented a major step forward in improving survival for patients with melanoma. The key difference with immunotherapy, in particular, is that you are not treating the tumor, you are treating the patient, and the patient treats the tumor. We already know that the immune system has a memory, and once you invoke that memory, you would imagine the responses would become more durable, and they are.
Question: What are the relevant toxicities associated with ipilimumab, and how are they managed?
Wolchok:The principal toxicities associated with ipilimumab therapy can be considered, in broad terms, as tissue-specific inflammation. A common area is the skin, in which we typically see a pruritus develop, for which topical emollients or corticosteroids work quite well. The other most common toxicity occurs in the GI tract, and the symptoms, principally diarrhea, resemble those of an enterocolitis or an acute inflammatory bowel disease. Again, corticosteroids are the mainstay of management for this event. A carefully derived, stepwise algorithm has been developed, beginning with dietary manipulation, reducing spicy foods, and so on, then proceeding to rule out infectious causes. If the diarrhea persists after a few days, we would typically start oral prednisone. In 90% to 95% of cases, a slow taper over 3 weeks is effective in controlling the diarrhea; rarely, we need to give something more potent, such as infliximab. A less common adverse event is inflammation of endocrine organs, such as thyroiditis. In most cases, thyroid replacement drugs are effective treatment, and these events can also be reversible in about 50% of cases. Steroids are also effective for other adverse events, such as liver function test elevations.
It’s important to give people a suitable amount of time to be on ipilimumab therapy before addressing possible events such as diarrhea. Indeed, there may be nontreatment-related causes for events such as diarrhea, and of course, we need to rule out infectious causes such as Clostridium difficile. It is important not to wait too long to treat, as there is a risk for death and serious events such as intestinal perforation. In practice, we typically wait a couple of days to rule out other causes and then give prednisone. An interesting observation is that, even in the face of immunosuppressive drugs to deal with the adverse events, one would think that this would also eliminate the anticancer activity, but it doesn’tand the mechanism behind that is still, to a large extent, unknown. It is also important to note that these events do not happen right away. The treatment is given every 3 weeks, and adverse events usually occur around the time of the third or fourth dose, so events emerge between weeks 7 and 12 after the start of therapy. It is rare to get side effects after finishing the 4 doses of the antibody.
Question: What other targeted therapies may be useful in combination with ipilimumab?
Wolchok:Right now, outside of a clinical trial, ipilimumab is only approved for use as a monotherapy. In general, people are not using this in combination with chemotherapy. There was some off-label use of this agent with vemurafenib, but in a phase I trial, we noted an excessive amount of liver toxicity, and the trial reinforced the notion that, although two agents may have distinct mechanisms of action and are approved for use in a given malignancy, this does not necessarily mean that they can be safely administered together.4In addition, notwithstanding the pitfalls of cross-trial comparisons, we found that therapy for melanoma with dacarbazine and ipilimumab did not appear to have much added benefit over ipilimumab alone.5Although the combination was significantly better than dacarbazine alone, this study was conducted before the approval of ipilimumab, and at this time there does not appear to be a strong rationale for using ipilimumab in combination with dacarbazine.5
One particular combination we are very interested in, however, is ipilimumab with the anti-PD-1 antibody, nivolumab. Use of these agents in combination is supported by their distinct mechanisms of action, in that PD-1 induces T-cell exhaustion and CTLA- 4 blocks earlier steps in T-cell activation.6Results from a phase I study showed that the two agents could be safely coadministered, and this combination caused more rapid and deep responses compared with either single-agent therapy.6Nivolumab looks very impressive in the phase I study, and as a result, we launched phase II and phase III studies simultaneously using ipilimumab in combination with nivolumab; we saw very rapid recruitment into these studies.
Question: What other cancers do you think immunotherapy may be useful for in the future?
Wolchok:A major turning point for immunotherapy occurred with the development of the PD-1 antibody, nivolumab. In 2012, Topalian and colleagues reported results from a pilot study examining the use of nivolumab in patients (N = 296) with a variety of cancers, including advanced melanoma, non-small cell lung cancer (NSCLC), renal cell cancer, and castrate-resistant prostate cancer.3The results showed durable responses across the range of cancers examined. Suddenly, these findings really took immunotherapy out of a niche where it was considered only applicable to melanoma and other selected cancers to having activity in a malignancy like NSCLC, which an oncologist sees in clinical practice every day; indeed, no one had ever considered NSCLC as amenable to immunotherapy.3In addition, based on the signals that we have now seen with the ipilimumab and nivolumab combination,6the regimen has now been rolled out to trials in lung cancer, kidney cancer, upper GI cancers, and others. Indeed, now that we have something that is generating a strong signal, it’s time to really survey some of these other challenging malignancies, which may not have been studied in depth with this type of therapy. Another PD-1-targeting therapy, MK3475 (Merck), also appears, thus far, similar to nivolumab, with activity in melanoma and in lung cancer.7There are also a number of PD-L1 (ligand) blocking antibodies in development which are showing early signs of activity: MPDL3280A (Genentech) and MEDI-4736 (Medimmune).