Abrogation of CTLA-4 in patients produces side effects known as "immune-related adverse events" (IRAEs). IRAEs are auto-inflammatory and may represent a breaking of tolerance to self-antigens.[16,17] The most common IRAEs are rash, colitis, and hepatitis. Other types of inflammation -- hypophysitis, pancreatitis, and sarcoid -- are more rare. IRAEs appear to be associated with tumor regression in patients with renal cell cancer and metastatic melanoma,[12,17-19] and a similar phenomenon may be observed in patients with prostate cancer.[14] There also appears to be a correlation between IRAEs and prolonged time to relapse in patients with resected high-risk melanoma.[12,17-19] The kinetic onset of IRAEs is highly variable and is likely dependent both on peak dosing and area under the curve of the drug. Similarly, the timing of the onset of antitumor responses can be variable and may be prolonged for weeks after cessation of ipilimumab[20]
(J Weber, unpublished data, 2007).
If these immunomodulators and others like them -- CD40 agonistic antibody, anti-41-BB antibody, and programmed death (PD)-1 antibody, which are entering early-phase clinical testing -- are approved for cancer treatment, then understanding the kinetics of antitumor responses, their relationship to IRAEs, and how to manage and minimize IRAEs will take on great importance.
Ongoing and Completed Trials With Ipilimumab and Tremelimumab
Ipilimumab has been used as a monotherapy or in combination with other therapies including chemotherapy, vaccines, and cytokines. In an initial phase 1 trial,[21] 17 patients with malignant melanoma received a single intravenous dose of ipilimumab 3 mg/kg. The drug was well tolerated, and there was evidence of immunologic and antitumor activity. In another phase 1 trial, Hodi and colleagues[13] reported that a single dose of ipilimumab 3 mg/kg may have increased antitumor immunity and induced necrosis in biopsied tumors in patients with metastatic melanoma who were previously vaccinated. No serious adverse events were noted in the 7 patients who received ipilimumab in that trial.
Because of the known mechanism of action of ipilimumab and experience in murine models, an important goal has been its evaluation in combination with antitumor vaccination. Attia and colleagues[12] reported that ipilimumab (3 mg/kg every 3 weeks or a 3-mg/kg initial dose followed by 1 mg/kg every 3 weeks) plus a peptide vaccine resulted in 2 complete responses (CRs) and 5 partial responses (PRs) among 56 patients with previously treated and progressive stage IV melanoma. The CRs were ongoing at 30 and 31 months, and 3 of the PRs continued at 25, 26, and 34 months. The remaining 2 PRs lasted for 4 and 6 months.
A trial is ongoing with ipilimumab plus a multipeptide vaccine in the adjuvant setting,[20] which includes patients with resected stage IIIC/IV melanoma and no evidence of disease. After a median follow-up of 12 months, 6 of 25 (24%) treated patients had relapsed. Patients who relapsed were managed either surgically or with biochemotherapy, and all were alive at the time of the report. Subsequently, 4 patients have died at a median follow-up of more than 2 years, but 19 are still free of disease. Time to progression is associated with development of IRAEs (J Weber et al, unpublished data, 2007).
Ipilimumab has also been administered in combination with cytokines. Maker and colleagues[22] reported data from a trial of ipilimumab 0.1-3 mg/kg every 3 weeks with IL-2 in 36 patients with advanced melanoma. Three patients (8%) sustained a CR and 5 (14%) had PRs, yielding an overall objective RR of 22%. Responses occurred in 1 of each of 3 patients treated with ipilimumab at 0.3, 1, and 2 mg/kg, and in 5 of 24 patients treated at 3 mg/kg. Six of the 8 responders had ongoing responses at follow-up periods of between 11 and 19 months.
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