REPLY: Immunosuppression Does Not Reduce Antitumor Efficacy

We thank Dr. Cao for his comments on our paper (1) and for asking a critical question: Does the use of systemic immunosuppression reduce the antitumor efficacy of immune checkpoint inhibitors? There are no data on whether immunosuppression for myocarditis from immune checkpoint inhibitors reduces the antitumor efficacy of these agents, but there are significant data when all immune-related adverse events (irAEs) are combined. For example, in a study of almost 300 patients with metastatic melanoma treated with an immune checkpoint inhibitor (ipilimumab, an anti-CTLA4 antibody), 85% developed an irAE; of these, 35% were treated with corticosteroids, with one third of these steroid recipients requiring further therapy with infliximab (2). Patients receiving immunosuppression had an overall median and 2-year survival similar to those who did not receive immunosuppression.

The use of immunosuppressive therapy to manage irAEs also does not seem to affect the cancer response to checkpoint inhibition with anti-programmed cell death receptor 1 antibodies (3). In a pooled analysis of 576 patients with melanoma, Weber et al. reported that 24% required immunosuppression for an irAE, and there was no difference in the objective response rate between those who received immunosuppressive treatment and those who did not (29.8% vs. 31.8%). An additional question is whether the dose of immunosuppression used may affect the antitumor response of immune checkpoint inhibitors. In our study (1), we found that higher doses of steroids for the treatment of myocarditis was associated with a lower rate of adverse cardiac events. Specifically, we found that those treated with a methylprednisolone-equivalent dose of 2.06 mg/kg had a lower rate of major adverse cardiac events than those treated with 0.8 mg/kg. In the study by Horvat et al. (2), the average steroid dose (in Solu-Medrol-equivalent) was 0.8 mg/kg, and there are no data on whether higher doses of steroids affected tumor response in that cohort.

In addition, based on our findings (1) of a beneficial effect on myocarditis outcomes with a higher dose and the pathological findings in which features were similar to cardiac transplant rejection, we have adopted an initial treatment strategy of 1,000 mg of Solu-Medrol (~15 mg/kg) with a rapid taper based on clinical and biomarker response (4). Further research is needed to test whether this high dose of steroids affects tumor efficacy or improves myocarditis outcomes (5) and, additionally, consider the risk of opportunistic infections among patients on prolonged, especially high-dose, immune suppression.