CTLA4 Blockade with Ipilimumab May Be Effective After HSCT

Allogeneic hematopoietic stem-cell transplantation (HSCT) is often curative in patients with advanced hematologic cancers. However, more than 30% of patients relapse and have limited treatment options. Immune checkpoint inhibitory pathways, including CTLA4 and PD-1, likely play a role in promoting immune escape and relapse after allogeneic HSCT. In preclinical mouse studies, CTLA4 blockade enhanced the graft-versus-tumor effect, in which donor immune cells attack tumor cells, without promoting significant graft-versus-host-disease (GVHD), in which donor immune cells attack host tissue, suggesting the potential for treating patients with hematologic cancer who relapse after HSCT. Davids and colleagues evaluated the safety and efficacy of the anti-CTLA4 antibody ipilimumab in a phase I/Ib, open-label clinical trial of 28 patients with hematologic cancer previously treated with allogeneic HSCT. Six patients received low-dose ipilimumab with only a single occurrence of dose-limiting toxicity, and the remaining 22 patients were administered a higher dose. None of the patients receiving the lower dose responded to ipilimumab. Of the 22 higher-dose patients, 5 achieved a complete response, 2 exhibited a partial response, and 6 experienced stable disease with some reduction in tumor burden. All 4 patients with extramedullary acute myeloid leukemia and 1 of 2 patients with myelodysplastic syndrome achieved complete responses. Dose-limiting toxicities resulted in discontinuation of ipilimumab in 5 patients, 4 with GVHD, and 1 patient who died due to severe immune-related adverse events. Durable response lasting more than 1 year occurred in 4 patients. Exploratory analysis revealed an association between clinical response and increased infiltration of cytotoxic CD8⁺ T cells, and reduced T regulatory cell activation. Collectively, these findings indicate that CTLA4 blockade with ipilimumab is a feasible approach to treat patients with relapsed hematologic cancer after HSCT despite the occurrence of immune-mediated toxicity and GVHD. Ipilimumab may lead to durable responses in certain hematologic cancer subtypes, and warrants further clinical investigation in larger trials.

Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 2016;375:143–53.

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