Phase I Study of Ipilimumab (Neutralizing Monoclonal Anti-CTLA4 Antibody) To Treat Relapse of Malignancy after Allogeneic Hematopoietic Stem Cell Transplantation: Evidence of Tumor Regression without Induction of GVHD.
Authors: Bashey Asad , Medina Bridget , Corringham Sue , Pasek Mildred , Carrier Ewa , Streicher Howard , Lowy Israel , Mason James R. , Soiffer Robert J. , Ball Edward D. 
Published: April 2020

Abstract
Failure of adoptive cellular immunotherapy is an important cause of relapse of malignancy (RM) and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is a negative regulator of activated T-cells. Therapeutic blockade of CTLA-4 has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. Although CTLA-4 blockade may augment graft-versus-malignancy following allo-HCT, GVHD and other immune complications may also be increased. We report the results of a completed phase I dose-escalation trial of a neutralizing human monoclonal anti-CTLA-4 antibody (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, &gt; 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for ≥ 6 weeks. Patients received a single dose of ipilimumab over 90 min. (Donor lymphocyte infusion (DLI) at a dose of 5 x 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and malignancy was present. Seventeen patients (13M, 4F; median age 42 (21–64); Hodgkin’s disease [HD] =7 Myeloma [MM]=3, CML=2, CLL=1, AML=1, NHL=1, Renal Ca =1, Breast Ca=1; 14 related donors, 3 unrelated; 5 myeloablative, 12 RICT) were treated at three centers (4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 3 at 3.0 mg/kg [DL5]). Six patients had failed prior DLI. Median time between BMT and ipilimumab was 374 d (125–2368). Seven patients received additional DLI. Ipilimumab was well tolerated in this setting. No DLT was seen at levels up to DL5. No infusional toxicity was seen. No patient developed clinically significant GVHD within 90 days following ipilimumab. One patient developed grade II acute GVHD of the skin 12 weeks following DLI. Two possible immune breakthrough events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, but also 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1, RhF+ pre- ipilimumab); grade 1 chemical hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Two patients developed objective evidence of disease response after ipilimumab alone: regression of refractory lymphadenopathy in a patient with mantle cell NHL lasting 3m [DL4]; CR in a patient with HD ongoing at 2m [DL5].Both patients had failed prior DLI. Two additional patients demonstrated possible anti-cancer effects (reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 2.5 yrs despite stopping imatinib, DL1). PK data will be presented. This study shows that clinically active doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD. Organ specific immune breakthrough events can be seen as in non-allo-HCT patients.