Phase I Study of a Neutralizing Monoclonal Anti-CTLA4 Antibody (MDX-010) in Patients with Relapse of Malignancy after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Bashey Asad , Medina Bridget , Corringham Sue , Pasek Mildred , Carrier Ewa , Streicher Howard , Lowy Israel , Mason James , Soiffer Robert J. , Ball Edward D. 
Published: October 2019

Abstract
Relapse of malignancy is an important cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HCT). Malignant cells may evade adoptive immunotherapy post allo-HCT by mechanisms including lack of co-stimulation and direct or indirect inhibition of T-cell activation. CTLA-4 is a homologue of CD28 which functions as a negative regulator of T-cell activation. Blockade of CTLA-4 using neutralizing antibodies has demonstrated potent anti-cancer effects in animal models. Phase I/II clinical trials of CTLA-4 blockade in advanced tumors have demonstrated durable tumor regressions as well as immune breakthrough phenomena. 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 phase I dose-escalation trial of a neutralizing human monoclonal anti-CTLA-4 antibody (MDX-010) in patients with relapse of malignancy following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, > 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 MDX-010 over 90 min. DLI at a dose of 5 x 10e6 CD3 cells/kg was allowed 8 weeks following MDX-010 if no GVHD occurred and progression of malignancy (PD) was present. Twelve patients (8M, 4F; median age 45; CML=2, CLL=1, AML=1, Hodgkins disease [HD] =3 Myeloma [MM]=3, Renal Ca =1, Breast Ca=1) have been treated (4 at dose-level 0.1 mg/kg, 3 at 0.33 mg/kg, 4 at 0.66 mg/kg and 1 at 1.0 mg/kg). Median time between BMT and MDX-010 infusion was 10.3 months (4–79). Four patients received additional DLI. MDX-010 was well tolerated in this setting. No infusional toxicity was seen. No patient has developed clinically significant GVHD following MDX-010 alone. 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 MDX-010, but also 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, dose 0.1mg/kg, RhF+ pre-MDX-010); grade 1 chemical hyperthyroidism with thyroid-stimulating antibody 6 weeks post MDX-010 (CLL, 0.66 mg/kg). Three patients have demonstrated possible anti-cancer responses following MDX-010 alone (partial remission of AML refractory to prior therapies at 0.1 mg/kg dose, molecular remission of CML maintained off imatinib at 0.1 mg/kg dose, stabilization of previously progressive MM (0.33mg/kg) and one patient developed regression of malignancy (HD) following additional DLI (0.66mg/kg). With a median follow-up of 195d (lead f/u 570d) from MDX-010 infusion three patients have died (PD), 8 are alive and 1 is in CR and 1 is in PR. Pharmacokinetic and correlative science data will be presented. This study shows tolerability with possible anti-tumor effects at the dose levels