A first-in-human phase I trial of NKG2D chimeric antigen receptor-T cells in AML/MDS and multiple myeloma.

Abstract

Background: Canonical CART cell constructs encode a single chain antibody variable fragment, costimulatory domain, and signaling domain of CD3 zeta. This restricts recognition to 1 tumor antigen and a limited set of cancers. This study employs a novel CAR fusing full-length human Natural Killer Group 2D (NKG2D) gene with the human CD3 zeta signaling domain. NKG2D CAR receives costimulation via naturally-expressed DAP10 and activates T cells directly to kill and secrete cytokines upon recognition of MIC-A, MIC-B, and UL-16 binding proteins. These NKG2D-ligands are up-regulated in many solid tumors and hematologic malignancies but absent or poorly expressed on healthy tissues. In multiple murine cancer models, NKG2D CART cells induced complete remissions, T-cell memory, and altered tumor microenvironment via cytokines. We demonstrated manufacture of autologous NKG2D CART cells in a GMP-environment from healthy adults and patients with AML and myeloma was feasible. Following isolation of mononuclear cells, T cells are activated with anti-CD3 mAb and IL-2, undergo 2 transductions with SFG retroviral vector containing NKG2D CAR construct, and expand in media containing IL-2. Validation studies yielded consistent viability, robust cell expansion, high vector-driven NKG2D expression on T cells, potent IFN-g production during tumor cell co-culture, viral copy number/cell < 5, and no replicationcompetent retrovirus in NKG2D CART (CM-CS1) cells. Methods: A phase 1 dose-escalation study to establish safety and feasibility of a single infusion of CM-CS1 T cells without lymphodepleting conditioning is currently enrolling subjects with AML/MDS-RAEB without standard therapy options or relapsed/refractory progressive multiple myeloma (ClinicalTrials.gov NCT02203825). Dose-escalation will proceed in 8 cohorts [1x10 6 to 3x10 9 CM-CS1 T cells] according to a 3+3 design followed by expansion cohorts at the MTDs in AML/MDS and myeloma.

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

“…CAR T-cell DNA was detected from one hour to one week after infusion in most patients. As expected, the investigators observed neither tumor response nor toxicity after anti-NKG2D CAR T-cell therapy [29].…”

NKG2D-based chimeric antigen receptor therapy induced remission in a relapsed/refractory acute myeloid leukemia patient

“…3,6 Single intravenous administration of low dose autologous CYAD-01 (maximum 3x10 7 flat dose), without prior chemotherapy, has been tested in a completed Phase I study (clinicaltrials.gov identifier 02203825) which evaluated 12 patients with relapsed/refractory AML (r/r AML), myelodysplastic syndrome (MDS), or multiple myeloma (MM). 11 The preliminary data obtained suggested encouraging signs of activity with one AML patient treated at the 3x10 7 CYAD-01 dose-level having hematologic improvement for three months post-CYAD-01 treatment. 11 Building on these initial results and preclinical data supporting multiple haematologica 2018; 103:e424 CASE REPORTS Figure 1.…”

“…11 The preliminary data obtained suggested encouraging signs of activity with one AML patient treated at the 3x10 7 CYAD-01 dose-level having hematologic improvement for three months post-CYAD-01 treatment. 11 Building on these initial results and preclinical data supporting multiple haematologica 2018; 103:e424 CASE REPORTS Figure 1. Relapsed AML patient treated with CYAD-01 CAR-T therapy.…”

Advances in Immunotherapy for Acute Myeloid Leukemia

“…Single dosing, however, resulted in no clinical leukemic responses future science group www.futuremedicine.com up to 28 days after infusion. Future studies investigating the efficacy of multiple CART-NKG2D infusions are planned [21].…”