Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy

Abstract

T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19 polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19 B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.

PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts

“…21 in published clinical trials. [1][2][3][4][5][6][7][8][9][10][11][12][13]30,[37][38][39][40][41][42][43][44] By administering diminishing doses of CAR19 T cell products with similar phenotype, including CD4:CD8 ratios, we found 4-1BB co-stimulation led to greater potency and control of repeat doses of B-ALL. These results are most likely a product of 4-1BB co-stimulation promoting longer CAR19 T cell persistence than CD28, a finding consistent with other pre-clinical studies [45][46][47] and clinical trials.…”

“…These results are most likely a product of 4-1BB co-stimulation promoting longer CAR19 T cell persistence than CD28, a finding consistent with other pre-clinical studies [45][46][47] and clinical trials. [2][3][4][5][6][7][8][9][10][11][12][13]37,40,44 Regardless of co-stimulatory domain, our final piggy-Bac-generated CAR19 T cell products all displayed a predominantly differentiated phenotype with elevated immuno-inhibitory markers. This may result from ex vivo expansion via repeated CAR stimulation.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] CARs are synthetic proteins that consist of a monoclonal antibody (mAb)derived single-chain variable fragment (scFv) that confers specificity, a spacer that projects the scFv from the cell surface, a transmembrane domain, and intracellular T cell-activating components usually comprising a CD28 or 4-1BB co-stimulatory domain, in addition to CD3z. 14 The majority of CAR19 T cell products used in trials to date have been produced using g-retroviral and lentiviral vectors to deliver the CAR transgene.…”

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

“…As in the first group, acute toxicities generally resolved within 3 weeks after cell infusion. In a long-term follow up study of these patients, duration of 4 of the 5 CRs ranged from 38þ to 56þ months [39]. More recently, the NCI, with research support from Kite Pharma, reported similar results with anti-CD19 CAR T cell therapy and low-dose conditioning like that used in the ZUMA-1 trial (300 or 500 mg/m 2 of cyclophosphamide and 30 mg/m 2 of fludarabine, each given daily on days À5, À4, and À3) in 22 patients with aggressive B cell lymphomas (19 with DBLCL, 2 with TFL, 1 with mantle cell lymphoma) [32].…”

Cellular Immunotherapy in B-Cell Malignancy

“…Intravenous substitution of immunoglobulin can help to reduce this risk. While sustained B-cell aplasia has been primarily reported in pediatric B-ALL patients [42,43], 2 studies in adult B-NHL patients have demonstrated that recovery of humoral immunity is possible following anti-CD19 CAR T-cell therapy even in the setting of ongoing CR [44,45].…”