Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment.
We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ+ non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express κ.CAR (κ.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 × 108 to 2 × 108 κ.CARTs/m2). No other lymphodepletion was used.
κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTs were observed.
κ.CART infusion is feasible and safe and can lead to complete clinical responses.
ClinicalTrials.gov NCT00881920.
National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.

Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell-specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes alpha2-6-linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition-based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

CD10 is a critical antigen for the distinction of follicle-center lymphoma from other B-cell lymphomas composed of small cells in fine-needle aspiration specimens, tissue core biopsies, and bone marrow. In addition, CD10 is expressed in a subset of diffuse large B-cell lymphomas (DLBCLs), where it may be an adverse prognostic indicator. We have previously demonstrated that CD10 expression detected by multiparameter flow cytometry (FC) with cluster analysis is highly sensitive and specific for follicle-center lymphoma in the differential diagnosis of small B-cell lymphomas. In this study, we assessed the utility of paraffin section immunohistochemistry (IHC) for CD10 compared with FC in a cohort of 50 DLBCLs. IHC for CD10 was technically successful in 47 of the 50 (94%) DLBCLs; 3 failed based on lack of internal CD10 reactivity. CD10 was expressed by FC in 20 of 47 DLBCLs (43%); CD10 was positive by IHC in 15 of these (75%). All 27 cases that were CD10(-) by FC were negative by IHC. The level of CD10 expression by FC in the 5 FC(+)/IHC(-) cases ranged from relatively dim to bright. Our results indicate 75% sensitivity and 100% specificity of CD10 expression by IHC compared with multiparameter FC with cluster analysis and a 6% technical failure rate.