Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes

Abstract

IntroductionThe potential of transfused T lymphocytes as potent immune effectors is well documented. Such a potential was initially discovered in the allogeneic context from the clinical outcome of patients who received bone marrow transplants, where unselected donor T lymphocytes transfused together with hematopoietic precursors were found to be responsible for the graft-versus-host reaction as well as the graft-versus-leukemia effect. 1 Manipulation of this allogeneic effect through infusion of donor lymphocytes was found to induce durable remission in patients with chronic myelogenous leukemia and in patients with acute myelogenous leukemia relapse following allogeneic bone marrow transplantation. 2 Even more impressive was the restoration of viral immunity in immunodeficient patients after the transfer of cytomegalovirus (CMV) 3,4 -or Epstein-Barr virus (EBV) 5-8 -specific T lymphocytes. Unfortunately, attempts to harness the immune potential of T cells against nonviral malignancies apart from in the context of allogeneic transplantation have been largely unsuccessful, with only a few recent exceptions. [9][10][11][12] In contrast, with the limited positive experience using adoptive transfer of lymphocytes, the clinical benefit of antibody treatment is now well documented. Adoptive immunotherapy with mAbs targeting molecules such as CD20 or Her2/Neu recently has shown its capability to produce a clear clinical benefit, 13 and it is thanks to these studies that the clinical pertinence of several antigens as immune therapeutic targets has been established. Such passively acquired antibodies can trigger apoptosis of tumor cells and activate complement-mediated (CDC) or antibody-dependent cellular cytotoxicity (ADCC) in treated patients. For rituximab, an anti-CD20 humanized mAb, several clinical observations suggested that ADCC mediated by Fc␥RIIIa (CD16)-bearing cells is a key mechanism of action. The gene coding Fc␥RIIIa displays a functional allelic dimorphism generating allotypes with either a phenylalanine (F) or a valine (V) residue at amino acid position 158. In vitro, natural killer (NK) cells from donors homozygous for Fc␥RIIIa-158V (VV) bound more human IgG1 and IgG3 than did NK cells from donors homozygous for Fc␥RIIIa-158F (FF). 14 In vivo, Cartron et al recently have shown that the genotype homozygous for Fc␥RIIIa-158V (VV) is associated with a higher clinical response to rituximab in the treatment of follicular non-Hodgkin lymphomas (NHLs). 15 For the anti-Her2/ Neu humanized mAb trastuzumab, which is widely used to treat Her2/neuϩ breast cancer, mechanisms thought to be responsible for the antitumor activity include down-modulation of the receptor, an antiangiogenic effect, complement-dependent cytotoxicity, a direct apoptotic effect, and ADCC. In fact, in a recent pilot study to elucidate the mechanism by which trastuzumab mediates its antitumor effect, Gennari et al observed that patients with complete or partial remission had a higher in situ leukocyte infiltration and a higher capacity to med...

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

“…The former two cellular outputs directly accounted for tumoricidal activity, and the latter two cellular activities were able to contribute to the durable antitumor effect observed in vivo. To our knowledge, no previous reports describing a similar concept have included in vivo experimental observations (18,34). Therefore, after confirming that rituximab-induced CDC was not present in NOG mouse serum (Fig.…”

“…In addition, these effector cells could be used in combination with almost all currently available ADCC-mediating anticancer mAbs. A similar concept was proposed by Cl emenceau and colleagues (18), who validated in vitro the applicability of CD3 þ T cells gene-modified to express a FcgRIIIa-158(V/V)-FceRIg chimeric receptor for ADCC against CD20 þ lymphoma cells in combination with rituximab, although the in vivo validation has not been described yet. Regarding the risk of leukemogenesis of infused gene-modified T cells, results from clinical trials using retroviral or lentiviral vector gene-modified T cells for adoptive cell therapy have proved the long-term safety of this approach (19,20).…”

T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing

“…Indeed, in side-to-side comparisons with a chimeric receptor containing the more common F158 variant, the CD16V-BB-z had a significantly higher capacity to bind human Ig Fc, and induced more vigorous proliferation and cytotoxicity, evoking results of recent studies addressing the role of affinity in chimeric antigen receptor function (42,43). Clemenceau and colleagues described a receptor containing the CD16 158V combined with the transmembrane and cytoplasmic domains of FceRIg, and found that selected Tcell clones expressing this receptor could lyse Epstein-Barr virus derived B-lymphoblastoid cells in the presence of rituximab (40). Current "second generation" chimeric receptors combine a stimulatory molecule with a costimulatory one to augment signaling and prevent activation-induced apoptosis.…”

Ligand Binding but Undetected Functional Response of FcR after Their Capture by T Cells via Trogocytosis

“…The 1H11-34 cell line is a T cell hybridoma specific for HEL [107][108][109][110][111][112][113][114][115][116] presented by I-E d (17). Activated human T cells transduced with the retroviral vector encoding human Fc␥RIIIA-FcR␥ chimera were generated, as described previously (18).…”