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Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.

Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

Infliximab, a chimeric monoclonal antibody (mAb) against tumor necrosis factor (TNF)-alpha, has shown activity against steroid refractory acute graft-versus-host disease (aGVHD). We conducted a prospective trial of infliximab for the prophylaxis of aGVHD. Patients older than 20 years undergoing myeloablative allogeneic stem cell transplantation (SCT) for hematologic malignancies were eligible. GVHD prophylaxis consisted of infliximab given 1 day prior to conditioning and then on days 0, +7, +14, +28, and +42, together with standard cyclosporine (CSA) and methotrexate (MTX). Nineteen patients with a median age of 53 years were enrolled. All patients received peripheral blood allografts from matched sibling (n = 14) or unrelated donors (n = 5). Results were compared with a matched historic control group (n = 30) treated contemporaneously at our institution. The cumulative incidences of grades II-IV aGVHD in the infliximab and control groups were 36.8% and 36.6%, respectively (P = .77). Rates of chronic GVHD were 78% and 61%, respectively (P = .22). Significantly more bacterial and invasive fungal infections were observed in the infliximab group (P = .01 and P = .02, respectively). Kaplan-Meier estimates of 2-year overall survival (OS) and progression free survival (PFS) for patients receiving infliximab were 42% and 36%, respectively. The corresponding numbers for patients in the control group were 46% and 43%, respectively. The addition of infliximab to standard GVHD prophylaxis did not lower the risk of GVHD and was associated with an increased risk of bacterial and invasive fungal infections.

The in vivo mechanism of action of alemtuzumab (anti-CD52; Campath-1H) remains unclear. With rituximab, FCGR3A and FCGR2A high-affinity polymorphisms have been associated with clinical response in lymphoma but not in CLL, suggesting potential divergent mechanisms of action between these 2 diseases. Herein, we examined FCGR3A (V/V, n = 4; V/F, n = 10; F/F, n = 19) and FCGR2A (A/A, n = 5; H/A, n = 22; H/H, n = 6) polymorphisms in 36 patients with relapsed CLL who were treated with thrice-weekly alemtuzumab for 12 weeks to assess the potential influence these high-affinity FcgammaR receptor polymorphisms had on response to alemtuzumab. Response to alemtuzumab was similar regardless of FCGR3A polymorphism (V/V, 25%; V/F, 40%; F/F, 32%) or FCGR2A polymorphism (A/A, 40%; H/A, 32%; H/H, 33%). These findings indicate that FCGR3A and FCGR2A polymorphisms may not predict response to alemtuzumab in CLL. Future studies examining larger cohorts of alemtuzumab-treated patients with CLL will be required to definitively determine the predictive value of specific FCGR polymorphisms to treatment response.

In follicular lymphoma (FL), genomic polymorphisms corresponding to the expression of valine (V) or phenylalanine (F) at amino acid 158 of Fc gamma RIIIa alter the binding affinity of immunoglobulin G1 (IgG1) to the receptor and have been associated with varied responses to rituximab. We examined Fc gamma RIIIa polymorphisms of 30 CLL patients with the phenotypes V/V (n = 6), V/F (n = 12), and F/F (n = 12) treated with thrice-weekly rituximab (375 mg/m(2)) for 4 weeks to correlate polymorphism type with infusion toxicity and response. Infusion toxicity (grade 3 or greater or hypoxia/hypotension requiring transient cessation of therapy) was observed equally among the groups (V/V, 50%; V/F, 33%; F/F, 41.6%; P =.78). The response to rituximab was also similar among the different polymorphism phenotypes (V/V, 33%; V/F, 41.6%; F/F, 50%). These data suggest that Fc gamma RIIIa polymorphisms are not predictive of response in CLL and that, unlike the case with FL, mechanisms of tumor clearance other than antibody-dependent cellular cytotoxicity may be more important.

Acute and chronic graft-versus-host disease (GvHD) remain major obstacles to successful allogeneic hematopoietic stem cell transplantation, contributing substantially to morbidity and non-relapse mortality. Better understanding of the immunopathophysiology of GvHD has identified a number of targets for intervention. Among newly developed agents suitable for the prevention and treatment of GvHD, monoclonal antibodies hold much promise. Monoclonal antibodies currently available, such as infliximab and anti-interferon-gamma (anti-IFN-gamma), are capable of blocking of the action of initiating and effector cytokines. Antibodies directed against activated T cells, including daclizumab, visilizumab and ABX-CBL, may offer more specificity than the more broadly acting pan-T-cell-depleting agents. Finally, the clinical investigation of antibodies to adhesion molecules (such as LFA-1), or distal effector mechanisms (such as FasL) may offer another level of specificity. Many of these monoclonal antibodies have already undergone clinical testing. Campath-1H has been used for the prevention of acute GvHD with success. Daclizumab, infliximab, visilizumab, and ABX-CBL have shown promising activity in steroid-resistant acute GvHD in early clinical testing. This review summarizes current experience with monoclonal antibodies in the management of acute and chronic GvHD. Over the next decade, however, the challenge will be to define the relative place of these antibodies in the therapeutic armamentarium for GvHD and their impact on long-term survival.