Immunotherapy for B-Cell Lymphoma: Current Status and Prospective Advances

Abstract

Therapy for non-Hodgkin’s lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radio labeled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect.

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…Four major mechanisms have been proposed for the action of rituximab: antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, complement-dependent cytotoxicity (CDC), direct induction of apoptosis, and "vaccination effect" resulting from cross-priming. These mechanisms have been demonstrated in vitro and in mouse models, and clinical observations support their activity in patients [37].As a single agent or in combination with chemotherapy, rituximab was able to improve the overall response rate (ORR), the duration of response and OS in several lymphoma subgroups [37]. Findings from one large trial showed an improvement in OS in patients with previously untreated CLL given fludarabine, cyclophosphamide, and rituximab compared with those given chemotherapy alone [16].…”

“…Among them, one of the most promising candidates is the fully human type I Ofatunumab. The monotherapy with this mAb seems to be ineffective in rituximab-refractory FL; however, studies of ofatumumab combined with CHOP chemotherapy in patients with FL are ongoing [37]. The mAb appears to be more effective in CLL than in FL, as demonstrated by the FDA approval and conditional approval in Europe for the treatment of refractory CLL [16].…”

“…A well-defined example is the FcR polymorphism FcRIIIa-V158F, which is associated with impaired ADCC in FL, even if it failed to predict the response to rituximab in CLL [19,37,42]. Host-related resistance may be mediated also by exhaustion of complement components or effector cells [37].To overcome these limitations and the onset of rituximab resistance, many combination therapies have been proposed to modulate intracellular signal transduction, to inhibit proliferation, and to induce apoptosis. For example, combining rituximab with inhibitors of specific pathways involved in CD20 down-modulation, such as Temsirolimus, or with antiproliferative agents able to sensitize lymphoma cells to rituximab, like Bortezomib, or with immunostimulatory molecules, which can boost ADCC, as GM-CSF or IL-2 [19,37].…”

“…Specific FcR or complement component polymorphisms correlate with reduced efficacy of rituximab-based immunotherapy. A well-defined example is the FcR polymorphism FcRIIIa-V158F, which is associated with impaired ADCC in FL, even if it failed to predict the response to rituximab in CLL [19,37,42]. Host-related resistance may be mediated also by exhaustion of complement components or effector cells [37].…”

“…Host-related resistance may be mediated also by exhaustion of complement components or effector cells [37].…”