Abstract
Follicular lymphoma (FL) is the most frequent indolent lymphoma in the Western world and is characterized in almost all cases by the t(14;18) translocation that results in overexpression of BCL2, an anti-apoptotic protein. The entity includes a spectrum of subentities that differ from an indolent to a very aggressive growth pattern. As a consequence, treatment can include watch & wait up to intensive chemotherapy including allogeneic stem cell transplantation. The immune cell microenvironment has been recognized as a major driver of outcome of FL patients and gene expression profiling has identified a clinically relevant gene expression signature that classifies an immune response to the lymphoma cells. It is known for some time that the immune cell composition of the lymphoma microenvironment is important because high numbers of tissue-infiltrating macrophages correlate with poor outcome in patients receiving chemotherapy but not in patients receiving the combination of chemotherapy and CD20-specific monoclonal antibody rituximab. In addition, TCR signaling of tumor-infiltrating lymphocytes is dysfunctional leading to an impaired capacity to form an intact immunologic synapse. Approaches restoring local T cell function, e.g., by usage of checkpoint inhibitors has demonstrated clinical activity (ORR 40%) and can achieve long-term remissions. Ongoing trials with re-programmed autologous CART cells achieve response rates in approximately 50% of FL patients with relapsed and even refractory disease. Responses lasting for more than 6 months might be durable, indicative for a successful restoration of a functional immune system. In summary, FL is a malignant disease where the control by the immune system ultimately decides about progression and transformation rate. The advent of monoclonal antibodies has changed the way we treat FL and new approaches restoring the individual immune control will hopefully improve results further.
Highlights
The aim of this review is to present the current therapeutic landscape of follicular lymphoma (FL) and to discuss early results of immunotherapies, e.g., checkpoint inhibitors and CAR T-cell therapies in the context of the immune system
Follicular lymphoma represents in the most instances an indolent disease and tolerance of the malignant clone by the immune system is very likely
It is quite likely that immunotherapy with checkpoint blockade inhibitors may not find a place in the early course of the disease
Summary
The aim of this review is to present the current therapeutic landscape of follicular lymphoma (FL) and to discuss early results of immunotherapies, e.g., checkpoint inhibitors and CAR T-cell therapies in the context of the immune system. E.g., monoclonal antibodies against CD20, in combination with a chemotherapy backbone is currently the standard of care for patients with advanced-stage FL in need of treatment [10,11,12,13]. Whether long-term control of FL like in some patients treated with rituximab monotherapy seen in SAKK 35/98 trial [26] is achievable with antibody-based ITs has to be seen in future. HIGH DOSE CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS OR ALLOGENIC STEM CELL TRANSPLANTATION Transplant concepts found their place in the pre-rituximab era, when relapses were more frequent and swift than after the introduction of the CD20 antibody.
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