Current Immunotherapy Approaches in Non-Hodgkin Lymphomas

Abstract

Non-Hodgkin lymphomas (NHLs) are lymphoid malignancies of B- or T-cell origin. Despite great advances in treatment options and significant improvement of survival parameters, a large part of NHL patients either present with a chemotherapy-refractory disease or experience lymphoma relapse. Chemotherapy-based salvage therapy of relapsed/refractory NHL is, however, capable of re-inducing long-term remissions only in a minority of patients. Immunotherapy-based approaches, including bispecific antibodies, immune checkpoint inhibitors and genetically engineered T-cells carrying chimeric antigen receptors, single-agent or in combination with therapeutic monoclonal antibodies, immunomodulatory agents, chemotherapy or targeted agents demonstrated unprecedented clinical activity in heavily-pretreated patients with NHL, including chemotherapy-refractory cases with complex karyotype changes and other adverse prognostic factors. In this review, we recapitulate currently used immunotherapy modalities in NHL and discuss future perspectives of combinatorial immunotherapy strategies, including patient-tailored approaches.

The Role of Bispecific Antibodies in Non-Hodgkin’s Lymphoma: From Structure to Prospective Clinical Use

“…To overcome these chemical and pharmacological issues, a variety of approaches have been tested, such as quadroma technology (now mostly outdated thanks to newer technologies), knobs-into-holes, common heavy-chain and common light-chain strategies, and CrossMab technology. Finally, genetic modifications and proteomic implementations have been introduced to optimize their production and efficacy [20][21][22][23][24][25][26][27][28][29][30][31].…”

“…They are usually small, which lends them a greater tissue penetration but a shorter half-life (although it can be increased, at the cost of a higher toxicity, for example by binding these molecules to albumin [17]). In addition, they do not suffer from the toxicities due to the Fc region [20,29,30].…”

“…IgG-like bsAbs, as stated above, are characterized by the presence of the Fc region which determines many of their unique properties. Indeed, bsAbs with a functional Fc region are considered trifunctional Abs, or Triomabs, since they can bind the C1q to activate complement and the Fc-γ receptors on NK cells, macrophages, or dendritic cells to elicit Ab-dependent cytotoxicity and phagocytosis [17,30]. These functions can also be enhanced through careful engineering of the molecule: For instance, introducing a point mutation in the CH 2 domain enhances binding to the Fc-γ receptor IIb and makes the Ab more effective [39].…”

Immunotherapies in Non-Hodgkin’s Lymphoma

“…While conventional mAbs can eliminate target cells via several mechanisms including antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC), they do not exploit the powerful cytotoxic machinery of T -cells that eradicates tumor cells by the formation of an immune synapse and the release of granzyme B/perforin vesicles. These types of antibodies represent a fast- growing area of immunotherapy, with over 100 different bispecific antibody (bsAbs) formats [ 8 , 9 , 10 ]. The majority of bsAbs in advanced stage clinical development for lymphoma are those containing the Fc region, that prolongs its half-life and it is usually re-engineered to reduce excessive cytokine release from recruited T cells and to minimize off-target toxicity such as T-cell mediated hepatotoxicity.…”

“…Finally, we would like to introduce the ICP inhibitors that serve to maintain self- tolerance and prevent autoimmunity and that further expanded the list of tumor immune-escape mechanisms [ 10 , 35 , 36 ]. These molecules are present on the cell surface of T cells and antigen-presenting cells controlling the efficacy of the formed immune synapse and therefore modulate the intensity and the duration of TCR-dependent T-cell responses [ 37 ].…”