Page 28 - 2022_01-Haematologica-web

D. Qualls and G. Salles
While some clinical trials were conducted in specific pop- ulations of patients, such as those with disease refractory to rituximab or to rituximab and alkylating agents (“dou- ble refractory”), there are few randomized clinical trials to guide our choice of a given therapy at a precise time. This is in part due to the broad array of options available after diagnosis, with a variety of mechanisms of action (Figure 1), and to the heterogeneity of patients entering clinical trials evaluating new agents in the relapsed/refractory set- ting. However, not all available drugs or regimens have similar clinical efficacy - both in terms of response rate, and more importantly, response duration.
A third key element is the patients’ quality of life, including short-term treatment-related side effects and convenience of therapeutic administration, as well as long-term and cumulative toxicities, which may result in cardiac, hematopoietic, infectious, or neurological comor- bidities, or increase the risk of potentially fatal secondary malignancies.7 Attractive oral therapies have emerged, although they have their own toxicity profiles, and are often administered for indefinite periods, presenting unique challenges. Overall, these different elements should be discussed with every patient, with transparen- cy regarding the benefits and risks of each strategy, keep-
Figure 1. Mechanisms of action and opportunities for synergy in follicular lymphoma-directed therapies. From top left, clockwise: Autologous chimeric antigen receptor T cells are engineered to target the CD19 epitope on follicular lymphoma (FL) cells, with co-stimulatory domains activating T-cell anti-tumor responses. Bispecific antibodies bind both CD20 on the lymphoma cells and CD3 on the surface of cytotoxic T cells, activating anti-tumor cytotoxicity. Tazemetostat inhibits EZH2- mediated suppression of differentiation genes in FL cells, and inhibits suppression of MHC expression, allowing for greater immune recognition of lymphoma cells. PI3K inhibitors block key molecular signal pathways for the growth and survival of lymphoma cells, and also inhibit T regulatory cell function, which may facilitate immune activation against FL cells. Lenalidomide functions via cereblon-mediated ubiquitination and degradation of transcriptional factors, which is directly cytotoxic to lymphoma cells, and potentiates the immune synapse, improving T-cell- and NK-cell-mediated recognition and killing of lymphoma cells. Lenalidomide is synergistic with monoclonal antibodies (rituximab and tafasitamab), which together promote antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotox- icity. Antibody-drug conjugates bind to the cell expressing the target antigen, are internalized, and deliver their cytotoxic payload directly in the cytoplasm. CD47 on FL interacts with SIRPα on macrophages to inhibit phagocytosis of cancer cells. Anti-CD47 antibodies block this checkpoint interaction, promoting macrophage phagocytosis. CAR: chimeric antibody receptor; TCR: T-cell receptor; IgG: immunoglobulin G; MHC: major histocompatibility complex; BCR: B-cell receptor; Ag: antigen; PI3K: phosphoinositide 3-kinase; TILs: tumor-inflitrating lymphocytes; NK: natural killer.
20
haematologica | 2022; 107(1)