Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

Abstract

Immune-based therapeutic strategies have drastically changed the landscape of hematological disorders, as they have introduced the concept of boosting immune responses against tumor cells. Anti-CD20 monoclonal antibodies have been the first form of immunotherapy successfully applied in the treatment of CLL, in the context of chemoimmunotherapy regimens. Since then, several immunotherapeutic approaches have been studied in CLL settings, with the aim of exploiting or eliciting anti-tumor immune responses against leukemia cells. Unfortunately, despite initial promising data, results from pilot clinical studies have not shown optimal results in terms of disease control - especially when immunotherapy was used individually - largely due to CLL-related immune dysfunctions hampering the achievement of effective anti-tumor responses. The growing understanding of the complex interactions between immune cells and the tumor cells has paved the way for the development of new combined approaches that rely on the synergism between novel agents and immunotherapy. In this review, we provide an overview of the most successful and promising immunotherapeutic modalities in CLL, including both antibody-based therapy (i.e. monoclonal antibodies, bispecific antibodies, bi- or tri- specific killer engagers) and adoptive cellular therapy (i.e. CAR T cells and NK cells). We also provide examples of successful new combination strategies and some insights on future perspectives.

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep?

“…All of these approaches aim to improve the intrinsic functionality of CAR T cells by acting on the patients’ immune system or, more specifically, on a wide range of T‐cell properties, and are paralleled by extensive studies—going beyond the scope of this article—aimed at identifying strategies to prevent or treat the onset of Ag‐negative relapses, such as the production of CAR T cells targeting more than 1 Ag (eg, CD19 and CD20, CD19 and CD22) through the use of dual or tandem CARs (reviewed in ref. 146 ).…”

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

“…Currently, several novel antibody-based and adoptive immunotherapies have shown promising efficacy as a monotherapy or in combination with targeted therapies in heavily pre-treated RR-CLL. 98 Monoclonal Antibodies (mAbs) CD20 has been considered a safe and effective target for B-cell malignancies including CLL. 99 Rituximab and obinutuzumab have been widely used for the treatment of CLL in combination with chemotherapies and targeted therapies.…”

Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions

“…56 This approach is bespoke for an individual patient and could, thus, have broader applicability than CAR-T therapy. No bispecific antibodies have been approved for CLL as yet, but since their therapeutic efficacy in B-cell lymphomas has become increasingly evident, 57 more CLL trials are in development. 44 Blinatumomab, a Bi-specific T-cell engagers (BiTEs) monoclonal antibody targeting CD19, has been shown to be effective in a single case of refractory Richter syndrome as a bridge to HSCT, 58 In addition, there are novel immunological strategies currently in development for other hematological malignancies, which could also be applicable to high-risk CLL.…”

“…This approach is bespoke for an individual patient and could, thus, have broader applicability than CAR‐T therapy. No bispecific antibodies have been approved for CLL as yet, but since their therapeutic efficacy in B‐cell lymphomas has become increasingly evident, 57 more CLL trials are in development 44 …”