Targeting the tumor microenvironment in chronic lymphocytic leukemia

The tumor microenvironment (TME) plays an essential role in the development, growth, and survival of the malignant B-cell clone in chronic lymphocytic leukemia (CLL). Within the proliferation niches of lymph nodes, bone marrow, and secondary lymphoid organs, a variety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, provide crucial survival signals, along with CLL-cellinduced suppression of antitumor immune responses. The B-cell receptor pathway plays a pivotal role in mediating the interaction between CLL cells and the TME. However, an increasing number of additional components of the multifactorial TME are being discovered. Although the majority of therapeutic strategies employed in CLL hitherto have focused on targeting the leukemic cells, emerging evidence implies that modulation of microenvironmental cells and CLL-TME interactions by novel therapeutic agents significantly affect their clinical efficacy. Thus, improving our understanding of CLL-TME interactions and how they are affected by current therapeutic agents may improve and guide treatment strategies. Identification of novel TME interactions may also pave the road for the development of novel therapeutic strategies targeting the TME. In this review, we summarize current evidence on the effects of therapeutic agents on cells and interactions within the TME. With a growing demand for improved and personalized treatment options in CLL, this review aims at inspiring future exploration of smart drug combination strategies, translational studies, and novel therapeutic targets in clinical trials

The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T-cells

CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B-cells and have been implicated in the pathogenesis of follicular lymphoma. To further define the role of these cells in follicular lymphoma, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next generation sequencing to analyze the T-cell receptor repertoire in follicular lymphoma lymph nodes. Multiparameter analysis of lymph nodes showed that the proportion of T-follicular helper cells in normal and neoplastic follicles is the same and that the previously reported increase in T-follicular helper cell numbers in follicular lymphoma is thus due to an increase in the number and not content of follicles. As in normal germinal centers, T-follicular helper cells were shown to have a close spatial correlation with proliferating B-cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of T-follicular helper cells in follicular lymphoma correlate with the rate of B-cell proliferation and T-follicular helper cells co-localized to Activation Induced Cytidine Deaminase expressing proliferating B-cells. T-cell receptor repertoire analysis of follicular lymphoma lymph nodes revealed that follicular areas are significantly more clonal when compared to the rest of the lymph node. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that T-follicular helper cells may play a role in driving B-cell proliferation and genomic evolution in follicular lymphoma. Our results also suggest that targeting this interaction would be an attractive therapeutic option

Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6-deficient process

Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5(+)CD19(+) cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet(+) T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center–like reaction that might reflect the cell of origin of this leukemia

Gene-edited healthy donor CAR T cells show superior anti-tumour activity compared to CAR T cells derived from patients with lymphoma in an in vivo model of high-grade lymphoma

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A Retrospective Cohort Study of Treatment Outcomes of Adult Patients With Relapsed or Refractory Follicular Lymphoma (ReCORD-FL)

This study (ReCORD-FL) sought to construct a historical control cohort to augment single-arm trials in relapsed/refractory follicular lymphoma (r/r FL). A retrospective study in 10 centers across North America and Europe was conducted. Adults with grade 1–3A FL were required to be r/r after ≥2 therapy lines including an anti-CD20 and an alkylator. After first becoming r/r, patients were required to initiate ≥1 additional therapy line, which defined the study index date. Endpoints were observed from start of each therapy line (including index line) until death, last follow-up, or December 31, 2020. Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment or death (TNT-D), event-free survival (EFS), and overall survival (OS). One hundred eighty-seven patients were identified. Most patients’ (80.2%) index therapy occurred in third line (3L) (range, 3L–6L). Median follow-up from FL diagnosis was 9 years (range, 1–21 years). CR and ORR to the index therapy were 39.0% and 70.6%, respectively. Median (95% confidence interval) EFS from index was 14.6 (11.0-18.0) months; median OS from index was 10.6 years. Outcomes worsened across successive treatment lines and for patients who were double refractory (r/r to both an anti-CD20 monoclonal antibody and an alkylator) or POD24 (progressed ≤24 months after front-line anti-CD20) at index. Findings demonstrate the unmet need of FL patients with multiply relapsed, double refractory, or POD24 disease. Based on robustness of the historical data collected and comparability with a previous study (SCHOLAR-5), ReCORD-FL presents a valuable source of control data for comparative studies in r/r FL