Preventing follicular lymphoma progression and transformation through precision therapy

ABSTRACT
Follicular lymphomas (FL) are germinal center (GC) B-cell derived, slow-growing tumors. Although initially
indolent, FLs are essentially incurable with many cases undergoing progression and a relapsing course during
which they become increasingly resistant to therapy. Additionally, as many as 45% of cases undergo histologic
transformation to an aggressive form of B-cell lymphoma, that is generally refractory to chemo-immunotherapy.
Hence there remains a critical unmet need to understand how low-grade FLs survive and are maintained, and
to develop rational therapeutic regimens able to prevent disease progression and transformation and eradicate
these tumors. The genetic hallmark of FLs include BCL2 translocations and somatic mutations of epigenetic
modifier genes such as EZH2. Histologically, FLs typically feature a rich microenvironment, most notably
featuring extensive follicular dendritic cell (FDC) networks with dendrites making extensive contact with
lymphoma cells. In recent work we showed that the main effect of EZH2 gain-of-function mutations in GC B-cells
is to enable them to become less dependent of T-cell help and strengthen their immune synapse formation with
FDCs, which induces aberrant proliferation and survival of GC centrocytes and hence formation of FLs and their
unique lymphoma-permissive immune niche. It is notable that even though GC B-cells are highly T-cell
dependent, FLs are generally resistant to T-cell augmentation therapies such as checkpoint inhibitors. EZH2
mutant GC B-cells do not require T-cell help and are unable to form stable interactions with T-cells that might
otherwise suppress these tumors (which might explain checkpoint inhibitors failure). However, we find that EZH2
inhibitors can recruit CD4 and CD8 cells back into these lymphomas, which we propose may represent the major
anti-tumor mechanism of this now FDA-approved treatment in FLs. Moreover we have shown that EZH2
inhibitors reduce apoptotic thresholds in primary human EZH2 mutant lymphoma cells and are highly synergistic
with BH3 mimetics in vivo and are implementing a clinical trial combining Tazemetostat and Venetoclax for FL
and DLBCL patients. Based on these considerations and other preliminary data we hypothesize that EZH2
mutant FLs are dependent on signals received from FDCs, most notably BAFF receptor. We propose that
therapeutic targeting of the FDC-FL B-cell immune synapse will yield a lethal blow to FLs, especially when
combined with EZH2 inhibitors to restore T-cell anti-lymphoma immunity and BH3 mimetics such as Venetoclax.
We expect these treatments to prevent FL progression and transformation. Our goals for this proposal are to
determine whether EZH2 mutant FL B-cells depend on FDCs for their survival, whether EZH2 inhibitors act
through restoring interactions of FL B-cells with T-cells, and to leverage this information to test novel combination
of therapeutic approaches to prevent progression of EZH2 mutant FLs and transformation to aggressive
lymphoma.

Grant Number: 5R01CA270245-04
NIH Institute/Center: NIH
Principal Investigator: Wendy Beguelin