Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

Abstract

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma (HL). Disappointingly, response rates have been low in the non-Hodgkin lymphomas (NHLs), with no activity seen in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we pre-clinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T cell responses. Immune modeling assays demonstrated that avadomide stimulated T cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments (TMEs) that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…In addition, the immunomodulatory drug lenalidomide has been shown to induce IFN β signaling in DLBCL that promotes tumor cell death ( 65 ). In contrast, lenalidomide and avadomide have anti-proliferative effects on CLL cells that are likely a direct effect of IFN signaling induction but does not induce direct tumor B cell apoptosis ( 66 , 67 ). Interestingly, the fusion of IFN α to anti-CD20 antibody induced a superior anti-lymphoma effect than anti-CD20 alone by direct and potent killing of type I IFNα receptor-positive lymphoma cells ( 68 ).…”

“…Recently, impaired IFN signaling in CLL B cells (loss of IFN regulatory factor 4, IRF4 using a murine model or its reduced expression in human CLL cells) has been linked to downregulated antigen presentation and co-stimulatory molecules that prevented the generation of activated, exhausted T cell responses and was associated with accelerated disease progression. In addition to this tumor immune evasion mechanism, T cells from treatment naïve CLL patients have been shown to express deregulated IFN type I and II signaling genes compared to healthy age-matched control T cells ( 67 ), in keeping with impaired IFN signaling in T cells representing a common immune defect in cancer ( 76 ). Together these recent findings provide evidence that reduced IFN signaling in the CLL TME could contribute the development of an immunosuppressive/non-inflamed TME.…”

“…Interestingly, non-inflamed lymphomas typically lack genetic aberrations that facilitate immune escape ( 111 ). We have recently demonstrated that CLL lymph nodes show salient features of non-inflamed tumors including sparse numbers of CD8 + T cells relative to reactive non-malignant tissues and low PD-L1 expression in the TME, as well as profound T cell functional exhaustion ( 67 ).…”

“…Therapeutic strategies include re-activation of autologous anti-tumor immune responses using CELMoDs ( e.g. avadomide) ( 67 ) or T-cell bispecific antibodies and fusion proteins (CD20-TCB, CD19-4-1BBL, Blinatumumab) ( 279 – 282 ). Anti-tumor immunity can also be induced by transferring CAR-T/NK effector cells that directly target cancer cells (CD19-CAR-T) ( 283 ).…”

The tumor microenvironment of lymphomas: Insights into the potential role and modes of actions of checkpoint inhibitors

“…As in other B‐cell lymphomas, applying immune checkpoint inhibitors in CLL has not resulted in major therapeutic advances so far 60 . A recent study in CLL could show that, similar to cHL, combination therapy by joining PD‐1/PD‐L1 immune checkpoint inhibition with immunomodulative substances such as avadomide, a cereblon E3 ligase modulator, activates T‐cells, and thus improves T‐cell responses, which then are not impeded by PD‐1/PD‐L1 signalling 69 …”