Triggering T-cell activity in CLL

In this issue of Blood, Ioannou et al¹  show that the lack of clinical activity of checkpoint inhibitors in chronic lymphocytic leukemia (CLL) results, at least in part, from an exhausted tumor microenvironment that can be overcome by inducing interferon (IFN) signaling in T cells in a preclinical model.

Immune checkpoint inhibitors blocking PD-1 or PD-L1 are highly active and clinically approved for solid tumors like malignant melanoma and lung cancer. Of the hematologic malignancies, Hodgkin lymphoma responds to checkpoint inhibitors, as does Richter transformation, an aggressive lymphoma transformed from CLL. In contrast, checkpoint inhibitors have no clinical activity in other lymphomas like diffuse large B-cell lymphoma or CLL itself.²  The last decade has seen approval of multiple new effective drugs for CLL including ibrutinib, an inhibitor of B-cell receptor signaling, the BCL2 antagonist venetoclax, and CD20-specific antibodies. However, these novel treatments are in general not curative, and many patients become resistant over time. Therefore, the need for new effective treatment modalities in CLL persists.

Avadomide (CC-122) is a new thalidomide derivative that induces degradation of lymphatic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) and other neo-substrates through the cereblon (CRBN) E3 ubiquitin ligase.^3,4  Degradation of IKZF1 and IKZF3 is implicated in direct cytotoxicity in multiple myeloma, CLL, and other B-cell lymphomas, as well as immunomodulatory effects including release of interleukin-2 and IFN by T cells.⁴  Avadomide has superior IKZF1 degradation activity, which is why avadomide is currently being tested in clinical trials in CLL and other B-cell lymphomas. Although results from these clinical trials have not yet been published, lenalidomide was shown to have moderate activity in CLL, despite its decreased capability to induce degradation of IKZF1 compared with avadomide.⁵ 

In the current study, Ioannou et al found that avadomide and anti–PD-L1/anti–PD-1 are synergistic, using primary human CLL and T cells in vitro and in xenograft mouse models. Mechanistically, avadomide activates CD8⁺ cytotoxic T cells by inducing IFN class I and II signaling, thereby stimulating migration, proliferation, and chemokine release of T cells. Surprisingly, avadomide also upregulates PD-L1 cell surface expression on T cells. PD-L1 that is usually expressed on the tumor cells and to a lower extent on immune cells inhibits T-cell activation as part of a negative feedback regulation of IFN signaling. Checkpoint inhibitors anti–PD-1/PD-L1 overcome this negative regulation and, together with avadomide, activate T cells to form immune synapses with CLL cells. The combination of both drugs results in effective T-cell–mediated cytotoxic killing of primary human CLL cells (see figure). These findings are corroborated by the observation that PD-L1 expression is also enhanced in T cells obtained from patients treated with avadomide in clinical trials. Avadomide thus transforms a low inflammatory T-cell state into an inflamed microenvironment with enhanced antitumor activity.

The high activity of combined checkpoint inhibition and avadomide in preclinical CLL models provides a rationale for testing this drug combination in clinical trials. However, these trials need to be carried out with caution because a combination of T-cell–activating therapies potentially has severe toxicity, which cannot be predicted from experiments in mouse xenograft models. In multiple myeloma, clinical trials combining the PD-1–specific antibody pembrolizumab with lenalidomide or pomalidomide had to be prematurely terminated because of high toxicity with an increased rate of treatment-related deaths.⁶  Nevertheless, immunotherapies hold the promise to be curative, potentially in combination with other effective drugs in CLL. Moreover, the findings by Ioannou et al further support that immunomodulatory drugs such as avadomide and lenalidomide induce IFN and other activating signaling pathways and thereby stimulate T-cell–based therapies. Immunomodulatory drugs like avadomide or lenalidomide may therefore hold promise for novel treatment avenues when given combined with chimeric antigen receptor T cells, checkpoint inhibitors, or bispecific antibodies. This combination approach could be applicable in hematologic malignancies and also in solid tumors.