Discussion
ovarian cancer, tumor, toxicity, cancer, hematologic malignancies, DLBCL, Tumors, TIL infiltration, tumors, Cancer
OVARIAN CANCER, TUMOR, CANCER, SOLID TUMORS, HEMATOLOGIC MALIGNANCIES, TUMORS, TUMORS, CANCER
Effective cancer immunotherapy is associated with TIL infiltration and upregulation of IFN-γ-related immune evasion pathways. Tumors demonstrating this phenotype have been described as T cell inflamed and generally express high PD-L1 levelsThe bispecific PD-1×LAG-3 design of tebotelimab has multiple potential attractive features. Tebotelimab was observed in cell-based functional assays to induce greater T cell activity and IFN-γ production as well as to modulate the TME more than individual PD-1 or LAG-3 antibodies alone or in combination. The design of tebotelimab with bivalent binding for both PD-1 and LAG-3 ensures independent blocking of each checkpoint pathway from binding its ligands (PD-L1/PD-L2 for PD-1 and MHC Class II/FGL1 for LAG-3) that is not dependent on the expression of the other. However, the molecule has the added benefit over a mAb combination in having the potential to provide cross-arm avidity binding in which anchoring to one target (either PD-1 or LAG-3) increases the local concentration of molecule available to bind and block the second target co-expressed on the same cell (including temporal expression of the second target potentially as a consequence of compensatory expression in response to blocking the first checkpoint). The enhanced activity of tebotelimab as compared to monoclonal anti-PD-1 plus anti-LAG-3 is consistent with other reports in the literature surrounding the immunologic impact of cross-arm avidity binding to enhance the activity of bispecific molecules via binding two antigens on the same cell surfaceExpanding the tumor types that might benefit from CPI and addressing resistance are some of the highest priority areas of unmet need across solid tumors. We observed activity of tebotelimab in tumors such as EOC, in which anti-PD-1 has minimal activity, particularly where LAG-3 expression was highest. Although combination immunotherapy targeting PD-1 with CTLA-4 has demonstrated improved outcomes in EOC, the toxicity of this regimen was considered unacceptableExpansion of immune CPI into hematologic malignancies also remains a priority; to this effect, we observed preliminary activity for tebotelimab in DLBCL. Across cancer types profiled in The Cancer Genome Atlas and confirmed by IHC in this study, LAG-3 expression in DLBCL was among the highest described, emphasizing a potential role for anti-LAG-3 immunotherapyThis study is limited by its small sample size and, in particular, by limited numbers of participants with any one tumor type, as well as by the absence of an internal therapeutic control arm. The clinical data are intended to be exploratory, although the favorable comparison to published data from other immunotherapies across several indications warrants confirmation in larger, randomized disease-specific trials. In summary, PD-1/LAG-3 blockade with tebotelimab enhances immune responses above those achieved by PD-1 inhibition alone, as demonstrated in various preclinical settings, and confers clinical responses in patients typically unresponsive to PD-1 inhibition, such as those with ovarian cancer and DLBCL. Tebotelimab anti-tumor activity correlates with baseline immune activity in the TME as predicted by IFN-γ-regulated gene expression or LAG-3 expression levels, providing approaches to enrich for responsive patients that can be explored in future clinical studies. Combination therapy with Fc-enhanced antibodies, such as margetuximab, which induce IFN-γ and LAG-3 expression, provides a potential approach to further broaden the patient population that is responsive to tebotelimab. The encouraging safety profile of tebotelimab may also facilitate immunotherapy opportunities in tumor types in which suboptimal exposures to anti-PD-1 or toxicity with CTLA-4 combinations have prevented clinical development. Tebotelimab may, therefore, offer clinical opportunities to checkpoint-naive patients as well as to checkpoint-experienced patients who have progressed on prior therapy with PD-1/PD-L1 inhibitors.