KIR Strategies Face Many Hurdles

Don M. Benson Jr, MD, PhD

Don M. Benson Jr, MD, PhD, is an associate professor and head of Translational Research for Hematology at the College of Medicine at Ohio State University Comprehensive Cancer Center. His laboratory and clinical research programs are focused on the development of novel immunotherapies for cancer, with a particular focus on natural killer (NK) cells.

OncLive: How do KIRs promote cancer?

How is the clinical development of KIR-targeted therapies going?

Benson describes killer immunoglobulin-like receptors (KIRs) as a family of proteins that modulate NK cell ability to discern “self” from “non-self.” He said that at least 17 KIRs have been discovered to date, “and some confer activation signals to NK cells while others confer inhibitory signals.”Benson: How KIRs could be involved in the development of cancer is incompletely understood. However, KIR—ligand relationships that are particularly inhibitory in nature appear to be overrepresented in some cases of cancer, including melanoma, breast cancer, acute and chronic leukemias, and Hodgkin lymphoma.The concept of KIR—ligand mismatching in therapy was first demonstrated in the setting of T-cell depleted, haploidentical hematopoietic stem cell transplantation for blood cancer. A high durable complete remission rate was observed when patients received a graft in which NK cell alloreactivity was present. Studies have also been performed in which KIR–ligand mismatched NK cells are expanded ex vivo and infused to a patient after chemotherapy.

Building on these ideas, IPH2101 was the first therapeutic anti-KIR antibody to enter clinical trials. This human, IgG₄ antibody recognized and bound to common inhibitory KIR, thus preventing KIR—ligand interaction and serving as an innate immune checkpoint inhibitor. To date, 4 trials have been published with IPH2101 in patients with multiple myeloma and acute myeloid leukemia. IPH2101 is no longer in clinical development and has been replaced by lirilumab, a second-generation anti-KIR antibody.

What are the most significant challenges that have arisen?

Lirilumab is under clinical investigation in acute myeloid leukemia and multiple myeloma, as well as solid tumors. Very recently, results were announced from a phase I/II trial of lirilumab in combination with the anti—PD-1 antibody nivolumab (Opdivo) in which a 24.1% objective response rate was reported in patients with previously treated squamous cell carcinoma of the head and neck.At least 4 challenges remain in targeting KIRs as a means of checkpoint inhibition for NK cells. First, NK cell reactivity is thought to be related to the balance of both activating and inhibitory signals received. Thus, theoretically, blocking inhibitory signaling would be insufficient to promote cytotoxicity unless this occurred in the setting of an activating signal received through another receptor—ligand signaling axis.

Second, inhibitory KIRs represent only one checkpoint pathway for NK cells. NKG2A, for example, is another powerful inhibitory receptor that recognizes non-classical MHC proteins, such as HLA-E. Some studies suggest that NKG2A may be especially important in cancers such as acute myeloid leukemia.

Third, in a recent study of IPH2101 in smoldering myeloma, an unexpected depletion of KIR2D-positive NK cells was observed which was apparently due to monocyte-mediated trogocytosis. This process may have negatively impacted KIR-dependent NK cell education, rendering the cells hyporesponsive.

Finally, complementary strategies may be needed to facilitate NK-cell checkpoint inhibition such as depletion of regulatory T cells and reduction of tumor-derived cytokines such as TGF-beta, which also suppress NK cell function. Co-administration of adoptive immune checkpoint blockade (eg, PD-1, CTLA-4) may also be necessary for optimal immune release.