The 2018 Nobel Prize in Physiology or Medicine was awarded to James Alison and Tasuku Honjo for their groundbreaking work on cancer therapy targeting the inhibition of immune checkpoints (IC), proteins that negatively regulate the immune response. Their work was groundbreaking because it opened a new powerful tool for the cure of cancer—immunotherapy (Fritz J. et Lenardo M., 2019).

The Cancer Revolution

At the beginning of cancer research, the immune system was not considered an important actor in cancer pathogenesis. But, in fact, the tumor microenvironment is filled with infiltrating immune cells attempting to fight the tumor. However, the tumor is a worthy adversary, and it evades the immune system through several mechanisms. Cancer cells protect themselves by (i) deregulating stress signals, (ii) hijacking immune cell functions to create a favorable inflammatory environment or (iii) engaging inhibitory receptors expressed on immune cells (Weiner L. 2019). This last mechanism involves the now famous IC that function as “brake” proteins and serve as crucial controls on the immune response. They downregulate immune activation and develop to prevent damaging over-activity of immune cells following activation. However, many cancer cells exploit these pathways, and express proteins that engage IC, thereby blocking specific lysis by cytotoxic CD8+ T cell or natural killer (NK) cells and evading antitumor immune responses.

So, picture the impact on tumors if we could release the CD8+ T cells or NK cells from inhibition. The revolution is in motion! Monoclonal antibodies (mAb) have been manufactured to break this negative axis by targeting the IC or its ligand on the cancer cells. Specifically, since their discovery by the two Nobel winners, the interaction of PD-1 or CTLA-4 proteins and their ligands on cancer cells is being exploited to boost the potency of tumor-specific CD8+ T cells. In particular, clinical studies assessing the blockade of PD-1 or its ligand PD-L1 have shown potent therapeutic efficacy against tumors such as melanoma, non-small-cell lung cancer, and urothelial cancers. These treatments are increasingly widely used in clinical practice. However, not all patients respond to IC blockade targeting PD-1 or CTLA-4, and there is a constant need to identify new targets to enhance antitumor immunity (Wilky B. 2019). A current area of investigation is looking at the potential role of NK cells in cancer therapy.

Monoclonal Antibodies to Recruit NK Cells

NK cells can efficiently discriminate between transformed or virally infected cells and normal cells without the need for prior sensitization with an antigen. As innate cytotoxic immune cells, they have the capacity to kill abnormal cells before more specific immunity develops, thereby containing and even clearing tumor development. NK cells lack antigen-specific receptors but can lyse target cells following the engagement of inhibitory and activating receptors. NK effector functions take place when activating signals overcome inhibitory ones (Cooper M. et al 2001).

One of the major NK cell receptors is NKG2A. This transduces inhibitory signals when interacting with its ligand HLA-E. In various type of tumors, HLA-E is overexpressed on cancer cells, even at a higher level than PD-L1. Engagement of NK-expressed NKG2A with HLA-E on cancer cells leads to the inhibition of NK cells.

Recent work by André and colleagues focused on human head and neck squamous cell carcinomas (HNSCC). They observed high expression of HLA-E and the presence of NKG2A^pos NK cells, but also NKG2A^pos CD8+ T cells within tumors. It seems that the inflammation in the tumor microenvironment also induced the expression of NKG2A on CD8+ T cells. André and colleagues saw the opportunity to test the effect of blocking NKG2A as a mechanism to enhance antitumor immunity, and developed a humanized NKG2A mAb: monalizumab (André P. et al, 2018).

The potential of monalizumab was assessed in vitro against various tumor cell lines, including a HNSCC cell line and in vivo in mice. Interestingly, it had an additive effect when given with other monoclonal antibodies such as durvalumab (anti-PD1 mAb) or the epidermal growth factor receptor (EGFR) mAb, cetuximab. This combination resulted in more potent NK cell effector function and in some conditions, greater CD8+ T cell function.

The authors also carried out a phase II clinical trial, to assess the safety and efficacy of monalizumab given with cetuximab, in patients with recurrent or metastatic HNSCC who had failed other therapies. Preliminary results from 31 patients demonstrated that this combination was safe, with minor side effects. Interestingly, the objective response rate (ORR) was 31% with this combination approach, as compared to an ORR of 13% in patients treated with cetuximab alone.

These findings highlight the potential of manipulating other immune checkpoints, including those expressed on NK cells, to increase antitumor activities of the immune system.

Only the Beginning: NK Cells Immunotherapy Potential

Monoclonal antibodies are only a small part of the immunotherapy toolkit that could be employed against cancer cells. New therapeutics to date have focused largely on specific CD8+ T cells effector function. The main advantage of NK cells lies in their capacity to kill any malignant target cell. They just require the right weapons (the right balance of activating and inhibitory receptors) and the right stimulation to engage.

Other potential approaches being investigated to target NK cells in cancer immunotherapy include:

1. Interleukin (IL)-15 treatment to specifically activate NK cells
2. Off-the-shelf therapies with chimeric antigen receptor (CAR) transfected in NK cells to weaponize them against a specific tumor
3. The well-described NK cell “memory” features that could be harnessed through vaccines.

All these tools are under investigation in clinical trials and carry a lot of hope for the future of antitumor treatment (Lucar O. et al. 2019).