As a promising alternative platform for cellular immunotherapy, natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell. NK cells can rapidly kill multiple adjacent cancer cells through non-MHC-restrictive effects. Although tumors may develop multiple resistance mechanisms to endogenous NK cell attack, in vitro activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and give them the ability to overcome drug resistance. Some of these approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies and solid tumors have thus far yielded many encouraging clinical results. CAR-T cells have exhibited great success in treating hematological malignancies, but their drawbacks include high manufacturing costs and potentially fatal toxicity, such as cytokine release syndrome. To overcome these issues, CAR-NK cells were generated through genetic engineering and demonstrated significant clinical responses and lower adverse effects compared with CAR-T cell therapy. In this review, we summarize recent advances in NK cell immunotherapy, focusing on NK cell biology and function, the types of NK cell therapy, and clinical trials and future perspectives on NK cell therapy. 

/pdf/natural-killer-cells-a-promising-immunotherapy-for-cancer-1z06jwgk.pdf

Natural killer cells: a promising immunotherapy for cancer

While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions ("don't eat me" signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction ("eat me" signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer-cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.

Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?

Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting.

https://www.mdpi.com/2072-6694/12/9/2691/pdf

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: What does still need to be addressed?

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial

Monalizumab in combination with cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck cancer (SCCHN) previously treated or not with PD-(L)1 inhibitors (IO): 1-year survival data

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Monalizumab in combination with cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck cancer (SCCHN) previously treated or not with PD-(L)1 inhibitors (IO): 1-year survival data