Allogeneic NK cells induce monocyte-to-dendritic cell conversion, control tumor growth, and trigger a pro-inflammatory shift in patient-derived cultures of primary and metastatic colorectal cancer.

INTRODUCTION: Natural killer (NK) cells are innate lymphocytes with a key role in the defense against tumors. Recently, allogeneic NK cell-based therapies have gained interest because of their ability to directly lyse tumor cells without inducing graft-versus-host disease. As NK cells are also able to influence the function of other immune cells (most notably dendritic cells (DC)), a better understanding of the effects of allogeneic NK cell products on the host immune system is required. In this study, we analyzed the effects of an allogeneic off-the-shelf NK cell product, on the tumor microenvironment (TME) of primary and metastatic colorectal cancer (pCRC and mCRC, respectively). Moreover, we explored if the combination of NK cells with R848, a toll-like receptors 7/8 ligand, could further enhance any pro-inflammatory effects. METHODS: Ex vivo expanded umbilical cord blood stem cell derived NK cells were co-cultured with pCRC or mCRC single-cell suspensions in the presence or absence of R848 for 5 days, during and after which flow cytometry and cytokine release profiling were performed. RESULTS: NK cells efficiently induced lysis of tumor cells in both pCRC and mCRC single-cell suspensions and thereby controlled growth rates during culture. They also induced differentiation of infiltrating monocytic cells to an activated DC phenotype. Importantly, this NK-mediated myeloid conversion was also apparent in cultures after tumor cell depletion and was further enhanced by combining NK cells with R848. Moreover, NK cells, and to a greater extent, the combination of NK cells and R848, triggered CD8+ and CD4+ T-cell activation as well as a reduction in activated regulatory T cell rates. Finally, the combination of NK cells and R848 induced a pro-inflammatory shift in the cytokine release profile resulting in higher levels of interferon (IFN)-γ, interleukin (IL)-2, IL-12p70, and IFN-α as well as a reduction in IL-6, in both pCRC and mCRC cultures. CONCLUSION: Allogeneic NK cells engaged in favorable myeloid crosstalk, displayed effective antitumor activity and, when combined with R848, induced a pro-inflammatory shift of the CRC TME. These findings prompt the investigation of NK cells and R848 as a combination therapy for solid tumors.

A Bispecific γδ T-cell Engager Targeting EGFR Activates a Potent Vγ9Vδ2 T cell-Mediated Immune Response against EGFR-Expressing Tumors.

Vγ9Vδ2 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vγ9Vδ2 T cells to EGFR-expressing tumors. An EGFR-Vδ2 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vγ9Vδ2 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vγ9Vδ2 T cells from peripheral blood and tumor specimens of patients with EGFR+ cancers had a distinct immune checkpoint expression profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vγ9Vδ2 T cells could be activated by EGFR-Vδ2 bsTCEs to mediate lysis of various EGFR+ patient-derived tumor samples, and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-Vδ2 bsTCEs exerted preferential activity toward EGFR+ tumor cells and induced downstream activation of CD4+ and CD8+ T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vγ9Vδ2 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-Vδ2 bsTCEs in patients with EGFR+ malignancies.

Enhancement of NK Cell Antitumor Effector Functions Using a Bispecific Single Domain Antibody Targeting CD16 and the Epidermal Growth Factor Receptor.

The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches.

Effects of physical exercise on natural killer cell activity during (neo)adjuvant chemotherapy: A randomized pilot study.

Natural killer (NK) cells are a population of innate immune cells known to play a pivotal role against tumor spread. In multiple murine models, it was shown that physical exercise had the potential to increase NK cell antitumor activity through their mobilization and tissue redistribution in an interleukin (IL)-6 and epinephrine-dependent manner. The translation of this finding to patients is unclear. In this randomized pilot trial, we analyzed blood samples of patients with resectable breast or colon cancer who were randomized into an evidence-based moderate-high intensity resistance and aerobic exercise intervention (n = 8) or a control group (n = 6) during the first 9-12 weeks of (neo)adjuvant chemotherapy. In this pilot, we did not solely focus on statistical significance, but also explored whether average between-group differences reached 10%. NK cell degranulation was preserved in the exercise group whereas it decreased in the control group resulting in a between-group difference of 11.4% CD107a+ degranulated NK cells (95%CI = 0.57;22.3, p = 0.04) in the presence and 13.8% (95%CI = -2.5;30.0, p = 0.09) in the absence of an anti-epidermal growth factor receptor monoclonal antibody (EGFR-mAb). In line, the between-group difference of tumor cell lysis was 7.4% (95%CI = -9.1;23.9, p = 0.34), and 13.7% (95%CI = -10.1;37.5, p = 0.23) in favor of the exercise group in the presence or absence of EGFR mAb, respectively. Current explorative analyses showed that exercise during (neo)adjuvant chemotherapy may benefit NK cell activity. Future studies with a larger sample size are needed to confirm this finding and to establish its clinical potential. Trial registration: Dutch trial register number NTR4105.

Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response.

Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function.

Metoclopramide, Dexamethasone, or Palonosetron for Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting After Moderately Emetogenic Chemotherapy (MEDEA): A Randomized, Phase III, Noninferiority Trial.

BACKGROUND: For the prevention of chemotherapy-induced nausea and vomiting (CINV) during the delayed phase (24-120 hours) after moderately emetogenic chemotherapy (MEC), the use of 3-day dexamethasone (DEX) is often recommended. This study compared the efficacy and safety of two DEX-sparing regimens with 3-day DEX, focusing on delayed nausea. PATIENTS AND METHODS: This open-label, randomized, phase III study was designed to demonstrate noninferiority of two DEX-sparing regimens: ondansetron + DEX on day 1 + metoclopramide on days 2-3 (MCP arm), and palonosetron + DEX on day 1 (PAL arm) versus ondansetron on day 1 + DEX on days 1-3 (DEX arm) in chemotherapy-naïve patients receiving MEC. Primary efficacy endpoint was total control (TC; no emetic episodes, no use of rescue medication, no nausea) in the delayed phase. Noninferiority was defined as a lower 95% CI greater than the noninferiority margin set at -20%. Secondary endpoints included no vomiting, no rescue medication, no (significant) nausea, impact of CINV on quality of life, and antiemetics-associated side effects. RESULTS: Treatment arms were comparable for 189 patients analyzed: predominantly male (55.7%), median age 65.0 years, colorectal cancer (85.7%), and oxaliplatin-based chemotherapy (81.5%). MCP demonstrated noninferiority to DEX for delayed TC (MCP 56.1% vs. DEX 50.0%; 95% CI, -11.3%, 23.5%). PAL also demonstrated noninferiority to DEX (PAL 55.6% vs. DEX 50.0%; 95% CI, -12.0%, 23.2%). There were no statistically significant differences for all secondary endpoints between treatment arms. CONCLUSION: This study showed that DEX-sparing regimens are noninferior to multiple-day DEX in terms of delayed TC rate in patients undergoing MEC. ClinicalTrials.gov identifier. NCT02135510. IMPLICATIONS FOR PRACTICE: Chemotherapy-induced nausea and vomiting (CINV) in the delayed phase (24-120 hours after chemotherapy) remains one of the most troublesome adverse effects associated with cancer treatment. In particular, delayed nausea is often poorly controlled. The role of dexamethasone (DEX) in the prevention of delayed nausea after moderately emetogenic chemotherapy (MEC) is controversial. This study is the first to include nausea assessment as a part of the primary study outcome to better gauge the effectiveness of CINV control and patients' experience. Results show that a DEX-sparing strategy does not result in any significant loss of overall antiemetic control: DEX-sparing strategies incorporating palonosetron or multiple-day metoclopramide are safe and at least as effective as standard treatment with a 3-day DEX regimen with ondansetron in controlling delayed CINV-and nausea in particular-following MEC.

Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin.

BACKGROUND: Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Concurrent chemoradiation (CRT) with high-dose cisplatin is associated with significant acute and late toxicities, including acute kidney injury (AKI). The aims of this study were to investigate the incidence of AKI in patients with LA-SCCHN during and after treatment with high-dose cisplatin-based CRT, to identify risk factors for cisplatin-induced AKI, and to describe the impact of AKI on long-term renal function and treatment outcomes. METHODS: This is a retrospective cohort study with measurements of renal function before CRT, weekly during CRT, every 1 or 2 days during hospitalizations, and 3 and 12 months after CRT in patients with LA-SCCHN. AKI was defined as increase in serum creatinine (sCr) of ≥1.5 times baseline or by ≥0.3 mg/dL (≥26.5 µmol/L) using the Kidney Disease Improving Global Outcomes (KDIGO) classification. Logistic regression models were estimated to analyze renal function over time and to identify predictors for AKI. RESULTS: One hundred twenty-four patients completed all measurements. AKI was reported in 85 patients (69%) with 112 episodes of AKI. Sixty of 85 patients experienced 1 AKI episode; 20 patients experienced ≥2 AKI episodes. Ninety-three (83%) AKI episodes were stage 1, 13 (12%) were stage 2, and 6 (5%) AKI episodes were stage 3. Median follow-up time was 29 months (Interquartile Range, IQR 22-33). Hypertension (Odds Ratio, OR 2.7, 95% Confidence Interval, CI 1.1-6.6; p = 0.03), and chemotherapy-induced nausea and vomiting (CINV; OR 4.3, 95% CI 1.6-11.3; p = 0.003) were associated with AKI. In patients with AKI, renal function was significantly more impaired at 3 and 12 months post-treatment compared to patients without AKI. AKI did not have a negative impact on treatment outcomes. CONCLUSION: AKI occurred in 69% of patients with LA-SCCHN undergoing CRT with high-dose cisplatin. Long-term renal function was significantly more impaired in patients with AKI. Hypertension and CINV are significant risk factors. Optimizing prevention strategies for CINV are urgently needed.