Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer

Abstract

Natural killer (NK) cells exhibit strong cytotoxic activity against tumor cells without prior sensitization, and have the potential to exert antibody-dependent cellular cytotoxicity (ADCC). In this clinical trial, we examined the safety and efficacy of the use of NK cells, generated using a novel expansion system, in combination with IgG1 antibodies for the treatment of advanced gastric or colorectal cancers. Treatment consisted of trastuzumab- or cetuximab-based chemotherapy, plus adoptive NK cell therapy. For administration of expanded NK cells, dose escalation with a sequential 3 + 3 design was performed in three steps, at doses of 0.5 × 10 , 1.0 × 10 , and 2.0 × 10 cells/injection (N = 9). After 3 days of IgG1 antibody administration, patients were infused with expanded NK cells three times at triweekly intervals. NK cell populations expanded with our system were confirmed as being enriched in NK cells (median 92.9%) with high expression of NKG2D (97.6%) and CD16 (69.6%). The combination therapy was very well tolerated with no severe adverse events. Among six evaluable patients, four presented stable disease (SD) and two presented progressive disease. Of the four SD patients, three showed an overall decrease in tumor size after combination therapy. Immune monitoring suggested that combination therapy enhanced whole blood IFN-γ production and reduced peripheral regulatory T cells (Tregs). In conclusion, this phase I trial provides evidence of good tolerability, induction of Th1 immune responses, and preliminary anti-tumor activity for this combination therapy, in patients with advanced gastric and colorectal cancer that have received previous therapy.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Trastuzumab treatment is also associated with high numbers of tumor infiltrating NK cells (203)(204)(205), and higher NK cell function and expansion may also correlate with response to Trastuzumab treatment (206,207). A recent phase I clinical study used adoptive NK cell therapy together with Trastuzumab administration, showing good tolerability, and induction of immune activity (208). Nevertheless, several patients still display intrinsic and acquired resistance to Trastuzumab therapy (209).…”

DNT Cell-based Immunotherapy: Progress and Applications

“…In 2018, the Nobel Prize in physiology or medicine was awarded to immunologists for the discovery of treatments that suppress negative immunoregulation, which conferred mainstream status on cancer immunotherapy [3,4]. Currently, tumor immunotherapies mainly include immune checkpoint inhibitors [5][6][7][8], oncolytic viruses [9], antitumor vaccines [10,11] and adoptive cellular immunotherapy (ACI) [12][13][14][15]. ACI has been used in the clinic and has achieved great clinical benefits for malignant tumors [16,17].…”

Standard therapies: solutions for improving therapeutic effects of immune checkpoint inhibitors on colorectal cancer

“…77 In this context, cetuximab-primed NK-mediated tumor cell lysis is deficient. To overcome this deficiency, several strategies have been developed, such as combinations with IL-21 to reverse NK cell exhaustion, 78,79 adoptive transfer of in vitro-expanded tumoricidal NK cells to increase in vivo numbers, 80 and agonizing CD137 to induce EGFR-specific CD8 + T cell generation. 81 In a similar manner, due to the upregulation of Tim-3 and PD-1 by exhausted NK cells, 77 ICI therapy has been proposed as a candidate to prevent NK cell exhaustion.…”