Utilizing Cytokines to Function-Enable Human NK Cells for the Immunotherapy of Cancer

Table 2

Summary of selected cytokine clinical trials and major findings.

Cytokine	Additional agent	Disease	Major biologic effects	Outcomes	Reference
IL-2*	Post NK cell infusion	AML, HL, RCC, and melanoma	In vivo activation and expansion of the NK cells in some of the patients	CR in some of the AML patients	[153]
IL-2	Post NK cell infusion	AML	Minimal expansion of the adoptively transferred NK cells	Prolonged persistence of CR in some patients	[154]
IL-2	Rituximab and NK cell infusion	CD20^+ NHL	Preferential expansion of recipient regulatory T cells	Induction of CR in some patients	[156]
IL-12	None	RCC	Profound increases in serum IFN-𝛾	No major responses noted; phase II part terminated due to major toxicities including 2 deaths	[109]
IL-12	None	Melanoma	Transient decrease in CD8^+ and CD16^+ lymphocytes in peripheral blood and neutrophils along with high serum levels of IFN-𝛾 and IL-10	Decrease in the size of tumors in some patients	[110]
IL-12	None	RCC, melanoma, CC, and others	Transient decrease in T cells, B cells, and NK cells. Transient increase in the expression of CD2, CD11a, and CD56 on NK cells. Increase in the cytotoxic activity of the NK cells	No major responses with IL-12 therapy reported in this trial	[111]
IL-18	Rituximab	RCC, melanoma, and HL	Transient decrease in lymphocytes (CD4^+, CD8^+, NK, and NKT cells, but most profoundly in the NK cells). Increased Fas ligand on NK cells, CD8^+ T cells, and NKT cells. Increased serum levels of IFN-𝛾, GM-CSF, IL-18 binding protein, and soluble Fas ligand. Some patients (38%) developed antibodies to rhIL-18	Partial response in few patients	[166] [123]
IL-18	None	Advanced melanoma and RCC	Transient lymphopenia (CD4^+ T cells, CD8^+ T cells, and NK cells) which correlated with the expression of CD69. Increased plasma concentrations of INF-𝛾, GM-CSF, TNF-𝛼, CXC chemokine IP-10, and CC chemokine MCP-1. Antibodies against hrIL-18 developed in 32% of the patients	No major responses reported though the drug was well tolerated without any major side effects	[125]
IL-18	Rituximab	Advanced CD20^+ NHL	Transient lymphopenia with undetectable circulating B cells. Increase in plasma concentrations of IFN-𝛾, GM-CSF, TNF-𝛼, MIG, IP-10, and MCP-1	Overall response rate of around 26%, complete response rate of 11%, and partial response rate of 16%	[124]
IL-21	None	Metastatic melanoma	Transient increase in the serum levels of sCD25 (an immune activation marker). Perforin-1 and granzyme B expression in CD8^+ T cells and NK cells. Increase in cytotoxic activity of the NK cells	Response seen only in one patient	[135]
IL-21	None	Metastatic melanoma	Increased serum levels of sCD25 and increased CD25 expression on NK cells and CD8^+ T cells. Increased expression of IFN-𝛾, perforin, and granzyme B in NK cells and CD8^+ T cells	Clinical response seen only in two patients	[136]
IL-21	Cetuximab	Metastatic colorectal carcinoma	Decreased number of NK cells, CD8^+ T cells, and B cells. Increase in the cytotoxic activity of NK cells. Increase in the absolute number and the expression of CD64 (Fc𝛾RI). Increased serum levels of sCD25	Stable disease was reported in 60% of the patients	[138]
IL-21	None	Metastatic melanoma	Increase in the serum sCD25 levels	Overall response rate was 23% and median overall survival of 12.4 months in these patients compared favorably with a median survival of 8.4 months predicted from historic controls	[137]

∗This table included IL-2 provided in the context of allogeneic NK cell infusions, while early studies of IL-2 have not been included in this table and have previously been reviewed [29], [74], [81].