Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Presently, new attention is given to type I interferons (IFNs) as essential factors linking innate and adaptive immunity. Several studies provided evidence about the importance of IFN-alpha in the differentiation of the Th1 subset, in the generation and activity of cytotoxic T lymphocytes, in the enhancement of a primary antibody response and in the activation of dendritic cells. Owing to their immunomodulatory properties, type I IFNs can represent good candidates to be used as adjuvants for vaccination. In the present review, we summarize recent studies in humans and in animal models, suggesting a possible application of type I IFNs as adjuvants for the development of more effective vaccines against infectious diseases and cancer.

Type I interferons as vaccine adjuvants against infectious diseases and cancer.

Purpose: IFN-α is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-α with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. Experimental Design: The phenotypic and functional effects of IFN-α were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-α administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-α and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. Results: We identified a dose and schedule of IFN-α that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8 + ) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-α distal to the site of vaccination. The combination of IFN-α and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA + adenocarcinomas. In mice with pancreatic tumors, IFN-α slowed tumor growth, induced CTL activity, and increased CD8 + tumor-infiltrating lymphocytes. Conclusions: These data suggest that IFN-α can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.

https://clincancerres.aacrjournals.org/content/clincanres/15/7/2387.full.pdf

The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines

76 According to current data, antitumor vaccines (AV) have high therapeutic efficiency if combined with adjuvants of various origin, and immune response inducing cytokines [1, 2]. Of particular scientific interest are the effects of interferon (IFN) relating to tumor’s increasing immunogenicity and changing sensitivity to T-lymphocyte cytotoxicity. It was shown that IFN directly impacts tumor growth and differentiation, and induces apoptosis [3]. Thus it is necessary to study its role as part of combination with other biological agents. Results of experimental and clinical studies substantiate the use of IFN- as an optimization element of complex treatment to reduce risks of metastasis and improve the quality of life for cancer patients [4, 5]. Discovery of the unique properties of IFN stimulated the search for substances activating the synthesis of endogenous IFN, so-called IFN inducers [6–8]. One of these is amixin (tilorone), oral low molecular weight inducer of endogenous IF, the which activity is related to the immunomodulatory properties [9–11]. Information on significant antitumor activity of amixin has been obtained in model tumor experimental studies, also in clinical trials in patients with melanoma, breast cancer, renal cell carcinoma [12, 13]. It has been shown that the combined use of antitumor drugs and amixin contributes to strengthening growth inhibition of model tumors, and reduces metastasis [10, 14, 15]. Particular attention is paid to studying effects of IFN combined with vaccinotherapy [4, 16, 17]. UDС 604.4.615.371 http://dx.doi.org/10.15407/biotech9.03.076

/pdf/antitumor-and-antimetastatic-efficiency-of-antitumor-vaccine-3db6n1yue9.pdf

Antitumor and antimetastatic efficiency of antitumor vaccine and amixin combined action in mice with Lewis lung carcinoma

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; IFN-α is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-α with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; The phenotypic and functional effects of IFN-α were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-α administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-α and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; We identified a dose and schedule of IFN-α that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8&lt;sup&gt;+&lt;/sup&gt;) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-α distal to the site of vaccination. The combination of IFN-α and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA&lt;sup&gt;+&lt;/sup&gt; adenocarcinomas. In mice with pancreatic tumors, IFN-α slowed tumor growth, induced CTL activity, and increased CD8&lt;sup&gt;+&lt;/sup&gt; tumor-infiltrating lymphocytes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; These data suggest that IFN-α can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.&lt;/p&gt;&lt;/div&gt; 

Data from The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines

Aim To study in in vivo model the efficacy of combined scheme of administration of cancer vaccine (CV) and interferon (IFN). Materials and methods Lewis lung carcinoma (LLC) was transplanted to male C57Bl mice. For treatment, CV prepared from LLC cells with the use of cytotoxic lectins of B. subtilis B-7025, and preparation of murine IFN-alpha were used. Therapeutic effect was evaluated by measurement of tumor volume and analysis of average life span (ALS) of treated animals. Immunologic study included determination of antitumor cytotoxicity of T-lymphocytes (CTL) and natural killer (NK) cells by radiometric method, functional activity of peritoneal macrophages (MP) - by colorimetric test with nitroazole blue, and evaluation of titers of tumor necrosis factor (TNF) and interleukins-1 and -2 (IL-1, 2). Results It has been shown that the use of IFN preparation significantly elevated efficacy of vaccine therapy of solid form of LLC: duration of latent period of tumor growth elevated by 25%, ALS - by 28%, index of tumor growth inhibition - by 35-40%. Upon combined use of CV and IFN, significant activation of the cells - effectors of nonspecific immune defense (MP), and specific one (CTL) was observed. Conclusion The obtained results evidence on perspectiveness of the development of combined schemes of administration of CV and IFN for elevation of the efficacy of vaccine therapy.

Experimental study of the efficacy of combined use of cancer vaccine and interferon.

Aim To study in vivo efficacy of combined administration of cancer vaccine (CV), interferon (IFN) and inducer of endogenous IFN - amixin. Materials and methods Sarcoma-37 cells were transplanted to female Balb/c mice. For the treatment, CV prepared from sarcoma-37 cells with the use of cytotoxic lectines from B. subtilis B-7025, murine IFN and amixin or their combinations were used. IFN production, content of circulating immune complexes and level of specific IgG antibodies in blood serum were determined by standard immunologic methods. Results Using solid form of sarcoma-37 it has been shown that introduction of IFN and amixin significantly elevated efficacy of vaccine therapy, in particular index of tumor growth inhibition reach 89.2% and 81.7%. Upon combined use of CV and IFN or CV and amixin (25 mg/kg) respectively. Significant prolongation of average life span of the animals treated with CV and IFN or CV and amixin (25 mg/kg) has been registered (up to 92.7 -/+ 10.4 and 95.0 -/+ 6.2 days respectively, vs 46.8 -/+ 1.5 days for control animals). Conclusion Obtained results have shown expediency of the development of schemes for combined introduction of CV with exogenous IFN, and with inducer of endogenous IFN (amixin) for elevation of efficacy of vaccine therapy.

Elevation of efficacy of cancer vaccine combined with interferon and inducer of endogeneous interferon synthesis amixin.

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Experimental study of the efficacy of combined use of cancer vaccine and interferon.

Elevation of efficacy of cancer vaccine combined with interferon and inducer of endogeneous interferon synthesis amixin.