The molecule IL-2 is a pleiotropic interleukin that is produced after the activation of the T cells (mostly CD4+) induced by antigens (Ag). This plays an essential role in the immune system, in its function as an autocrine as well as a paracrine growth factor.
The molecule induces the proliferation of the natural killer cells or NK lymphocytes, increasing their cytolytic or cytotoxic activity, as well as it has an essential role in the initialization and generation of memory CD8+ T cells (Gillis and Smith, 1977; Morgan et al., 1976). The combined actions of the IL-2 on the NK and the CD8+ T cells are postulated as its main mechanism to stimulate the antitumor activity. In a very outstanding way, the IL-2 particularly determines the development and the homeostasis of the T lymphocytes with CD4+FOXP3+ phenotype or regulatory T cells (Tregs).
These cells have an immune suppressive function and primarily they mediate the natural tolerance, being they are vital to prevent the occurrence of autoimmune illnesses, to limit excessive inflammatory responses and to maintain the general homeostasis of the immune system (Malek and Bayer, 2004; Setoguchi et al., 2005).
Nevertheless, preclinical and clinical studies have documented the capacity of some tumors attracting/expanding the Tregs, contributing to limit the antitumor response against the malignant neoplasia. The IL-2/IL-2R signaling mediated by the STAT5 phosphorylation also contributes to stabilize the expression of FOXP3 in the Tregs, increasing with its suppressive capacity. The over expression (constitutive) of the IL-2R alpha chain (CD25) and its contribution to form the high affinity trimeric receptor is decisive for the survival and suppressor function of the Tregs. For example, a recent study demonstrated that the capacity of the Tregs to capture IL-2 and to deprive it from the CD8+ T cells in vivo, suppresses the expansion and uncontrolled activation thereof. High doses of IL-2 has been used for many years in the therapy of cancer, by itself and in combination with different vaccines.
Several studies showed a significant antitumor effect in metastatic Melanoma and metastatic Renal Carcinoma patients, something which made possible the registration of this drug by the FDA in 1992. The use of high doses of IL-2 in the medical practice had consistently shown that a small percent (15 – 16%) of the treated patients has a significant antitumor response of relatively long duration. In particular 5-6% of the treated patients have complete response and they were virtually cured after 10 years of following up.
Recent preclinical and clinical studies have revived the interest in an old drug as it is the IL-2. A clinical study in melanoma where a combination of this interleukin was used with an anti-CTLA4 antibody showed strengthening evidence in the reached anti-tumor response. Similar results have been documented in preclinical models with different anti-checkpoints antibodies: i.e. anti-CTLA4; anti-PD1/PD-L1. Other authors document as advantageous the use of the IL-2 to expand tumor infiltrating lymphocytes (TILs) or engineered T cells (CART) so much in vitro as well as in vivo in the context of the modern therapies of adoptive transference.
The preferential action of the IL-2 on the Tregs cells in vivo is undoubtedly an obstacle for its therapeutic exploitation in different contexts. In particular several studies in patients and in mice have shown that the capacity of the IL-2 to expand the Tregs limits significantly its anti-tumor effect. In patients a clear correlation between the expansion of Tregs ICOS+ and the absence of clinical effectiveness has been observed. Another bigger disadvantage for the native IL-2, concerning its therapeutic exploitation is its great toxicity. It is reported that the therapy with high doses of IL-2 induces serious adverse events and that many patients are forced to suspend the therapy due to the induced toxicity (Vial and Descotes, 1992).
In fact, only patients with a very good general state can be subjected to the therapy, limiting significantly the impact. The main toxic effect caused by the IL-2 is the Syndrome of Capillary Fragility or Vascular Leak Syndrome (VLS). Recent articles suggest that this syndrome is mediated by the direct signaling of the IL-2 on the endothelial cells that express the high affinity trimeric receptor. The mIL-2 is a variant of the human IL-2 designed to preferentially stimulate the cells responsible for the antitumor activity, mainly the cytotoxic CD8+ T cells and the NK natural killer cells, without expanding/activating the Tregs cells.
Contrary to the human native IL-2, the mIL-2 has affected the capacity to interact with the alpha chain of its receptor (Carmenate et al., 2013). Therefore it has a very low capacity to stimulate the Treg cells that suppress the antitumor activity. It is for this reason that the mIL-2 shows bigger antitumor effect that the native IL-2 in vivo since it is able to increase the proportion between the effector lymphocytes and the regulatory T cells, favoring the antitumor response (Carmenate et al., 2013). Additionally, the mIL-2 has demonstrated that it induces less toxic effects than the native IL2 even when it is administered at doses substantially bigger than necessary to induce the antitumor effect in mice.
The explanation of this low toxicity is not totally elucidated, but it could derive from its smallest capacity to interact with the high affinity trimeric receptors expressed on the endothelial cells of the lung and other organs. As a whole, the increased capacity to expand the CD8+ T and NK cells, in relation to the Tregs, and its reduced toxicity makes the mIL-2 a better candidate that the native IL-2 for the therapy of cancer. Particularly attractive is the exploration of its effect in combination with other therapies. For example: 1) The denominated anti-Checkpoints (anti-CTLA4/PD1/PDL1) that fundamentally liberate the brakes to the cytotoxic activity of the CD8+ T cells against mutated antigens in the tumor. It could be particularly useful in combination with tumors where the Tregs are outstanding in the tumor microenvironment or in the context where the activation of NK cell complements the CD8+T cells’ cytotoxicity, limiting the tumor escape by MHC-I expression decreases. 2) Therapeutic vaccines of cancer that seek to expand a CD8+ T cell response. In this context the mutant of IL-2 can contribute to expand the CD8+ T cells, stimulating them directly and making them independent from the regulation mediated by the Tregs.
Therapies of adoptive transference of T cells, native or engineered. Of particular interest can be the use in vivo of the mutant, to expand the CD8+ T or NK cell effectors that have been infused in a patient, without expanding those potentially noxious Tregs.