When an immune intervention (vaccination or adoptive immunotherapy) is performed during the recovery phase that follows the damage, also tumorspecific immune cells can take advantage of the drugmediated immunomodulation. == Physique 6. == Highlights == Chemotherapy strongly enhances anticancer efficacy of immunotherapeutic strategies. Three mechanisms of synergism have been hypothesized: ldquo;subtractive rdquo;, ldquo;immunogenic rdquo; and ldquo;propulsive rdquo;. Chemoimmunotherapy can effectively be used as secondary prevention against tumor relapse. == Abbreviations == adoptive cell transfer Association for Research against Malignancy cytosine arabinoside carcinoembryonic antigen Ctype lectin receptor calreticulin cyclophosphamide dendritic cells donor lymphocyte infusion dacarbazine graft versus host disease Highmobility group box 1 protein hematopoietic stem cell stress response factor interferon interleukin chemokine (CXC motif) ligand10 mannose binding lectin monocyte chemotactic protein1 myeloidderived suppressor cells pattern acknowledgement receptor stem cell transplant total body irradiation T helper 1 T helper 17 tolllike receptor temozolomide regulatory T cells == 1. Introduction == Recently, a renewed interest has been focused on combining chemotherapy with immunotherapy for the treatment of cancer patients. Such interest is mostly explained by the discovery of new effects of certain chemotherapeutic brokers, which suggest novel rationales for any different and selected use in combination with immunotherapy, including malignancy vaccines (Emens, 2010;Moschella et al., 2010;Sistigu et al., 2011). The history of pharmacology is usually scattered by the discovery of drugs whose therapeutic use changed from time to time. Anticancer drugs are no exception. The first studies around the toxic effect of mustard gas (sulfur mustards), chemical compounds used as poisoning gas during World War I, led to the discovery of their anticarcinogenic activity in experimental models (Berenblum, 1929). The results obtained by Berenblum were unexpected and suggested the first repositioning of the activity of this class of compounds. The anticancer activity of mustard gas derivatives was definitely proved after the so called Disaster at Bari, the only European city to experience an accidental chemical warfare in the course of World War II (Disaster at Bari by Glenn B. Infield). Studies LUF6000 performed by Goodman and Philips, including observations around the casualties produced in Bari harbor by the explosion of the Liberty ship John Harvey, which was transporting mustard gas, were published after war time (Gilman and Philips, 1946), demonstrating that these compounds could exert cytotoxic actions on a variety of tissues, particularly related to the degree of their proliferative activity. Many studies have been subsequently conducted leading to the discovery of other LUF6000 types of alkylating brokers, many of which are in clinical practice today. Cyclophosphamide (CTX) was the major drug under experimental and clinical investigation (Comparative clinical and biological effects of alkylating brokers. Monograph of the New Academy LUF6000 of Sciences; 1958). Many other chemical compounds were added to the antineoplastic drugs armamentarium over the years, all having the goal of directly and selectively interfering with the growth of malignant cells. Most LDOC1L antibody of these compounds are not, however, devoid of side effects, among which the most significant are the myelo and immunosuppressive activities. Because of these side effects, which impair the proliferative and effector functions of peripheral LUF6000 T cells, CTX and methotrexate are currently used for the treatment of many autoimmune diseases, and for the same reason they have LUF6000 been historically regarded as detrimental to antitumor immunity. This dogma was challenged at the beginning of the 1970s suggesting a second repositioning of the pharmacologic activity of these compounds (Maguire and Ettore, 1967;Vadlamudi et al., 1971). Several authors subsequently showed that combination therapy consisting of CTX and adoptive immunotherapy induced total regression of experimental large tumors (Cheever et al., 1980;Greenberg et al., 1980;North, 1982). Noticeably, Robert North explained the toxic effect of CTX against a T lymphocyte subpopulation endowed with immune suppressive activity (North, 1982). North’s studies were particularly farsighted as he envisaged both the presence of a T cell populace, which will be later characterized as CD4+CD25+regulatory T cells (Treg) (Sakaguchi et al., 1995), and the selective sensitivity of this populace to the harmful effect of CTX, as recently proved byGhiringhelli et al. (2004). Following the way paved by North, the combination of CTX and adoptive immunotherapy has been tested in several experimental settings to revert tumorinduced tolerance for malignancy treatment. The first results were extremely encouraging and made it possible to turn the adoptive transfer of.