Rationalized immunotherapy by immune signature characterization

UnrestrictedGreat strides in the understanding of cancer biology have provided a multitude of approaches to the medical treatment of cancer. While chemotherapy alone has succeeded in making many malignancies into treatable diseases, certain cancers remain elusive despite the current arsenal, and for many patients the toxicities of chemotherapies are intolerable or even fatal. One attractive alternative to chemotherapy is cancer immunotherapy, an approach that seeks to harness the power of the immune system to treat cancer. Despite achieving only modest clinical successes to-date, immunotherapy offers the promise of a physiological treatment as opposed to a treatment based on semi-selective toxicity. This manuscript begins by describing a new murine immunotherapeutic reagent, constructed by genetically linking the antibody Fc backbone to the molecule OX40L, which can provide a T cell activating second-signal and simultaneously inhibit the effects of suppressor T cells known as Tregs. The resultant Fc-mOX40L fusion protein has demonstrated striking anti-tumor effects in two murine experimental tumor models. Though similar fusion protein strategies have been described in the literature, this manuscript goes on to describe a novel approach to delineating tumors' "escape" strategies and identifying the immunotherapy with the greatest capacity for impeding those mechanisms of tumor escape. Using real-time PCR, it was possible to create immune signatures that characterize the T cell activation profile of five murine tumor models as well as human breast and colorectal tumor specimens. This technique identified several cancer-induced immunotherapy targets in human ductal adenocarcinoma of the breast, including high expression of immunoinhibitory B7-H4 and low expression of immune activating CD28 and CD83.; Finally, this manuscript describes how our "immunotyping" approach was used to reveal the immunological mechanisms of action of a combination immunotherapy regimen known to producedifferential responses in different murine tumor models. Ultimately, the degree of Treg cell involvement was identified as the determining factor for the degree of response to treatment. Though the age of "personalized medicine" has been considered by many to be a pipedream with respect to complex diseases like cancer, the technology and analysis herein described make a case for rationalized immunotherapeutics being close on the horizon