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anti–phospho-stress-activated protein

The Johnson Laboratory uses animal models of in vivo solid tumor growth to study the contribution of indoleamine 2,3-dioxygenase (IDO) to immunological tumor tolerance. Normally, IDO functions to limit immune responses against innocuous exposures, such as commensal bacteria and normal dying (apoptotic) cells. However, IDO is also widely expressed in human tumors and tumor draining lymph nodes, where it can suppress desirable anti-cancer immune responses (In Kalinski P, ed. The Microenvironment in Cancer Progression and Cancer Therapy. New York: Springer, in press). Recently, the Johnson Laboratory also made the novel discovery that when IDO is blocked: (i) conventional chemotherapy can drive intense intratumoral vasculitis, and (ii) conventional chemotherapy with radiation can drive complement-mediated tumor rejection. Thus, blocking IDO during chemo-radiation therapy elicits synergistic effects on survival and changes the nature of the tumor response in tumor models. The central hypothesis is that the interaction between IDO and complement functions as a previously unrecognized regulator of intratumoral inflammation following chemo-radiation therapy, and that this pathway critically regulates the ability of chemo-radiation to cause tumor destruction. The Johnson Laboratory has ongoing projects to study (i) the role of IDO and complement in tumor immunology, testing the hypothesis that IDO acts as a crucial modulator of therapy-induced inflammation in solid tumors by inhibiting the production of pro-inflammatory cytokines and suppressing activation of complement, and (ii) IDO-based immunotherapy for brain tumors using animal models to test the hypothesis that IDO is a critical vascular quiescence factor in brain tumor biology. Dr. Johnson’s team has successfully translated laboratory findings to clinical trials using indoximod to block IDO during standard chemotherapy and/or radiation for patients with glioblastoma. Clinical trials developed as a result of research in the Johnson Laboratory include:  “A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors” (PI: Frank Mott, GRU Cancer Center; Co-I: Johnson, NCT02052648, open at 11 sites in 9 states for patients 16 years and older with glioblastoma)  “Phase I trial of indoximod in combination with temozolomide-based therapy for children with progressive primary brain tumors” (PI: Johnson, NCT02502708, open at 2 sites in Georgia for children age 3-21 years with relapsed or progressive brain tumors) These clinical trials will test the hypothesis that adding IDO-blockade to standard temozolomide therapy, or to radiation therapy followed by temozolomide, will be safe and tolerable in adults and children with relapsed brain tumors, and that this combination immuno-chemotherapy will show preliminary evidence of synergistic efficacy.