Common use of SCIENTIFIC BACKGROUND Clause in Contracts

SCIENTIFIC BACKGROUND. The enzyme IDO catalyzes tryptophan degradation. IDO can be a potent effector of immunosuppression and of tolerance induction in certain settings; for example, expression of IDO in the placenta maintains maternal tolerance towards the fetus. Tumors create a state of immunologic unresponsiveness (tolerance) toward their own antigens, which allows tumors to escape the host’s immune system. This also imposes a barrier to effective anti-tumor immunotherapy. One molecular mechanism contributing to this tolerance is expression of the immunosuppressive enzyme IDO, leading to inhibition of T-cell response. Expression of IDO by human and mouse antigen-presenting cells inhibits T cell mediated immune responses in vitro and in vivo. Tumor cells transfected with IDO become immunosuppressive in vivo, and expression of IDO has been reported in tumor cells from a variety of human tumors. IDO is also expressed by a population of host antigen-presenting cells (dendritic cells) found in tumor-draining lymph nodes of melanoma, breast cancer, and a variety of other tumors, which may act to create tolerance to tumor antigens. Therefore, IDO may be a primary molecular target for cancer immunotherapy and inhibition of the IDO pathway may assist in breaking tumor tolerance. Studies have shown that the small-molecule 1MT possesses immune-enhancing activity by inhibiting IDO in a variety of animal models. 1MT can inhibit IDO enzyme activity in vitro and can prevent IDO-mediated immunosuppression in vivo. 1MT has also been shown to be synergistic with a number of commonly used chemotherapeutic agents. Thus, 1MT may potentially be used as a novel immune modulator in cancer immunotherapy.

SCIENTIFIC BACKGROUND. The enzyme IDO catalyzes tryptophan degradation. IDO can be a potent effector of immunosuppression and of tolerance induction in certain settings; for example, expression of IDO in the placenta maintains maternal tolerance towards the fetus. Tumors create a state of immunologic unresponsiveness (tolerance) toward their own antigens, which allows tumors [ * ] = Certain confidential information contained in this document, marked by brackets, is filed with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended. APPENDIX D Letter of Intent for Proposed CRADA #2166 to escape the host’s immune system. This also imposes a barrier to effective anti-tumor immunotherapy. One molecular mechanism contributing to this tolerance is expression of the immunosuppressive enzyme IDO, leading to inhibition of T-cell response. Expression of IDO by human and mouse antigen-presenting cells inhibits T cell mediated immune responses in vitro and in vivo. Tumor cells transfected with IDO become immunosuppressive in vivo, and expression of IDO has been reported in tumor cells from a variety of human tumors. IDO is also expressed by a population of host antigen-presenting cells (dendritic cells) found in tumor-draining lymph nodes of melanoma, breast cancer, and a variety of other tumors, which may act to create tolerance to tumor antigens. Therefore, IDO may be a primary molecular target for cancer immunotherapy and inhibition of the IDO pathway may assist in breaking tumor tolerance. Studies have shown that the small-molecule 1MT possesses immune-enhancing activity by inhibiting IDO in a variety of animal models. 1MT can inhibit IDO enzyme activity in vitro and can prevent IDO-mediated immunosuppression in vivo. 1MT has also been shown to be synergistic with a number of commonly used chemotherapeutic agents. Thus, 1MT may potentially be used as a novel immune modulator in cancer immunotherapy.

SCIENTIFIC BACKGROUND. The enzyme IDO catalyzes tryptophan degradation. IDO can be a potent effector of immunosuppression and of tolerance induction in certain settings; for example, expression of IDO in the placenta maintains maternal tolerance towards the fetus. Tumors create a state of immunologic unresponsiveness (tolerance) toward their own antigens, which allows tumors to escape the host’s immune system. This also imposes a barrier to effective anti-tumor immunotherapy. One molecular mechanism contributing to this tolerance is expression of the immunosuppressive enzyme IDO, leading to inhibition of T-cell response. Expression of IDO by human and mouse antigen-presenting cells inhibits T cell mediated immune responses in vitro and in vivo. Tumor cells transfected with IDO become immunosuppressive in vivo, and expression of IDO has been reported in tumor cells from a variety of human tumors. IDO is also expressed by a population of host antigen-presenting cells (dendritic cells) found in tumor-draining lymph nodes of melanoma, breast cancer, and a variety of other tumors, which may act to create tolerance to tumor antigens. Therefore, IDO may be a primary molecular target for cancer immunotherapy and inhibition of the IDO pathway may assist in breaking tumor tolerance. [ * ] = Certain confidential information contained in this document, marked by brackets, is filed with the Securities and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as amended. NCI - NewLink CRADA (CACR-2166), Appendix A Studies have shown that the small-molecule 1MT possesses immune-enhancing activity by inhibiting IDO in a variety of animal models. 1MT can inhibit IDO enzyme activity in vitro and can prevent IDO-mediated immunosuppression in vivo. 1MT has also been shown to be synergistic with a number of commonly used chemotherapeutic agents. Thus, 1MT may potentially be used as a novel immune modulator in cancer immunotherapy.