Experimental Therapy of Cancer by Costimulated Immunity

描述（由申请人提供）：可以针对“非自身”建立强有力的T细胞应答，同时这种应答受到严格控制和调节，以防止通过免疫调节分子的潜在有害破坏。我们将探索最近发现的共信号通路的治疗潜力，该通路包括两种称为B7-DC和B7-H1的配体以及两种受体，共抑制程序性死亡-1（PD-1）和尚未鉴定的共刺激受体（CoR）。通过计算分子建模和定点突变，我们成功分离出B7-DC突变体（B7-DC*），其失去了与PD-1的结合能力，但保留了共刺激功能。此外，我们还产生了具有增强T细胞应答能力的PD-1阻断mAb。在本提案中，我们将检验通过CoR的选择性刺激和PD-1的抑制将增强治疗性肿瘤免疫的假设。我们将首先评估B7-DC* 共刺激在引发针对免疫原性较差的癌症的治疗免疫中的作用。此外，B7-DC* 将被进一步工程化以增加其亲合力，并将测试其与B7-1共刺激的协同效应以及潜在机制。为了开发PD-1阻断方法，将测试PD-1 mAb在癌症治疗期间诱导自身免疫性疾病的潜力，并将通过组合CD 137和B7-DC* 共刺激来测试新策略，以进一步增强肿瘤免疫并消除自身免疫。我们还将验证我们最近的发现，即淋巴瘤上的PD-1表达有利于免疫力的产生。最后，我们将开发和表征人B7-DC* 和PD-1 mAb，作为将实验室研究转化为临床的第一步。我们的研究将为癌症免疫治疗的新方法奠定基础。

DESCRIPTION (provided by applicant): Vigorous T-cell responses could be mounted against "non-self" while such responses are tightly controlled and tuned to prevent potentially harmful destruction through immune regulatory molecules. We will explore therapeutic potentials of a recently identified co-signal pathway, which includes two ligands called B7-DC and B7-H1 as well as two receptors, a coinhibitory programmed death-1 (PD-1) and a yet unidentified costimulatory receptor (CoR). By computational molecular modeling and site-directed mutagenesis, we have successfully isolated B7-DC mutants (B7-DC*), which lose binding capacity to PD-1 but retain costimulatory function. Furthermore we have also generated blocking mAb to PD-1 with capacity to enhance T cell responses. In this proposal, we will test the hypothesis that selective stimulation through CoR and inhibition of PD-1 will enhance therapeutic tumor immunity. We will first evaluate the role of B7-DC* costimulation in eliciting therapeutic immunity against poorly immunogenic cancers. In addition, B7-DC* will be further engineered to increase its avidity and will be tested for its synergistic effect with B7-1 costimulation as well as underlying mechanisms. To develop PD-1 blockade approach, PD-1 mAb will be tested for its potential in the induction of autoimmune diseases during cancer therapy and new strategies will be tested by combining CD 137 and B7-DC* costimulation to further enhance tumor immunity and eliminate autoimmunity. We will also validate our recent finding implicating that PD-1 expression on lymphoma is beneficial for the generation of immunity. Finally, we will develop and characterize human B7-DC* and PD-1 mAb as a first step towards translation of laboratory study to clinic. Our studies will form the foundation for new approaches towards immunotherapy of cancers.