Immunity & Immunotherapy of Human Cancer in Scid Mice

Heretofore it has been difficult to study and periodically monitor the anti-tumor immune response of cancer patients for prolonged periods of time in vivo. The co-engraftment of patients~ tumor and their peripheral blood lymphocytes (PBL) into severe combined immunodeficient (SCID) mice provides an opportunity for the first time to study patients~ anti-tumor response and to evaluate the potential of immunotherapeutic strategies in an in vivo model. The model has two embodiments. In the first model patients~ PBL are co-injected with patient~s tumor cells subcutaneously into SCID mice and the xenograft monitored for changes in tumor volume, mitotic and apoptotic indices. In the second model patients~ PBI (made tolerant to mouse tissue antigens) are inoculated intraperitoneally into SCID mice and subsequently challenged with tumor cells with or without immunotherapy. In both models PBL-mediated anti-tumor responses and enhancement of these responses with cytokines or vaccination have been established. The initial goal of this proposal is to demonstrate, monitor and characterize lung cancer patients~ immune response to their tumor at selected intervals after the surgical removal of the tumor. By titrating the number of PBI required to inhibit the growth of a tumor xenograft it is possible to demonstrate an anti-tumor response and to determine if the response changes wit time after the cytoreduction of the tumor. Cell phenotype and cytokines contributing to the patients~ PBL mediated tumor suppression will be defined. The information obtained from these initial studies (i.e., the optimal cytokine or cytokine combination, time after surgery required for recovery of PBL response to tumors, number and phenotype of PBL required for tumor suppression) will be utilized to design immunotherapeutic strategies that will be evaluated in the chimeric human/scidmouse models. These strategies include cytokine gene therapies and tumor vaccination employing dendritic cells. These studies are expected to contributed substantially to our understanding of lung cancer patients~ anti-tumor immunity and to provide a more rational approach to the design and evaluation of immunotherapy of lung cancer.