Our efforts to produce effective cancer therapy focus on methods to address the immune deficits in the lung tumor microenvironment. To restore tumor antigen presentation and antitumor effector activities we are evaluating the intratumoral administration of CCL21 gene modified dendritic cells (DC-AdCCL21) or fibroblasts (Fib-AdCCL21) or replicating deficient adenovirus expressing CCL21 (AdCCL21). Defining alternative strategies for AdCCL21 delivery for intratumoral expression will provide us with more options and further enhance the translational significance of the proposal. Based on our initial findings in the laboratory, we are now translating intratumoral DC-AdCCL21 method to treat lung cancer patients supported by NCI R21 and the NIH RAID program. We have IRB, RAC and FDA approved protocol for a phase1 trial to evaluate DC-AdCCL21 in patients with advanced NSCLC. The trial includes a dose-escalation of DC-AdCCL21 administered intratumorally by injection in patients with inoperable non-small cell lung cancer. Patients will be monitored for specific immune responses. While these translational investigations proceed, in this proposal, in an established orthotopic murine lung cancer model, we will define the cellular and molecular pathways of novel approaches to augment CCL21 therapy. Based on our data in the laboratory we note that while small tumors (5-7 day old) are highly responsive to CCR7 ligand therapy, larger tumors (>10 day old) progress despite therapy. Based on our studies of the tumor microenvironment, we anticipate that therapies targeting multiple immunologic pathways will be necessary to combat lung cancer. Our intent is to translate the findings of this research to treat patients with lung cancer to enhance the efficacy of DC-AdCCL21 therapy. Hypothesis: We hypothesize that rational multimodal targeting of discrete immune effector pathways will circumvent tumor induced immune suppression, facilitate survival of effector cells in the tumor microenvironment, and augment innate and adaptive immunity in lung cancer. We hypothesize that: (1) COX- 2 inhibitors will effectively overcome the immunosuppressive environment within the tumor, (2) IL-7 will effectively expand and facilitate the survival of effector T and NK cells and (3) restoration of SMAD7 in T lymphocytes by IL-7 will serve to heighten the resistance to TGF2 mediated immunosuppressive effects.
Specific Aims : We will define the specific cellular and molecular mechanistic pathways whereby COX-2 inhibition or IL-7 augment CCL21 immune responses in a murine lung cancer model. We will evaluate anti tumor efficacy (as quantified by changes in tumor burden and in survival), and characterize the mechanisms (innate and tumor specific lymphocyte responses, modulation of Treg cell and myeloid immune suppressor cell activities) underlying the effects.
Lung cancer is the leading cause of cancer death in the United States and with the existing therapeutic efforts; only about 15 % of the patients survive 5 years following diagnosis. This statistic has changed minimally in the last 30 years and, therefore, new therapeutic strategies are clearly needed. The experiments in this proposal to test novel combined immune-based approaches and characterize in detail the antitumor immune mechanisms are relevant because it will lead to a highly significant area of clinical application and has the potential to improve lung cancer immunotherapy. ? ? ?
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