We propose to evaluate the cellular and molecular mechanisms of immune responses following stimulation with therapeutic vaccination and immune checkpoint blockade to establish effective immune responses in lung cancer. We will target the programmed cell death protein 1 (PD-1) pathway that has shown benefit in patients with lung cancer. Patients do not benefit from PD-1 blockade therapy if they lack lymphocytic infiltration of the tumors. We have a novel means to cause tumor T cell infiltration with CCL21 chemokine to make the PD-1 pathway therapy even more effective. To induce enhanced T cell infiltration in the tumors, we will administer CCL21 gene modified dendritic cells (DC-AdCCL21) pulsed with autologous tumor antigens. We have found that although administration of tumor antigen pulsed DC-CCL21 inhibits tumor growth, PD-1 expression is upregulated on T cells in the TME. We anticipate that this limitation can be overcome by PD-1 blockade combined with therapeutic vaccination. We have found that IFN? and TNF? are induced specifically in the tumor and systemically following therapy. [The IFN? induced chemokines CXCL9 and CXCL10 are induced in the tumor following therapeutic vaccination]. Our central hypothesis is that the CCL21 based therapeutic vaccination will augment immune recognition in lung cancer and modulate PD-1 immune checkpoint blockade therapy. [We hypothesize that CXCL9 or CXCL10 induced in the TME following therapeutic vaccination will recruit activated T cell infiltrates in the tumor]. We hypothesize that the individual or combined therapy will enhance DC maturation and functional activity]. We hypothesize that that the CTL activities following combined therapy will be greater than the therapies administered individually. Utilizing preclinical murine lung cancer models, we will address the following aims.
Aim 1 A will determine the therapeutic value of anti-PD-1 and tumor antigen (lysate or peptide) pulsed DC- CCL21 vaccination on the modulation of anti-tumor immune efficacy in vivo. [Aim 1B will determine the role CXCL9 or CXCL10 on CTL infiltration in the tumors following therapeutic vaccination or combined therapy].
Aim 2 will determine the effects of [individual or combined therapy] on DC maturation, DC functional activity in the TME and systemically.
These aims are innovative and have not been addressed previously.
These aims will improve our understanding of combined therapeutic vaccination and PD-1 blockade in lung cancer and aid in the development of ef fective treatment options for this disease. As a measure of anti-tumor efficacy in both aims, tumor burden, survival and changes in the frequency and functional activities of immune effectors [T (CD4, CD8), NK, NKT and DC] and immune suppressors [tumor associated macrophage (TAM), myeloid suppressor cells (MDSC) and T regulatory (Treg)] will be quantified.
Lung cancer is the leading cause of cancer death in the world and among our Veteran population. With the existing therapeutic interventions, the long term survival for lung cancer patients remain low and only 15% survive for 5 years following diagnosis. New therapeutic strategies are needed. Findings from this study has potential for the development of novel immune based therapy for lung cancer.
