UCLA researchers at David Geffen School of Medicine have developed a novel approach of in situ vaccination by intratumorally injecting chemokine gene-modified dendritic cells to sensitize non-responsive non-small cell lung cancer (NSCLC) to anti-PD-1/PD-L1 immunotherapy.
BACKGROUND:
The treatment of non-small cell lung cancer (NSCLC) has been greatly improved since the approval of anti-PD-1/PD-L1 immunotherapy. However, once patients progress on a PD -1 and/or PD-L1 inhibitor, the alternative treatment options are very limited. There is an urgent unmet need to develop alternative treatments for patients resistant to anti-PD-1/PD-L1 immunotherapy. Approaches that enhance tumor antigen presentation, overcome the immunosuppressive tumor microenvironment (TME), and inhibit tumor angiogenesis are anticipated to lead to improved efficacy of PD-1/PD-L1 blockade.
INNOVATION:
UCLA researchers at David Geffen School of Medicine have developed a novel approach to overcome the immunosuppressive TME utilizing in situ vaccination with chemokine gene-modified functional antigen presenting cells (APCs) to enhance tumor antigen presentation and promote tumor-specific T cell activation. The intratumoral injection of CXCL9/10-secreting dendritic cells (CXCL9/10-DCs) has be shown to potentiate the response to anti-PD-1 therapy in genetically engineered murine model of lung cancer bearing increased tumor mutational. This approach of in situ vaccination with CXCL9/10-DC has great potential to sensitize non-responsive NSCLC to anti-PD-1/PD-L1 immunotherapy.
POTENTIAL APPLICATIONS:
• Combined chemo-immunotherapy for advanced non-small cell lung cancer (NSCLC)
• Effective treatment for patients after progression on a PD -1 and/or PD-L1 inhibitor
ADVANTAGES:
• Enhanced efficacy of anti-PD-1 shown by murine lung cancer model
• Significant correlation between CXCL9/10 gene expression levels and the infiltration of DC and CD8+ T Cells
DEVELOPMENT-TO-DATE:
In vitro application to genetically engineered murine model of lung cancer demonstrated significantly Enhanced efficacy of anti-PD-1.
RELATED PAPERS:
Lee JM, Lee MH, Garon E, Goldman JW, Salehi-Rad R, Baratelli FE, Schaue D, Wang G, Rosen F, Yanagawa J, Walser TC, Lin Y, Park SJ, Adams S, Marincola FM, Tumeh PC, Abtin F, Suh R, Reckamp KL, Lee G, Wallace WD, Lee S, Zeng G, Elashoff DA, Sharma S, Dubinett SM. Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8(+) T-cell Infiltration. Clin Cancer Res. 2017 Aug 15; 23(16):4556-4568.
Yang SC, Hillinger S, Riedl K, Zhang L, Zhu L, Huang M, Atianzar K, Kuo BY, Gardner B, Batra RK, Strieter RM, Dubinett SM, Sharma S. Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin Cancer Res. 2004 Apr 15; 10(8):2891-901.
Sharma S, Yang SC, Hillinger S, Zhu LX, Huang M, Batra RK, Lin JF, Burdick MD, Strieter RM, Dubinett SM. SLC/CCL21-mediated anti-tumor responses require IFNgamma, MIG/CXCL9 and IP-10/CXCL10. Mol Cancer. 2003 Apr 15; 2:22.