UCLA researchers in the Departments of Medicine and Pulmonary Disease have recently developed a novel approach for improving the long-term efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer. Anti-PD-1 immunotherapy is used for treatment despite the typically low response rate. This rate is attributed to the immunosuppressive tumor microenvironment (TME) and acquired resistance to immune checkpoint inhibitors that frequently occurs following the first treatment with anti-PD-1 therapy.

Despite its poor response to Anti-PD-1 therapy, NSCLC, is well-suited for immunotherapy since it produces many tumor antigens. Recognition of these antigens by tumor-infiltrating lymphocytes (TILs) initiates an anti-tumor response that can be leveraged as a therapeutic. While TILs are rare, type 1 dendritic cells (cDC1s) have been identified as candidate proxies for them. These cDC1s are responsible for entering the TME, processing tumor antigens from dead or dying tumor cells, and presenting them to promote T cell-mediated anti-tumor immune responses. Presence of cDC1s is correlated with positive responses to anti-PD-1 therapy, however optimizing the generation of cDC1s is critical in maintaining this anti-tumor immune response.

INNOVATION: Researchers at UCLA led by Dr. Steven Dubinett have developed an in situ injection (ISV) method using gene-modified cDC1s to boost anti-tumor immune response in anti-PD-1 therapy resistant NSCLC tumors. These cDC1s are engineered with FLT3L to increase differentiation of endogenous cDC1s and expand intratumoral cDC1 populations. Researchers demonstrated that Flt3l gene-modified cDC1s increase T cell infiltration in the TME in murine models. Coupled with anti-PD-1 therapy, FLT3L gene-modified cDC1s improve treatment efficacy and introduce systemic tumor immune memory.

POTENTIAL APPLICATIONS:

• FLT3L cDC1 anti-PD-1 coupled therapy for treatment of NSCLC
• Expansion of endogenous cDC1 populations
• Promotion of anti-tumor immune response

ADVANTAGES:

• Increased efficacy of anti-PD-1 therapy
• Intratumoral injection allows for targeted delivery into tumor site and reduced off-target effects
• Systemic tumor-specific immune memory reduces risk of cancer reoccurrence

DEVELOPMENT-TO-DATE: The efficacy of intratumoral injection of gene-engineered cDC1s with FLT3L in combination with anti-PD-1 therapy has been shown to promote long lasting, anti-tumor response in NSCLC in clinical and pre-clinical studies.

Related Papers (from the inventors only):

1. Jensen Abascal, Ramin Salhi-Rad, Michael S Oh, William P Crosson, Camelia Dumitras, Bin Liu, Steven M Dubinett; Abstract A033: In situ vaccination with Flt3l gene-modified CD103⁺ type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC). Cancer Immunol Res 1 February 2025; 13 (2_Supplement): A033. https://doi.org/10.1158/2326-6074.IO2025-A033
2. Abascal J, Oh MS, Liclican EL, Dubinett SM, Salehi-Rad R, Liu B. Dendritic Cell Vaccination in Non-Small Cell Lung Cancer: Remodeling the Tumor Immune Microenvironment. Cells. 2023 Oct 4;12(19):2404. doi: 10.3390/cells12192404. PMID: 37830618; PMCID: PMC10571973.

Keywords: lung cancer, immunotherapy, dendritic cells, anti-PD-L1/anti-PD-1therapy, non-small cell lung cancer, in situ injection, tumor-infiltrating lymphocytes, tumor antigens