Intratumoral immunotherapy to enhance T cell infiltration and augment immune checkpoint blockade responses across molecular subtypes of breast cancer

肿瘤内免疫疗法可增强 T 细胞浸润并增强乳腺癌分子亚型的免疫检查点阻断反应

• 批准号: 10689654
• 负责人: ERIKA J CROSBY
• 金额: $ 11.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689654
• 关键词: Address; Antitumor Response; BRCA1 gene; Biological Markers; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; CRISPR screen; CXCL9 gene; CXCR3 gene; Cells; Clinical; Clinical Data; Clinical Research; Combination immunotherapy; Data; Data Set; Disease; ERBB2 gene; Electroporation; Electroporation Therapy; Engineering; Funding; Gene Targeting; Generations; Genes; Goals; Grant; Half-Life; Immune; Immune checkpoint inhibitor; Immunologics; Immunotherapy; Individual; Infiltration; Injections; Interleukin-12; K22 Award; Lesion; Licensing; Ligands; Mammary Neoplasms; Modeling; Molecular; Monitor; Oncogenes; Oncogenic; Outcome; PD-1/PD-L1; PTEN gene; Paclitaxel; Pathway interactions; Patients; Plasmids; Productivity; Progression-Free Survivals; Proteins; Publishing; Recombinant Interleukin-12; Recurrence; Research; Research Design; Resources; Role; Signal Transduction; Site; T cell infiltration; T-Lymphocyte; T-Lymphocyte Epitopes; TP53 gene; Testing; Time; Toxic effect; Transgenic Organisms; Translating; Treatment Protocols; Up-Regulation; Work; adaptive immune response; anti-PD-L1; anti-PD-L1 therapy; anti-tumor immune response; cancer infiltrating T cells; cancer type; chemokine; design; disorder control; follow-up; genetic signature; genomic tools; immune activation; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; immunogenic; improved; improved outcome; individualized medicine; insight; knock-down; malignant breast neoplasm; migration; molecular subtypes; mouse model; phase 2 study; pre-clinical; prognostic; programs; receptor; response; single-cell RNA sequencing; survival outcome; systemic toxicity; trafficking; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

1 Abstract 2 Breast cancer (BC) encompasses multiple diseases made up of different molecular subtypes that are 3 characterized by distinct oncogenic drivers and unique treatment regimens. Despite these differences, across all 4 subtypes, individuals with advanced, recurrent, or metastatic disease still have limited treatment options and 5 poor overall survival outcomes. Immunotherapies offer an opportunity to treat patients regardless of molecular 6 subtypes. This proposal leverages intratumoral (IT) immunotherapy as an alternative to ‘license’ treated lesions 7 to yield productive ratios of T cells to suppressive immune subsets while amplifying immune checkpoint axes 8 and ultimately increasing sensitivity to immune checkpoint inhibitors (ICI). Using a model of TNBC and single 9 cell RNA sequencing, we demonstrate that IT plasmid IL-12 (pIL-12) can convert poorly immunogenic/low 10 TIL tumors into highly inflamed, immunologically active lesions through the coordinated upregulation of the 11 CXCR3 axis in infiltrating immune cells that impacts the migration, differentiation, and activation of both 12 innate and adaptive immune cells. This CXCR3 signature was also significantly enhanced in patients that had 13 an increase in CD8 T cell infiltration into treated tumors post IT pIL-12 therapy and prognostic of improved 14 overall survival. We hypothesize that targeting the CXCR3 axis IT will enhance TILs and convert patients into 15 ICI responders across all molecular subtypes of BC. The proposed work will leverage this preliminary data in 16 the following 3 aims: 1.) Demonstrate increased infiltration of tumor-specific T cells following IT pIL-12-EP 17 treatment and validate the induction of a CXCR3 or trafficking-associated gene signature in ICI responders 2.) 18 Evaluate the role of trafficking-associated proteins in enhancing responsiveness to anti-PDL1 in TNBC using a 19 CRISPR based screen; 3.) Assess IT injection of plasmid CXCL9 to determine if direct targeting of the CXCR3 20 axis is sufficient to enhance T cell infiltration. Dr. Crosby’s long-term goal is to build a research program that 21 contributes to an understanding of immune cell infiltration into tumors to better design, combine, and predict 22 responses to immunotherapies, with a specific focus on BC. A critical impediment to these types of studies is 23 the lack of oncogene-driven, spontaneous BC tumor models which hampers the translational applicability of 24 many pre-clinical findings. Key resources for Dr. Crosby’s independent research are the spontaneous HER2- 25 driven and p53/BRCA1/PTEN-driven TNBC models that she has created, published, and will uniquely possess 26 to perform these and many other studies. Addressing the basic question of how to enhance T cell infiltration 27 into tumors has significant implications for changing the paradigm of treatment for BC patients, particularly 28 using an intratumoral plasmid approach that is easily altered to follow up on newly identified targets. The 29 funding provided by this K22 award will protect Dr. Crosby’s research time to develop and publish these 30 foundational, studies which will support subsequent R01 grant submissions.

1)抽象