*3.3.2 Methods*

*Advances in Precision Medicine Oncology*

sion-free survival and months of overall survival.

line therapy for advanced pancreatic adenocarcinoma.

*3.2.4 Conclusions/future directions*

**(CCNG1) inhibitor-treated tumors**

*3.3.1 Background & rationale*

*3.2.2 Methods*

*3.2.3 Published results*

This prompted USFDA Orphan Drug status, leading to progressive clinical trials in the United States, using DeltaRex-G to treat chemotherapy-resistant advanced pancreatic adenocarcinoma, soft tissue sarcoma, osteosarcoma, and breast cancers. This study reports the results compiled from a Phase I-II clinical trial using intrave-

Twenty patients with chemotherapy-resistant metastatic pancreatic cancer were enrolled in the trial. Target lesions were identified in each patient and changes in tumor size were measured using RECIST v1.0 criteria. Patients were grouped and treated at 3 escalating doses of DeltaRex-G, with six patients at Dose 0-I, seven patients at dose level II, and seven patients at dose level III. Fifteen patients completed at least one full 4-week treatment cycle and had a follow-up PET-CT scan. These fifteen subjects comprised the modified intent-to-treat (mITT) population and were evaluated in terms of their response to the treatment, months of progres-

The safety analysis revealed no clinically significant dose-limiting toxicities at any of the 3 dose levels, with no serious adverse events related to the study drug. None of the patients tested positive for vector neutralizing antibodies, replicationcompetent retrovirus in peripheral blood lymphocytes, antibodies to gp70, or vector integration into the genomic DNA of peripheral blood lymphocytes. According to the RECIST v1.0 evaluations of tumor responses, one patient achieved a complete response, two patients, partial response, and 12 patients, stable disease with 100% disease control rate. The median progression free survival by RECIST v1.0 was 2.7 months, 4.0 months, and 5.6 months at Dose levels I, II, and III, respectively. Median overall survival was 4.3 months, 9.2 months, and 9.2 months at Dose levels I, II, and III, respectively. A dose response relationship was shown between duration of survival and DeltaRex-G dosage (p = 0.03). Consequently, fast track designation was given by the USFDA for a planned Phase 2/3 study using DeltaRex-G as second

DeltaRex-G is a potent cytotoxic cell cycle checkpoint inhibitor. Complete and partial responses were observed at dose levels II and III, suggesting a significant dose–response relationship between the dose of DeltaRex-G given and the level of response seen in the tumors. This relationship is further implied by the increase in months of progression free survival as the dosages were increased. Additionally, CCNG1 is expressed in over 50% of various different malignancies other than pancreatic cancer, suggesting DeltaRex-G's potential efficacy in other cancer types [10].

**3.3 Immune cell trafficking in the tumor microenvironment of human cyclin G1** 

Cell cycle checkpoint pathways that govern uninhibited cell proliferation can be rendered ineffective by a variety of cancer-induced immunosuppressive mechanisms [53]. The experimental cancer gene therapy, DeltaRex-G, is a pathotropic

nous infusions of DeltaRex-G as treatment for advanced pancreatic cancer.

**16**

A review of published literature was conducted on articles pertaining to the efficacy of DeltaRex-G in influencing the tumor microenvironment. The tumor types identified throughout the literature review included pancreatic adenocarcinoma metastatic to the liver, melanoma metastatic to the inguinal lymph node, colorectal cancer metastatic to the lungs, pancreatic B-cell lymphoma metastatic to the liver and cervical lymph nodes, recurrent breast ductal adenocarcinoma, and non-small cell lung carcinoma metastatic to the adrenal gland. The presence of tumorinfiltrating lymphocytes in excised tumors of patients treated with DeltaRex-G was assessed using immunohistochemical staining, and anti-tumor immune cells were differentiated from pro-tumor immune cells by their cytological characteristics. Agents included in the category of anti-tumor immune cells included dendritic cells, helper T-cells, natural killer cells, and killer T-cells. Regulatory T-cells and B-cells have the ability to encourage tumor growth by preventing antigen presentation and killer T-cell activation, thus were categorized as possibly pro-tumor immune cells. M1 macrophages were categorized as anti-tumor, although M2-type tumor-associated macrophages can promote tumor pathogenicity by overpowering M1-type tumor-infiltrating macrophages that elicit anti-tumor inflammation and were therefore categorized as pro-tumor. Results were reported based on cancer type.

### *3.3.3 Published results*

Killer T-cells were identified in the tumor microenvironment of all cancers analyzed and helper T-cells were identified in all tumor types except for pancreatic B-cell lymphoma metastatic to the liver and cervical lymph nodes. Dendritic cells were found in metastatic pancreatic adenocarcinoma, metastatic melanoma, breast ductal adenocarcinoma and metastatic non-small cell lung cancer. Natural killer cells were seen in metastatic pancreatic adenocarcinoma and metastatic non-small cell lung cancer. M1 macrophages were seen in breast ductal adenocarcinoma.

B-cells, possible pro-tumor cells, were seen in metastatic pancreatic adenocarcinoma, metastatic colorectal cancer, breast ductal adenocarcinoma and metastatic non-small cell lung cancer. Leukocyte common antigen was seen in metastatic pancreatic adenocarcinoma, metastatic melanoma, and non-small cell lung cancer. Pro-tumor macrophages were seen in breast ductal carcinoma.
