*3.4.2 Methods*

*Advances in Precision Medicine Oncology*

*3.3.4 Conclusions/future directions*

**Investigator**

*3.4.1 Background & rationale*

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.

Activating and optimizing the body's own immune system is at the core of precision medicine. Pathologic review showed evidence of **enhanced immune cell trafficking in the tumor microenvironment of patients treated with DeltaRex-G, suggesting that this treatment activates the innate immune response**. This implies that DeltaRex-G may enhance the performance of an immunotherapy agent when used simultaneously. Three patients identified in the literature with metastatic pancreatic cancer, B-cell lymphoma and metastatic osteosarcoma, respectively, have survived over 10 years following treatment with DeltaRex-G, no cancers have recurred, and no additional treatments have been needed. This clinical evidence strongly suggests that **DeltaRex-G has the ability to promote cancer immunization in situ through CCNG1 inhibition without causing deleterious immune suppression** [9]. Therefore, further evaluation of the role of DeltaRex-G in enhancing immune cell trafficking in the tumor microenvironment is warranted.

**3.4 The Genevieve Protocol: Phase I/II Evaluation of a Dual Targeted Approach to Cancer Gene Therapy/Immunotherapy. Jorge G. Ignacio, Principal** 

Patients whose cancer has recurred or progressed after therapy have likely exhausted their treatment options [57]. This is where the need for research towards the development of personalized targeted treatments becomes both vital and urgent. The GeneVieve (Genes for Life) Protocol was a dose-seeking study for chemoresistant solid malignancies and B-cell lymphoma, that evaluated the efficacy and safety profile of a dual targeted gene therapy regimen using DeltaRex-G and DeltaVax (Former name: Reximmune-C), two personalized vaccination strategies aimed to augment immune cell trafficking within the tumor microenvironment for in situ autoimmunization. DeltaRex-G is a retrovector encoding a cytocidal "dominant-negative" mutant construct of the human CCNG1 (Cyclin G1) oncogene. This retrovector is designed to destroy cancer cells, its tumor vasculature and tumor associated fibroblasts, expose neoantigens created by the tumor debris, inhibit the production of the extracellular matrix and enable immune cells to safely enter the tumor microenvironment. DeltaVax is a retrovector encoding the human GM-CSF gene, used for evoking T-cell proliferation, dendritic cell maturation and polarization of M1 macrophages. United States- and Philippine-based Phase I/II studies using DeltaRex-G for sarcoma, pancreatic cancer, and breast cancer led to its accelerated approval in the Philippines for all chemoresistant solid malignancies and subsequent USFDA approved Orphan Drug status for pancreatic cancer, soft tissue sarcoma and osteosarcoma. In 2009, DeltaRex-G received Fast Track designation for a pivotal Phase II/III trial for pancreatic cancer in the United States. The GeneVieve protocol added a second retrovector strategically to the DeltaRex-G

Pro-tumor macrophages were seen in breast ductal carcinoma.

**18**

The patient population consisted of 16 adults with unresectable advanced or metastatic disease. All subjects had an ECOG score between 0 and 1, adequate hematological, kidney and hepatic function, and an estimated survival of 3 months or more. A chemistry panel and complete blood count were assessed weekly during treatment. DeltaRex-G was administered with escalating doses of DeltaVax, five patients at Dose Level I, four patients at Dose Level II, and seven patients at Dose Level III. All patients received a minimum of two cycles of treatment over an 8-week period. Toxicity was assessed prior to each infusion and subsequent treatment cycles using NCI CT-CAE version 3.0 criteria. A staging assessment was performed every 4 weeks with an FDG PET-CT scan. All images were performed and reviewed independently by the radiologists and RECIST v1.0 and International PET criteria were used to assess overall tumor response and progression-free survival.
