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

#### *3.4.1 Background & rationale*

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

**19**

*Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy*

treatment that encoded a GM-CSF gene to examine the role localized GMCSF might play in further improving treatment outcomes and inducing long lasting anti-tumor

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.

No dose-limiting toxicities were observed at any of the three Dose Levels of DeltaVax, and no deaths that occurred were considered to be related to the treatment. None of the patients tested positive for vector neutralizing antibodies, replication-competent retrovirus in peripheral blood lymphocytes, antibodies to gp70 or vector integration into genomic DNA of peripheral blood lymphocytes. Using RECIST v1.0 criteria, three patients achieved a partial response, nine patients achieved stable disease, and two patients had progressive disease. The median progression free survival was 4.5, 9.0, and 13.0 months for Dose Levels I, II, and III respectively, and the median overall survival was 17, 13 and > 21 months for Dose

Histopathologic examination of patients' residual tumor tissues showed vector localization as well as GM-CSF transgene expression in necrotic tissue, displaying the accuracy in delivery of both treatments. Safety and tolerability are displayed by the lack of adverse reactions associated with the study drugs. The one-year survival rate of 86% in patients who received higher doses of DeltaVax suggests that the combination regimen of DeltaRex-G and Deltavax has significant anti-tumor activity in patients with chemoresistant solid malignancies and B-cell lymphoma. In addition, the substantial increase in progression free survival with each increased dosage of DeltaVax suggests a trend towards a positive dose–response relationship

DeltaRex-G has displayed through numerous clinical trials its cytocidal effect on cancer cells. This effect introduces neoantigens from the tumor into the tumor microenvironment to be recognized by the immune system and targeted for destruction through T-cell mediation. Nevertheless, these cytotoxic immune responses may not be significant enough to overcome the suppressive signals from surrounding regulatory T-cells that may also be recruited to the tumor microenvironment. The addition of DeltaVax is hypothesized to heighten the development of dendritic cells and increase proliferation and activation of T-cells, thereby improving the potency of tumor-targeted DeltaRex-G. These activated T-cells can then go

*DOI: http://dx.doi.org/10.5772/intechopen.96664*

immunity.

*3.4.2 Methods*

*3.4.3 Published results*

Levels I, II, III respectively.

between the two treatments.

*3.4.4 Conclusions/future directions*

treatment that encoded a GM-CSF gene to examine the role localized GMCSF might play in further improving treatment outcomes and inducing long lasting anti-tumor immunity.
