*3.3.1 Background & rationale*

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

**17**

cer type.

*3.3.3 Published results*

*3.3.2 Methods*

*Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy*

(disease-seeking) retrovector designed to disrupt the cell cycle machinery of proliferative tumor cells, forcing them to undergo apoptosis. This is accomplished through "precise" tumor-targeted gene delivery to block the Cyclin G1/Cdk/cMyc/ Mdm2/p53 Axis, effectively arresting the dividing tumor cell in G1 phase of the cell cycle undermining CCNG1 oncogene addiction. Clinical trials using DeltaRex-G to treat cancers that are unresponsive to traditional therapy have shown remarkable efficacy in evoking long term cancer-free survival with monotherapy (>10 years) in a number of patients with pancreatic cancer, osteosarcoma, soft tissue sarcomas, breast cancer, and B-cell lymphoma [54]. Although DeltaRex-G is involved in cell cycle checkpoint inhibition, it has also been shown to reduce extracellular matrix production by tumor cells and increase immune cell entry into the tumor microenvironment, which raises the clinical potential for DeltaRex-G to work synergisti-

One persistent thought is that blanket recruitment of immune cells to the tumor microenvironment may not always be advantageous in creating an effective antitumor response. Certain tumor-infiltrating immune cells of myeloid origin have been shown to aid in tumor metastasis [55]. Cancers often progress and metastasize using immunosuppressive mechanisms that includes production and secretion of molecules that recruit cells involved in immune responses to the tumor microenvironment, and by exploiting checkpoint altering pathways [56]. Alternatively, and plausibly, this is how the innate immune system works in a healthy individual, with its molecular start and stop switches to prevent exaggerated immune responses and autoimmune disease. This study reviews published literature on the specific tumorinfiltrating immune cells seen in tumors of patients treated with DeltaRex-G.

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 tumor-

infiltrating 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 can-

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

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

cally with specific immune checkpoint inhibitors.

#### *Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy DOI: http://dx.doi.org/10.5772/intechopen.96664*

(disease-seeking) retrovector designed to disrupt the cell cycle machinery of proliferative tumor cells, forcing them to undergo apoptosis. This is accomplished through "precise" tumor-targeted gene delivery to block the Cyclin G1/Cdk/cMyc/ Mdm2/p53 Axis, effectively arresting the dividing tumor cell in G1 phase of the cell cycle undermining CCNG1 oncogene addiction. Clinical trials using DeltaRex-G to treat cancers that are unresponsive to traditional therapy have shown remarkable efficacy in evoking long term cancer-free survival with monotherapy (>10 years) in a number of patients with pancreatic cancer, osteosarcoma, soft tissue sarcomas, breast cancer, and B-cell lymphoma [54]. Although DeltaRex-G is involved in cell cycle checkpoint inhibition, it has also been shown to reduce extracellular matrix production by tumor cells and increase immune cell entry into the tumor microenvironment, which raises the clinical potential for DeltaRex-G to work synergistically with specific immune checkpoint inhibitors.

One persistent thought is that blanket recruitment of immune cells to the tumor microenvironment may not always be advantageous in creating an effective antitumor response. Certain tumor-infiltrating immune cells of myeloid origin have been shown to aid in tumor metastasis [55]. Cancers often progress and metastasize using immunosuppressive mechanisms that includes production and secretion of molecules that recruit cells involved in immune responses to the tumor microenvironment, and by exploiting checkpoint altering pathways [56]. Alternatively, and plausibly, this is how the innate immune system works in a healthy individual, with its molecular start and stop switches to prevent exaggerated immune responses and autoimmune disease. This study reviews published literature on the specific tumorinfiltrating immune cells seen in tumors of patients treated with DeltaRex-G.
