**3. Past clinical research**

**3.1 Immune Design: A Randomized, Open-Label, Phase II Trial of CMB305 (Sequentially Administered LV305 [lentiviral vector expressing NYESO-1 gene] and G305[NY-ESO-1 recombinant protein plus GLA-SE]) and Atezolizumab in Patients with Locally Advanced, Relapsed, or Metastatic Sarcoma Expressing NY-ESO-1 (NCT02609984) Sant P. Chawla, Principal Investigator**

#### *3.1.1 Background & rationale*

NY-ESO-1 is a protein that is normally expressed in fetal and testicular tissues, although some solid malignancies have been known to express an abnormal NY-ESO-1 protein that has become a target for emerging antigen-directed cancer therapies [43, 44]. Previous studies looking at NY-ESO-1 expression in cancer cells have reported its presence in the majority of synovial sarcomas tested, as well as sporadic expression in a number of other sarcoma subsets [45]. The immunogenicity of NY-ESO-1 has been demonstrated by the discovery of receptors against NY-ESO-1 on CD8+ T-cells. A 2011 clinical trial conducted by the National Cancer Institute was the first to report promising anticancer effects of NY-ESO-1-targeted immunotherapy in patients with metastatic synovial sarcoma using adoptively transferred autologous T-cells containing a T-cell receptor against NY-ESO-1 [46], suggesting its potential to be effective in other sarcomas as well. Since then, numerous trials targeting NY-ESO-1 in various cancer types using both adoptive T-cell therapy and vaccination approaches have concluded that there is a clear clinical benefit in pursuing NY-ESO-1 as an immunotherapeutic target [47].

The drug being studied is CMB305, a prime-boost immunotherapeutic vaccine regimen developed to prime the immune system and enhance its subsequent response to immunotherapeutic agents. The priming component of CMB305 is an integration-deficient, replication-incompetent lentiviral vector containing RNA coding for NY-ESO-1. The boost component contains a recombinant E. coli-produced NY-ESO-1 protein that, as a single agent, can initiate anti-NY-ESO-1-specific CD4+ T-cell and antibody responses. The combination of the primer and the booster was designed with the intention of eliciting an enhanced T-cell response.

The goal of this study was to investigate the ability of a prime-boost immunotherapy regimen that is able to elicit NY-ESO-1-specific CD8+ T-cells to synergistically enhance the efficacy of PD-L1 checkpoint inhibition therapy in advanced or metastatic sarcoma patients whose tumors are positive for NY-ESO-1 expression.

#### *3.1.2 Methods*

The primary objective of this study was to compare the progression-free survival in locally advanced or metastatic sarcoma patients whose tumors expressed NY-ESO-1 when treated with CMB305 in combination with atezolizumab versus patients treated with atezolizumab alone. The secondary objectives of this study were to evaluate the safety of this combination treatment, as well as to evaluate the best overall response rate using RECIST v1.1 modified to use immune-related response criteria. The overall survival of the two groups will be evaluated.

Twelve patients were randomized 1:1 in a safety run-in evaluation. Next, 80 patients were randomized and stratified by disease. Tumor samples from all patients were tested for levels of PD-L1 and NY-ESO-1 expression prior to treatment, and again on Day 42 in order to assess the extent of successful immune cell invasion in the tumor. Re-staging imaging studies were performed every six

**15**

*Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy*

weeks for the first twelve months, followed by staging every twelve weeks until the patient displayed symptomatic progression. CMB305 treatment was administered in seven doses over a three-month period, while atezolizumab was administered intravenously every three weeks, and was continued up to two years or until toxicities began to develop. An additional booster dose was also given every six weeks for the first year or until the patient displayed disease progression. Blood samples were collected to test for lentivirus vector persistence at baseline, six, twelve and twenty-four months following the initial treatment. Adverse events were recorded as related or unrelated to the study drug and graded based on CTCAE c4.03 criteria.

Phase I of this trial was the first of its kind to test a prime-boost vaccination regimen to treat patients with advanced cancer. In 2018, Immune Design released information stating that an early analysis of the Phase II clinical trial results showed the combination treatment of atezolizumab with CMB305 suggested that it is unlikely this regimen will show enhanced survival time of patients with recurrent

synovial sarcoma [48]. A Phase III trial has not yet been pursued.

**Morse, Howard Bruckner, Principal Investigators**

**3.2 A Phase I-II Study Using DeltaRex-G (Former name:Rexin-G)Tumor-**

**Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer (NCT00504998) Sant P. Chawla, Michael** 

Advanced pancreatic adenocarcinoma is the third most common cancer type in the Unites States, although diagnostic tests are non-specific which leads to early-stage disease frequently going undetected [49, 50]. Once pancreatic adenocarcinoma reaches an advanced stage, it has likely become intractable and there is no cure. Previous targeted therapies revolved around the epidermal growth factor receptor (EGFR) signaling pathway, one of the most significant factors regulating cell growth, survival, differentiation and proliferation, making it a promising target for precision medicine [51]. EGFR signaling has been identified as an oncogenic driver in multiple cancer types, and EGFR inhibitors have been used as targeted

DeltaRex-G is the first injectable tumor-targeted gene delivery system to be developed for cancer that blocks the G1 checkpoint of the cell division cycle of cancer cells by inhibiting the CCNG1 gene. DeltaRex-G includes a mutant construct of the CCNG1 gene that inhibits human cyclin G1, a proto-oncogene that promotes cell competence, cell survival, and stem cell proliferation. When administered systemically, DeltaRex-G seeks out and accumulates in tumor tissues by binding abnormal collagenous signature (SIG) proteins that are characteristically exposed as anaplasia during tumor invasion. Once the DeltaRex-G retrovector is incorporated in rapidly dividing cells, a cytocidal CCNG1 inhibitor protein is expressed that effectively blocks the cell division cycle, resulting in apoptosis and subsequent eradication of

Clinical data from DeltaRex-G trials conducted initially in the Philippines showed promising results for patients with advanced pancreatic adenocarcinoma.

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

*3.1.3 Published results*

Not Available.

*3.1.4 Conclusions/future directions*

*3.2.1 Background & rationale*

therapy for pancreatic cancer [52].

cancer cells, proliferative vasculature, and stroma.

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

weeks for the first twelve months, followed by staging every twelve weeks until the patient displayed symptomatic progression. CMB305 treatment was administered in seven doses over a three-month period, while atezolizumab was administered intravenously every three weeks, and was continued up to two years or until toxicities began to develop. An additional booster dose was also given every six weeks for the first year or until the patient displayed disease progression. Blood samples were collected to test for lentivirus vector persistence at baseline, six, twelve and twenty-four months following the initial treatment. Adverse events were recorded as related or unrelated to the study drug and graded based on CTCAE c4.03 criteria.
