**2. Ongoing clinical research**

Ongoing clinical research is either investigator-initiated or company sponsored. In the case of investigator-initiated research, CCSC/SORC serves as the sponsor, conceives and designs the clinical protocol, and manages the entire clinical trial with or without funding by a pharmaceutical company, the FDA or the NIH. Company-sponsored research is developed, monitored, and funded by a pharmaceutical company.

#### **2.1 Investigator initiated research**

*2.1.1 SAINT: An Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab, and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma (NCT03138161). Erlinda M. Gordon, Principal Investigator*

#### *2.1.1.1 Background & rationale*

Soft tissue sarcomas comprise a rare, heterogenous category of malignancies originating from connective tissue, blood vessels or lymphatic tissue [11]. This group accounts for only 1% of adult cancers in the United States, but it has a higher mortality rate than testicular cancer, thyroid cancer, and Hodgkin lymphoma combined [12]. The most commonly used modalities of treatment for sarcoma have been surgery, radiation and chemotherapy. Currently, chemotherapy treatment options have been shown to slow down disease progression but are ineffective in keeping most patients from eventually developing recurrent and metastatic disease [13]. Once unresectable or metastatic, the majority of soft tissue sarcomas remain incurable with chemotherapy. Immune checkpoint blockades do not act directly on the cancer cell, thus they can theoretically be applied to the treatment of any type of solid tumor, including the rarest and most aggressive malignancies. The precedent set by the approval of immune checkpoint inhibition for the treatment of numerous cancer types provides a strong rationale for studying their effects on soft tissue sarcoma. Studies with ipilimumab and nivolumab have since been done showing promising results when used in patients with advanced soft tissue sarcoma [14]. The third drug in this trial is a marine-derived alkaloid, trabectedin, an FDA approved chemotherapy treatment for leiomyosarcoma and liposarcoma [15]. A recently published retroactive analysis of 442 patients treated with trabectedin over a 10 year period confirms that trabectedin can prolong progression free survival (PFS) in patients with advanced sarcoma [16].

Gordon et al. designed the SAINT protocol based on the fact that sarcoma cells are most immunogenic early in the disease process [17] and prior to any other treatment, allowing immune checkpoint inhibitors to exploit this advantage and deploy the immune system to recognize and destroy them. This study was designed to evaluate the best objective response rates (BORR) assessed via CT scan or MRI and to assess the overall survival (OS) and progression-free survival (PFS) after 6 months of treatment.

#### *2.1.1.2 Methods*

Eligible patients for this Phase II clinical trial were treatment-naïve adult patients with advanced unresectable or metastatic soft tissue sarcoma. Trabectedin was administered to the study subjects at the maximum tolerated dose determined previously in the dose escalation phase of this trial. Ipilimumab and nivolumab were be administered at defined doses in order to assess the overall safety profile and potential efficacy of this treatment regimen. Patients continued on the treatment until they experienced significant disease progression or unmanageable toxicities. Best objective response was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using CT scan or MRI. Median progression-free survival (PFS) and overall survival (OS) were also measured in months. Adverse events were assessed and categorized as related or unrelated to the treatment and listed by severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

### *2.1.1.3 Preliminary results were presented at the Connective Tissue Oncology Society Meetings, November, 2020*

Sixty subjects were evaluated using RECIST v1.1 for analysis of treatment efficacy. Twenty-five percent (25%) had either a complete response (11.7%) or a partial response (13.3%), and 37 patients (61.7%) had stable disease. Disease control rate was 86.6%. The median PFS was >6.7 months (6-month OS rate: 90%; 6-month PFS rate: 51%), while the median OS was >17.0 months.

Grade 3 TRAEs included fatigue (n = 6), adrenal insufficiency (n = 1), hyperglycemia (n = 1), dehydration (n = 1), hyponatremia (n = 2), bipedal edema (n = 2),

**7**

checkpoints [20].

*Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy*

increased AST (n = 6), increased ALT (n = 19), increased ALP (n = 1), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 3), thrombocytopenia (n = 2), leukopenia (n = 1), and neutropenia (n = 3). Grade 4 TRAES include anemia (n = 1), neutropenia (n = 1), thrombocytopenia (n = 1), and increased CPK (n = 2). Grade 5 TRAES include rhabdomyolysis (n = 1). Therapy related AML

The positive results from this trial thus far strongly suggest that using combination therapy with ipilimumab, nivolumab, and trabectedin as first-line treatment in patients with advanced or metastatic sarcoma allows the treatments to engage synergistically without causing any additive toxicities. This combination may be superior to known therapies for STS. Overall, the adverse events experienced less severe than toxicities typically experienced with standard first line treatment (doxorubicin/ifosfamide) for metastatic soft tissue sarcoma. Future Phase 3 randomized studies are proposed to evaluate the safety and efficacy of first-line combinatorial therapy with ipilimumab, nivolumab and trabectedin in comparison

The significant immunotherapeutic potential of oncolytic virotherapy is due to its ability to induce a multifaceted anti-tumor response involving aspects of both the innate and adaptive immune systems [18]. A multitude of viral vectors have been explored for their potential oncolytic properties, particularly as a method of delivering targeted treatment to sites of malignant disease [19]. The ability to genetically modify these viruses to target and exploit essential oncogenic signaling pathways has kept them at the forefront of immuno-oncology research [20]. This particular vulnerability triggers selective replication of the viral genome and directly contributes to furthering the oncolytic process. Infected tumor cells secrete viral progeny composed in part by tumor-associated antigens and neoantigens in response to their infection, causing the innate immune system to activate an NK cell-mediated cytotoxic response. The tumor-associated antigens that are released into the tumor microenvironment are phagocytosed by antigen-presenting cells, thus initiating the process of T-cell-mediated adaptive anti-tumor immunity. In addition to the anti-tumor response, the presence of the oncolytic virus also triggers a concurrent anti-viral response, and regulatory mechanisms become crucial to ensuring a controlled immune response, including the upregulation of immune

Oncolytic viruses derived from Herpes simplex virus 1 (HSV-1) vectors are amongst the most frequently investigated in pre-clinical trials and have been shown to encompass the combined ability to induce oncolysis and anti-tumor immune responses simultaneously [21]. Talimogene Laherparepvec (T-VEC) is an injectable live, attenuated, oncolytic HSV-1 virus that has been genetically engineered to express human granulocyte-macrophage colony-stimulating factor (huGM-CSF), a known immune modulator and hematopoietic growth factor that stimulates the

to standard therapy for patients with advanced soft tissue sarcomas.

*2.1.2 The TNT Protocol: A Phase II Study Using Talimogene Laherparepvec, Nivolumab, and Trabectedin as First, Second/Third Line Therapy for Advanced Sarcoma, including Desmoid Tumor and Chordoma (NCT03886311). Sant P. Chawla and Erlinda M. Gordon, co-Principal* 

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

occurred in one patient.

*Investigators*

*2.1.2.1 Background & rationale*

*2.1.1.4 Conclusions/future directions*

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

increased AST (n = 6), increased ALT (n = 19), increased ALP (n = 1), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 3), thrombocytopenia (n = 2), leukopenia (n = 1), and neutropenia (n = 3). Grade 4 TRAES include anemia (n = 1), neutropenia (n = 1), thrombocytopenia (n = 1), and increased CPK (n = 2). Grade 5 TRAES include rhabdomyolysis (n = 1). Therapy related AML occurred in one patient.
