*2.2.2.4 Conclusions/future directions*

The results of this study demonstrate an acceptable safety profile and clinical benefit of combination treatment with nivolumab and apatinib that is worth exploring further in additional clinical studies.

*2.2.3 Phase 1, Open-Label, Safety Study of Escalating Doses of Ex Vivo Expanded, Autologous Natural Killer Cells in Patients With Pathologically Confirmed Cancer Refractory to Conventional Therapy (NCT03941262). Sant P. Chawla, Principal Investigator*

### *2.2.3.1 Background & rationale*

Natural killer (NK) cells are the cytotoxic lymphocytes of the innate immune system [38]. As a rapid, first line of defense, NK cells are able to lyse tumor cells independent of the expression of tumor-associated antigens and/or the presence of major histocompatibility complex class I (MHC-I) molecules. This ability is crucial as cancer cells have been shown to downregulate the expression of MHC-I on their cell surface as a way to evade detection by immunosurveillance mechanisms [39].

**13**

activity.

*Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy*

Since the expression of MHC-I on cancer cells is needed for their detection and destruction by T-cells, evolving a loss of MHC-I expression has been a way for tumor cells to remain undetectable and this loss has therefore been reported "as a mechanism of resistance to anti–PD-1 therapy" [40]. In order to avoid the development of resistance to PD-1 checkpoint inhibition therapy, exploration of NK cell therapy is warranted, especially because of the NK cell's specific role in the recognition and destruction of cancer cells that display a loss of MHC-I. Additionally, the broad ability of NK cells to destroy tumor cells irrespective of prior sensitization or immunization therapy make them ideal candidates for engineered cell

Discoveries regarding the NK cell's role in anti-tumor immunity coupled with advancements in the field of hematopoietic stem cell transplantation have brought to light the potential in using NK cell-mediated immunotherapeutic strategies to fight cancer [41]. Adoptive immunotherapy using donor-derived autologous NK cell products can be engineered by using monoclonal antibodies alone, or in combination with in vivo and ex vivo NK cell activation techniques [42]. This is done by obtaining a patient's NK cells and incubating them as highly active NK cells, giving them the ability to mass produce NK cells which are then infused back into the patient. This study explores the safety and tolerability of treating cancer with

This study is a nonrandomized, multicenter safety study of adoptively infused, ex vivo expanded autologous NK cells to treat male and female adult patients with advanced or metastatic, intractable cancer. Study subjects were placed in one of three cohorts and received SNK01 in an open-label fashion according to a 3 + 3 Phase 1 dose-escalation method. Patients received 5 weekly infusions for a period of 5 weeks, and restaging imaging was performed on week 6. The primary objective of this study was a safety assessment based on the incidence and severity of dose-limiting toxicities and other adverse events observed by evaluating vital signs, clinical laboratory findings and physical examination abnormalities. The adverse events were graded according to the CTCAE v5.0 criteria. Subjects' performance status was assessed and recorded using ECOG criteria. The secondary objective is to evaluate the efficacy of the treatment by measuring the objective response rate of

In order to effectively achieve immune surveillance, immunosuppressive signals within the tumor microenvironment must be interrupted. The PD-1/PD-L1 signaling blockade was developed in accordance with this principle. Tumors have been shown to secrete cytokines associated with suppression of T-cells and NK cells, and past murine studies have shown circulating IL-18 in low levels originating from tumor cells can suppress NK anti-tumor activity [41]. The principles of checkpoint blockade can be applied here with the development of a neutralizing antibody to IL-18, suggesting the potential of checkpoint inhibition to improve in vivo NK cell

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

SNK01 (autologous natural killer cells).

target lesions observed via CT scan using iRECIST criteria.

therapies.

*2.2.3.2 Methods*

*2.2.3.3 Preliminary results*

Not yet available.

*2.2.3.4 Conclusions/future directions*

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

Since the expression of MHC-I on cancer cells is needed for their detection and destruction by T-cells, evolving a loss of MHC-I expression has been a way for tumor cells to remain undetectable and this loss has therefore been reported "as a mechanism of resistance to anti–PD-1 therapy" [40]. In order to avoid the development of resistance to PD-1 checkpoint inhibition therapy, exploration of NK cell therapy is warranted, especially because of the NK cell's specific role in the recognition and destruction of cancer cells that display a loss of MHC-I. Additionally, the broad ability of NK cells to destroy tumor cells irrespective of prior sensitization or immunization therapy make them ideal candidates for engineered cell therapies.

Discoveries regarding the NK cell's role in anti-tumor immunity coupled with advancements in the field of hematopoietic stem cell transplantation have brought to light the potential in using NK cell-mediated immunotherapeutic strategies to fight cancer [41]. Adoptive immunotherapy using donor-derived autologous NK cell products can be engineered by using monoclonal antibodies alone, or in combination with in vivo and ex vivo NK cell activation techniques [42]. This is done by obtaining a patient's NK cells and incubating them as highly active NK cells, giving them the ability to mass produce NK cells which are then infused back into the patient. This study explores the safety and tolerability of treating cancer with SNK01 (autologous natural killer cells).
