**1. Introduction**

The immune system is physiologically able to detect and destroy abnormal cells and to curb the growth of clinically meaningful cancers [1]. However, during carcinogenesis, immune tolerance and immunosuppression mechanisms become more and more prevalent and critically detectable tumor masses start to appear in patients [2]. Recognized mechanisms are for instance: (1) genetic changes that make cancer cells less visible to the immune system [3], (2) release of specific molecular factors that subvert normal mesenchymal cells and certain immune cells into alleys [3, 4], (3) expression and/or overexpression of specific cancer cell surface proteins, such as checkpoint regulators, that directly inhibit immune cell activation [5].

**Figure 1** provides an overview of the immunosuppressive interplay between a cancerous cell and the immune system into the tumor microenvironment. Cancer cells modulate their expression of receptors, release specific molecules and microvesicles in order not only to avoid destruction but to also recruit immune system components in their favor.

#### **Figure 1.**

*Immune regulation within the tumor microenvironment.*

Only quite recently scientists have started to learn how to interfere with such mechanisms and several types of immunotherapies (**Table 1**) have become available to clinicians [6, 7].

One main area of anticancer immunotherapy is that of adoptive cell transfer (ACT) therapy, which has shown remarkable activity against blood malignancies and even solid tumors [8–10]. In this therapy, immune cells are taken from patients' blood, selected, cultured, genetically modified and multiplied in the laboratory, before being reinfused to patients. Chimeric antigen receptor (CAR) T cells, in particular, are genetically modified in order to express specific very efficient receptors able to target cancer cells. These techniques actually require very special laboratories and expensive resources to be performed. Therefore, they are still out of reach for most of the patients worldwide.

**Figure 2** is a schematic representation of chimeric antigen receptor (CAR) constructs delivered by retroviral transfection in T cell collected from patients and grown in culture. First-generation constructs employ a single-chain variable fragment (SCvf) connected by a linker to a transmembrane domain and an intracellular signaling domain. In second-generation constructs, one co-stimulatory domain (such as 4-1BB) has been added. In third-generation constructs, two co-stimulatory domains (such as 4-1BB or CD 134) have been employed. In fourth-generation constructs, a transgene protein for cytokines or chemokines has also been added. Despite this elaborated design, much research is still needed in order to improve CAR T cells efficacy and limit or control their toxicity.


*Recently FDA-approved immunotherapies (left column) with indication of respective immunotherapeutic categories (right column).*

**163**

lesions [20].

**Figure 2.**

target [23–25].

*Repurposing Infectious Pathogen Vaccines in Cancer Immunotherapy*

Checkpoint inhibitors (CIs) are monoclonal antibodies developed to specifically target checkpoint regulators that are responsible of immunosuppression by cancer cells in many cases. They are arguably becoming the most successful agents in the clinical practice. Some of them are already approved by regulatory agencies and broadly used in oncology practice (cf. **Table 1**). They show considerable efficacy, albeit still in a small percentage of patients, and much research is needed in order to improve their efficacy, avoid resistance development by cancer cells, and, also,

According to various reports, CIs efficacy is very much dependent on the presence and the number of tumor-infiltrating lymphocytes (TILs) in tumor lesions [5] and so various strategies in clinical trials try to increase tumor recognition by the immune system, to turn cold turn cold (immunosuppressed) tumors into hot

CIs are combined with chemotherapy which, inducing cytolysis and release of neoantigens, can trigger an activation of the immune system. The problem with this approach is that most chemotherapies are myelotoxic and immunosuppressive in nature, to the point that the immune system can become so weakened and impaired to effectively fight against left-over cancer cells. Chemotherapeutic agents, such as cyclophosphamide and gemcitabine, having relatively lower myelotoxic effects,

Radiotherapy is also employed because it is able to cause immunogenic cell death, cytolysis, and neoantigen release [14, 17–19]. In principle, it should induce lesser systemic immunosuppression than chemotherapy. In addition, the so-called abscopal effect enable extending immunotherapeutic effects to nonirradiated

Other physics-based techniques, such as cryotherapy, radiofrequency, electrochemotherapy, phototherapy, chemoembolization, and others, can synergize with CIs as well, by causing release of neoantigens secondary to induced cancer cell death [20–22]. Another interesting area of combination therapy with CIs is that with intratumoral delivery of pathogen-associated molecules, which could be used to activate the immune system inside the tumor microenvironment. This approach is the focus of the next sections of this writing. It must be pointed out that it heavily relies on the possibility of delivering molecules directly into tumor lesions by interventional radiology/oncology techniques, because if delivered systemically these molecules would be neutralised by the immune system before they could even reach their

appear among the best candidates for this approach [14–16].

*DOI: http://dx.doi.org/10.5772/intechopen.92780*

reduce their systemic toxicity [10–12].

*Chimeric antigen receptor (CAR) constructs.*

(immunoactive) ones [11, 13].

#### **Table 1.**

*Recent milestone drugs approved for immune oncology.*

#### *Repurposing Infectious Pathogen Vaccines in Cancer Immunotherapy DOI: http://dx.doi.org/10.5772/intechopen.92780*

**Figure 2.**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

Only quite recently scientists have started to learn how to interfere with such mechanisms and several types of immunotherapies (**Table 1**) have become available

One main area of anticancer immunotherapy is that of adoptive cell transfer (ACT) therapy, which has shown remarkable activity against blood malignancies and even solid tumors [8–10]. In this therapy, immune cells are taken from patients' blood, selected, cultured, genetically modified and multiplied in the laboratory, before being reinfused to patients. Chimeric antigen receptor (CAR) T cells, in particular, are genetically modified in order to express specific very efficient receptors able to target cancer cells. These techniques actually require very special laboratories and expensive resources to be performed. Therefore, they are still out

**Figure 2** is a schematic representation of chimeric antigen receptor (CAR) constructs delivered by retroviral transfection in T cell collected from patients and grown in culture. First-generation constructs employ a single-chain variable fragment (SCvf) connected by a linker to a transmembrane domain and an intracellular signaling domain. In second-generation constructs, one co-stimulatory domain (such as 4-1BB) has been added. In third-generation constructs, two co-stimulatory domains (such as 4-1BB or CD 134) have been employed. In fourth-generation constructs, a transgene protein for cytokines or chemokines has also been added. Despite this elaborated design, much research is still needed in order to improve CAR T cells efficacy and limit or control their

**Approved drug Immunotherapeutic category** Nivolumab, pembrolizumab Anti-PD-1 monoclonal antibodies Atezolizumab, darvalumab, avelumab Anti-PDL-1 monoclonal antibodies Ipilimumab Anti-CTLA-4 monoclonal antibodies Sipuleucel-T Dendritic cell-based vaccines

*Recently FDA-approved immunotherapies (left column) with indication of respective immunotherapeutic categories* 

Tisagenlecleucel, axicabtagene ciloleucel (CD19 targeting) CAR T cells Talimogene laherparepvec Oncolytic viruses recombinant IL-2 and INFa Immunostimulants Imiquimod (TLR7 agonist) Toll-like receptor agonists

**162**

*(right column).*

*Recent milestone drugs approved for immune oncology.*

**Table 1.**

toxicity.

to clinicians [6, 7].

**Figure 1.**

of reach for most of the patients worldwide.

*Immune regulation within the tumor microenvironment.*

*Chimeric antigen receptor (CAR) constructs.*

Checkpoint inhibitors (CIs) are monoclonal antibodies developed to specifically target checkpoint regulators that are responsible of immunosuppression by cancer cells in many cases. They are arguably becoming the most successful agents in the clinical practice. Some of them are already approved by regulatory agencies and broadly used in oncology practice (cf. **Table 1**). They show considerable efficacy, albeit still in a small percentage of patients, and much research is needed in order to improve their efficacy, avoid resistance development by cancer cells, and, also, reduce their systemic toxicity [10–12].

According to various reports, CIs efficacy is very much dependent on the presence and the number of tumor-infiltrating lymphocytes (TILs) in tumor lesions [5] and so various strategies in clinical trials try to increase tumor recognition by the immune system, to turn cold turn cold (immunosuppressed) tumors into hot (immunoactive) ones [11, 13].

CIs are combined with chemotherapy which, inducing cytolysis and release of neoantigens, can trigger an activation of the immune system. The problem with this approach is that most chemotherapies are myelotoxic and immunosuppressive in nature, to the point that the immune system can become so weakened and impaired to effectively fight against left-over cancer cells. Chemotherapeutic agents, such as cyclophosphamide and gemcitabine, having relatively lower myelotoxic effects, appear among the best candidates for this approach [14–16].

Radiotherapy is also employed because it is able to cause immunogenic cell death, cytolysis, and neoantigen release [14, 17–19]. In principle, it should induce lesser systemic immunosuppression than chemotherapy. In addition, the so-called abscopal effect enable extending immunotherapeutic effects to nonirradiated lesions [20].

Other physics-based techniques, such as cryotherapy, radiofrequency, electrochemotherapy, phototherapy, chemoembolization, and others, can synergize with CIs as well, by causing release of neoantigens secondary to induced cancer cell death [20–22].

Another interesting area of combination therapy with CIs is that with intratumoral delivery of pathogen-associated molecules, which could be used to activate the immune system inside the tumor microenvironment. This approach is the focus of the next sections of this writing. It must be pointed out that it heavily relies on the possibility of delivering molecules directly into tumor lesions by interventional radiology/oncology techniques, because if delivered systemically these molecules would be neutralised by the immune system before they could even reach their target [23–25].
