**2. Immune interventions promoting active responses against tumor cells**

Therapeutic strategies that target immune activation have shown significantly increased survival and quality of life for cancer patients [17]. Cancer immunotherapy comprises a variety of treatment approaches and combinations, incorporating the specificity of the adaptive immune response (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity [18]. In this section, we provide an overview of key immunotherapeutic approaches.

Some of these strategies involve the application of soluble antibody molecules that specifically recognize and bind TAAs, resulting in blocked receptor signaling and/or passive immunotherapy. In particular, targeting tumor cells by engaging surface antigens differentially expressed in cancers has been widely used. For example, rituximab targets CD20 in non-Hodgkin B cell lymphoma. At least nine monoclonal antibodies (mAbs) targeting six TAAs (HER2/Neu, EGFR, VEGF, CD20, CD52 and CD33) are approved for the treatment of solid and hematological malignancies [19].

they are infused in the patient [31]. One of the most advanced ACTs in clinical use is called CAR (chimeric antigen receptor) T cell therapy, which involves genetic modification of the patient's T cells to enhance their ability to recognize and attack cancer cells [32]. CAR-T cells have been engineered to express multiple CARs that recognize several tumor antigens. This technology has been successfully applied in clinical trials for hematological malignancies, with durable and complete remission in acute lymphoblastic leukemia [33], chronic lymphocytic leukemia [34] and B-cell lymphomas [35]. Another interesting application is the introduction of CARs targeting negative regulatory receptors, such as PD-1, resulting in reversal

Gene-based Interventions for Cancer Immunotherapy http://dx.doi.org/10.5772/intechopen.80386

While cancer immunotherapies continue to evolve, the recurring role for gene transfer as a fundamental component of many of these approaches is quite evident. Here, we explore several immunotherapy approaches that rely on some aspects of gene transfer, highlighting both clinical and technological advances, especially as related to virotherapy, suicide genes,

Genetic instability intrinsic to cancer generates innumerable missense mutations in tumor cells and thus generates specific targets for T cell immunity [37]. Since these neoantigens are not expressed in normal somatic cells, they are inviting targets for the development of cancer

Although the term vaccine initially referred to the use of prophylactic immunizations for bacterial or viral infections, there are vaccines for therapeutic purposes, especially when we refer to cancer. This strategy has been gaining prominence lately as it offers the opportunity for a lasting effector response and with far fewer side effects than established traditional treatments, such as chemotherapy. In general terms, cancer vaccines seek to restore the ability of the immune system to recognize and eliminate neoplastic cells. In addition, the possibility of generating memory T cells favors long-lasting protective effects, including the prevention of metastasis after primary remission, which would greatly increase the survival and quality of life of these patients.

One of the earliest reports of cancer immunotherapy was conducted by William B. Coley. After observing that established tumors associated with fever or infection generally had higher rates of spontaneous regression, Streptococcus (Coley's toxin) was injected into an inoperable bone tumor. Despite generating data with difficult interpretation, it sparked a debate and numerous other fronts of investigation [39]. Corroborating this hypothesis, Lamm et al. demonstrated that Bacillus Calmette-Guerin (BCG) could be used to activate the immune system and thus enable the treatment of bladder cancer. This therapy, approved by the FDA, is still

In both of the pioneering works described above, bacterial components having immunostimulatory properties were used. It is now clear that the formulation of vaccines should include

vaccines and rational combinations of immunotherapies [38].

of immunosuppression in the tumor [36].

vaccines and CAR-T cells.

**3. Cancer vaccines**

in clinical use [40].

**3.1. Improving vaccine efficacy**

Approved by the Food and Drug Administration (FDA) in 2011, ipilimumab is a mAb against cytotoxic T lymphocyte–associated protein 4 (CTLA-4), a negative checkpoint of T cell function. Thus, checkpoint blockade with ipilimumab releases the brakes of the immune system, promoting T cells to combat cancer cells, and has already benefited thousands of patients with advanced melanoma, a disease that typically kills in less than a year [20]. Additional targets of immune checkpoint therapy include programmed cell death protein 1 (PD1) and its ligand PD-L1, which are even more effective and have fewer side effects as compared to anti-CTLA4 [21]. Moreover, checkpoint inhibitors may be used in combination with each other or with other therapies resulting in the induction of sustained antitumor responses in a wide variety of tumors [22–25]. Checkpoint blockade has undoubtedly been one of the most impressive advancements in cancer therapeutics in recent years, prolonging and saving the lives of many cancer patients. Even so, this approach does not directly induce a *de novo* immune response but releases experienced T cells from inhibitory signaling.

Vaccines are strategies to activate effector immune cells upon stimulation with tumor antigens, promoting the patient's own immune system to mount an immune response against neoplastic cells. Numerous vaccine approaches have been attempted and share the goal of providing effective target antigens while reverting, perhaps, the immunosuppressive tumor microenvironment and activating the ability of DCs to present these antigens. One example is GVAX (Cell Genesys, Inc., South San Francisco, CA), a polyvalent vaccine derived from a cultured cancer cell line expressing a plurality of shared tumor antigens. In addition, the cells have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-modulatory cytokine that can activate antigen-presenting cells (APCs) locally at the vaccine site. Indeed, autologous and/or allogeneic GM-CSF-secreting tumor cell vaccines have demonstrated evidence of immunologic responses in patients with various types of cancers, for example, chronic myeloid leukemia [26], melanoma [27], pancreatic adenocarcinoma [28] and prostate cancer [29].

Oncolytic virotherapy (OV) is a novel form of cancer therapy that employs native or engineered viruses that selectively replicate in and kill cancer cells. OVs act as immunotherapies, promoting antitumor responses due to the viral infection of tumor cells and their acute lysis. An example of this therapy is an intralesional injection with talimogene laherparepvec (Imlygic, T-VEC, Amgen, Thousand Oaks, CA), a genetically engineered oncolytic HSV (herpes simplex virus), with mutations in infectious cell proteins (ICPs) 34.5 and 47, and expressing US11 and GM-CSF [30].

Alternatively, the patient's own T cells or NK cells may be used as a therapeutic agent. Such adoptive cell therapy (ACT) involves the recovery and *ex vivo* expansion of the patient's cells, providing the opportunity for selection and activation of tumor-specific populations, before they are infused in the patient [31]. One of the most advanced ACTs in clinical use is called CAR (chimeric antigen receptor) T cell therapy, which involves genetic modification of the patient's T cells to enhance their ability to recognize and attack cancer cells [32]. CAR-T cells have been engineered to express multiple CARs that recognize several tumor antigens. This technology has been successfully applied in clinical trials for hematological malignancies, with durable and complete remission in acute lymphoblastic leukemia [33], chronic lymphocytic leukemia [34] and B-cell lymphomas [35]. Another interesting application is the introduction of CARs targeting negative regulatory receptors, such as PD-1, resulting in reversal of immunosuppression in the tumor [36].

While cancer immunotherapies continue to evolve, the recurring role for gene transfer as a fundamental component of many of these approaches is quite evident. Here, we explore several immunotherapy approaches that rely on some aspects of gene transfer, highlighting both clinical and technological advances, especially as related to virotherapy, suicide genes, vaccines and CAR-T cells.
