**3. Intratumoral delivery of pathogens**

Entire pathogens, in particular recombinant oncolytic viruses, have been engineered to sustain selective replication into malignant cells [46, 47]. However, experience with the use of these oncolytic viruses, originally thought as cytolytic agents, has shown that antitumor immune response against viral-infected cells is a fundamental factor for their anticancer efficacy [48]. Therefore, modern viral vectors are genetically engineered to also express cytokines and other immune stimulating factors [49].

Vaccinia and herpes viruses have proven most effective when engineered to encode for immune-promoting genes such as interleukin 12 (IL-12) and granulocyte macrophage colony-stimulating factor (GM-CSF) [49, 50]. These agents are dramatically enhanced in their therapeutic performances by concomitant administration of PD-1/PDL-1 and CTLA-4 blocking Abs [51] as well as anti-CD137 or anti-OX40 agonist Abs [52–54]. Vectors based on vaccinia virus encoding GM-CSF (JX-594) are also under clinical development with promising results [55, 56].

The most successful agent so far in this category is herpes virus (HSV-1) modified to encode GM-CSF, named T-vec (talimogene). It has been granted Food and Drug Administration approval for unresectable melanoma [57]. Essentially, engineered pathogen preparations are delivered intratumorally in the neoadjuvant setting (essentially according to the scheme in **Figure 3**).
