Background: Rationale and evidence for intratumoral immunotherapy
Systemic immunotherapy mainly in the form of immune checkpoint inhibitors has transformed the oncology treatment landscape, providing robust antitumor responses in various tumor types [1-3]. However, the vast majority of cancers do not respond to systemic immunotherapy due to a series of obstacles which include an immunosuppressive tumour microenvironment (i.e. immunologically “cold” tumors), physical barriers restricting immune cell invasion of tumors, insufficient drug penetration into tumours, and systemic toxicities [4, 5]. Direct intratumoral delivery of oncolytic immunotherapies could overcome many of these barriers by changing the tumor microenvironment and ignite a powerful patient specific immune response [6].
Oncolytic viruses (OVs) preferentially replicate in tumors as compared to normal tissue and promote immunogenic cell death and induction of host systemic anti-tumor immunity against the antigens released. Much of the existing body of contemporary clinical evidence surrounding intratumoral immunotherapy is derived from studies of talimogene laherparepvec (T-VEC), the only oncolytic immunotherapy to date approved by the US Food and Drug Administration and European Medicines Agency for intralesional treatment of melanoma. T-VEC is derived from a genetically modified herpes simplex virus type 1 engineered to expresses granulocyte-macrophage colony-stimulating factor an immune stimulatory protein, that selectively replicates in and lyses tumor cells [7]. Since its initial approval in 2015, T-VEC has been tested as monotherapy and combined with other therapies, such as immune checkpoint inhibitors, but many of these studies reported low response rates, revealing challenges associated with the clinical use of T-VEC, such as optimal dosing schedule [7]. Encouraging outcomes were reported in the phase 1b portion of the MASTERKEY-265 trial evaluating the staggered combination of intralesional T-VEC plus intravenous pembrolizumab in 21 patients with advanced melanoma (objective response rate: 62%; complete response rate: 43%) [8]. However, the phase 3 portion of the trial evaluating T-VEC plus pembrolizumab (initiated simultaneously) vs pembrolizumab alone failed to demonstrate a significant difference in the dual primary endpoints of progression-free survival and overall survival [9]. Next generation oncolytic viruses target multiple pathways with a single agent. For example, a series of herpes simplex virus type 1–based oncolytic immunotherapies (RP1–RP3) encodes sequences for multiple genes, including a fusogenic membrane glycoprotein (gibbon ape leukemia virus) that increases immunogenic cell death, granulocyte-macrophage colony-stimulating factor, an anti–cytotoxic T-lymphocyte antigen 4 antibody-like molecule, and immune costimulatory ligands (CD40L, 4-1BBL) in various combinations [10], with multiple ongoing clinical trials.
Practical considerations and optimizing workflow for intratumoral immunotherapy programs
Considerations for intratumoral immunotherapy programs include lesion selection and prioritization, delivery technique, needle design, and outcomes assessments.
The initial evaluation should include the assessment of all tumor locations. Common considerations include tumor size and accessibility for needle access. A tumor diameter below 1 cm creates additional challenges for accurate and reproducible intratumoral drug delivery. As the tumor depth affects the accuracy of needle placement , it is advisable to have a compromise between tumor size and tumor depth. In addition, tumor composition with necrosis, vascularity, and immune infiltration can modify drug exposure to viable tumor cells. Recent PET scans or DWI MRI can assist in identifying active tumor and can even be used to target a particularly active component of the tumor [11].
Regarding optimal needle design, a 21–23-gauge needle is recommended for deep intratumoral injections, whereas needles as small as 30-gauge may be suitable for skin lesions [12]. End-hole needles are generally appropriate for small (<1 cm) lesions, but are commonly used for lesions of all sizes. For larger deep-seated lesions, multiside-hole or multipronged needles may offer an advantage over an end-hole needle to distribute the injectate more uniformly [12-14]. Luer lock syringes prevent leakage and inadvertent displacement of the needle during injections. Biosafety concerns may be associated with the use of oncolytic immunotherapies. In clinical trials, few incidents of occupational exposure to herpes simplex virus type 1 through needlestick or splash were reported and those that occurred were effectively treated with acyclovir when appropriate [15,16]. Further, there have been no reported cases of viral transmission to close contacts. For patients who are immunosuppressed, additional safety warnings and procedures may be necessary [16].
Intratumoral injection of oncolytic viruses for solid tumours could help circumvent many of the barriers associated with systemic administration while still inducing a robust systemic antitumor response beyond the injection site. Interventional radiologist in close collaboration with medical and surgical oncologists, play a central role in optimizing workflows and logistics for intratumoral administration of immunotherapeutics and ensuring optimal treatment outcomes for patients.
