Interventional Radiology for Local Immunotherapy in Oncology

Interventional radiology procedures provide minimally invasive targeted treatments for personalized oncology care (1). Several important image-guided diagnostic and therapeutic options include needle biopsy; thermal ablations; intra-arterial therapies; and palliative treatments, such as consolidation of pathologic fractures. As imaging techniques and procedure devices have improved, so have therapeutic results for localized tumors. Recent breakthroughs in systemic immunotherapy have piqued interests in combining immuno-oncology strategies with interventional radiology techniques (2). Early preclinical and clinical studies have evaluated the immunomodulating impact of applying interventional radiology percutaneous ablation or intraarterial therapies together with immunotherapies and have shown encouraging results (3), with multiple ongoing clinical trials (4).

While systemic immunotherapies have revolutionized cancer care, objective response rates for many cancer histologies remain low (5), in part due to barriers imposed upon the immune system by immunosuppressive elements within the tumor microenvironment. Given that locoregional therapies such as ablation can modulate the tumor immune microenvironment, and that local immune activation can lead to systemic antitumor immunity, there has been renewed interest in such therapies not only for their ability to achieve local tumor kill but also to stimulate the adaptive immune response. Likewise, the conventional repertoire of locoregional therapies has recently been expanded through the development of numerous human intratumoral immunotherapies (HIT-IT). HIT-IT applies the simple principle of direct delivery of immunomodulatory therapies into the tumor via percutaneously placed needles, with promising results in early trials, but also a phase III trial (6, 7).

Image-guided access directly into the tumor aims at increasing the intratumoral drug concentration while minimizing its systemic exposure to enhance the therapeutic index of such treatments. While the concept of direct injection of a medication into a tumor seems straightforward, it actually raises many practical questions, such as tumor selection, tumor portion to inject, delivery platform, delivery scheme and rhythm, injection rate, concentration, and volume. However, no current guideline exists for intratumoral injection techniques.

Several technical methods have been developed to optimize HIT-IT drug dispersal within a tumor lesion. Preliminary experience in tertiary cancer institutes provide key practical information to guide and standardize HIT-IT techniques (8, 9). Factors to consider include selection of patients who can most benefit from the treatment, selection of the most suitable organ and tumor to inject, and selection of the delivery system and dispersal technique (10).

This article provides a thorough examination of these factors as they are currently understood, in an attempt to better standardize HIT-IT delivery techniques to improve the patients' experience and their outcomes.

Patient selection for HIT-IT is best approached with multidisciplinary input (Fig. 1). At minimum, both a medical or surgical oncologist and an interventional radiologist are critical. The oncologist identifies the patient who might most benefit from HIT-IT in accordance with the inclusion/exclusion criteria of the protocol if the treatment is provided within a clinical trial. The interventional radiologist provides the procedural assessment of tumor accessibility by image-guided needle access. Inclusion of this process within a larger multidisciplinary setting that meets regularly would ensure a more comprehensive approach and appropriate inclusion of all patients who might benefit from HIT-IT.

Current research trial designs have focused HIT-IT on two subsets of patients: (i) those with immune-sensitive tumors who have demonstrated progression or toxicity after first-line anti-PD(L)1 systemic immunotherapy, or (ii) those with a tumor subtype known to be immunoresistant for whom a high concentration of or a novel immunotherapeutic agent directly into the tumor aims to overcome this immune resistance. HIT-IT treatment has also been recently proposed to be applied in the neoadjuvant setting with the idea of priming a specific immune response to minimize postoperative recurrence (11).

Once a patient has been selected for treatment, a coordinated interdisciplinary effort is required between the investigational oncology team and the interventional radiology team. Both teams would benefit from dedicated research coordinators, as ongoing trials require specific sequences of drug preparation, repeated imaging of injected and noninjected lesions, drug administrations, sample acquisitions for laboratories, and comprehensive data monitoring. The research coordinators help to coordinate with patients, ensure an organized patient flow, and warrant the clinical data entry into the study case report form, all of which are critical to ensure similar standards are met across the globe. An illustration of the logistical challenges of those activities have been provided by the clinical development of T-VEC (12). Finally, for combination trials that require the injection of several different immunotherapeutic medications, a specific order should be predefined.

The patient population that currently benefits from HIT-IT often has multiple metastases that are often located in different organs. While a common response to this challenge may be to inject all tumor locations, this might not be technically feasible. Furthermore, potentiation of immune response after injection of one or several metastases should confer some treatment response of noninjected (abscopal or anenestic) lesions. Current scientific understanding to guide selection of the most appropriate tumor location remains undetermined. Organ-based benefit might well vary by the specific type of immunotherapy drug. For example, the response to a tumor in the liver versus in a lymph node might depend on which of the following drug types is delivered: Toll-like receptor or Sting agonists, PD(L)-1 or CTLA-4 directed antibodies, oncolytic virus, oncolytic peptides, chimeric antigen receptor (CAR)-T cells, or small molecules. As these questions have yet to be answered, the selection of the appropriate tumor to inject often relies on the following three parameters: tumor characterization, tumor visibility and accessibility, and procedural safety.

The initial evaluation should include the assessment of all tumor locations (Fig. 1). 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 (Supplementary Data; Supplementary Fig. S1), 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. Large tumors are known to be less homogeneous and difficult to spread the drug throughout the entire tumor volume, consequently tumor larger than 5 cm should be questioned for HIT-IT.

Improved HIT-IT outcome can be attained by treatment of a tumor with viable tumor cells. Recent PET scans can assist in identifying active tumor and can even be used to target a particularly active component of the tumor (13). In the absence of a recent PET scan, or in nonavid tumor types, alternative imaging can also prove helpful. The identification of a new or enlarging tumor in a location distal to any recent locoregional therapy is more likely to have a high percentage of active cancer cells. Contrast-enhanced imaging can evaluate the tumor vascularization and be used as a surrogate of activity for certain tumors; low vascularity suggests low tumor activity (14). Targeting of necrotic tumors or fibrotic components that could be more immunotolerant should not be prioritized. In the setting of uncertain viability of a certain tumor location, a percutaneous biopsy can be obtained to evaluate for necrosis and immune infiltrates. Conversely to what is commonly admitted, viable tumor cells are not more frequently at the tumors' periphery. Indeed, a prospective study with tumor cell quantification of all samples showed that for one third of the patients, central biopsies presented a higher tumor cell percentage; for one third it was the opposite; and no difference was observed among central or peripheral tumor samples for the last third (14).

Other important considerations in tumor selection include a location or rate of progression that might predispose to significant clinical sequela in case of continued growth by compression of a critical structure, such as a central biliary branch, the urinary tract, or neural structures.

Discussions should also identify whether multiple tumors should be injected in the same or altering procedural settings, and whether repeat injections are anticipated. Injecting various organs might induce distinct types of immune response with the emergence of lymphocytes endowed with different combinations of adhesion molecules that allow them to have distinct migration patterns in the body (injecting only the skin might give rise to lymphocytes that have a predilection to go back to the skin because of a4B7 integrin or cutaneous lymphocyte antigen expression). Thus, a more diffuse immune response could be induced if several organs are injected.

Some tumor sites might require the support of additional specialties for access or risk assessment, such as endoscopy or surgery.

Finally, the need to identify a noninjected lesion should be discussed. In several research trials, the noninjected lesion can be used to monitor distant effect (abscopal or anenestic) by imaging and/or percutaneous biopsy.

Procedural risk assessment is crucial to prevent harm and ensure the medication is delivered in toto. Risks of percutaneous needle access are related to the organ targeted, the caliber of the needle, and the structures along the needle path. Small 22-gauge (G) needles are sufficient for drug injections. But if a biopsy is associated with the intratumoral injection, then a larger coaxial needle caliber of 17–18G is necessary and consequently increases risks of complications. These risk factors have been thoroughly reported in the literature on percutaneous image-guided biopsies (15–17). Given the decreased risk for bleeding and easiness of accessibility, the most common locations for HIT-IT are lesions located in the subdermal soft tissues, muscles, and superficial lymphatic chains. In the absence of these options, the most common targeted deep organ is typically liver lesions given the high prevalence of metastases to this location. While complications of needle access to liver lesions are often acceptable (18), injection of subcapsular and exophytic tumors should be avoided to prevent hemorrhagic and seeding complications related to tumor rupture. The lung is also an organ predisposed to metastases. As percutaneous needle access carries the risk of pneumothorax or pulmonary hemorrhage (17), the preferred lung targets are more superficial locations (Fig. 2).

Particular attention should be paid to kidney and spleen injections, as both organs might bare a slightly increased hemorrhagic risk. Furthermore, injections into the adrenal gland may induce catecholamine secretions with potential effects on the cardiocirculatory system.

Finally, injecting tumors abutting or encased within major vessels (>3–5 mm in diameter) or those deemed to have a risk of bleeding should be discussed in a multidisciplinary setting. Beyond the risk of needle puncture, vascular catastrophes caused by major tumor necrosis or inadvertent intravascular systemic injection of the injected product or major peritumoral leak should be anticipated; the most common clinical setting in which this scenario arises is patients with head and neck malignancies that encase the carotid artery and jugular vein. Tumors with macroscopic intravascular invasion, for example, hepatocellular carcinoma with portal tumor thrombus, should also be questioned before treating them with HIT-IT (8).

Procedural safety issues can also be associated with local toxicity of the drug delivered. Agreement between the oncology and interventional radiology teams is necessary to plan for scenarios that might require modifications of injection locations due to this local drug toxicity or from a mixed tumor response. Furthermore, a flexible strategy should be defined in case of local complications or major patient discomfort to prevent repetitive injections into the same tumor location.

The patient experience and the procedural methods can have an impact on an HIT-IT program, depending on the patient's willingness to proceed and the technical variables of needle type, dispersal method, and duration of drug administration (Table 1).

A positive patient experience and acceptance of complete therapy rely on pain control and the patient's understanding of procedural expectations. The patient's education on the procedure methods, potential complications, and potential pain are all important information to convey. Deep organ punctures are generally more painful than superficial ones because of the liver capsule, pleura, muscles, and peritoneum innervation. The number of tumors injected during a session and the need for concomitant biopsies are important factors as well. Furthermore, the patient should be aware that multiple injections are anticipated, and be prepared to follow through with the repetitive treatments according to schedule. Finally, the patient procedural experience can be greatly improved with premedication for anxiety and appropriate intraprocedural pain management techniques (19, 20).

Before needle insertion, appropriate sterile precautions and medication verification should be completed. For the majority of immunotherapies, standard sterile technique used for percutaneous needle procedures can be followed. In some instances, such as for virotherapy, additional precautions should be used by the operator, including full barrier surgical gowns, double gloving, and goggles. Preparation of the medication to be injected should follow simple, clear protocols that verify drug stability, concentration and volume before administration. The interventional radiologist should verify that the product to be injected is compliant with the product approval or protocol (e.g., injection within a given timeframe postpreparation). Most of the products are stable for several hours, permitting centralized preparation and flexibility for administration during the day. For products that require cold storage, syringe preparation can be done just prior to administration by the interventional radiologist. A volume to inject lower than 0.5 mL increases the variability of total amount of delivered drug, and higher than 10 mL carries the risk of significant leakage outside the tumor.

Percutaneous direct intratumoral administration of immunotherapies is the most frequent administration route for HIT-IT (Fig. 3). Intra-arterial administration has been reported for CAR-T cell infusion (21) to decrease cytokine release syndrome magnitude. Intra-arterial administration has also been applied to improve results for immunoresistant tumors, such as uveal melanomas (22), or to decrease the risk of recurrence in a neoadjuvant setting (22). Intracavitary infusions have also been reported in a phase I trial evaluating intrapleural injections of CAR-T cells targeting mesothelin for the treatment of mesothelioma (23), and could be of interest for peritoneal carcinomatosis (24) management similar to intraperitoneal chemotherapy. Finally, access to the lymphatic vessels is today technically possible due to refinement in interventional radiology techniques, namely through direct access of inguinal lymph nodes (not macroscopically involved by tumor). However, to our knowledge, this route of administration has never been reported for HIT-IT, although specific immune cell populations could be targeted this way (25).

Successful and safe HIT-IT requires clear imaging visibility during percutaneous needle access. Adequate conspicuity on CT without injection of contrast medium is a key parameter to select a tumor to be injected, as per procedural MR guidance or PET-CT guidance is poorly available (26). If the target is only seen on contrast-enhanced imaging, this will impact feasibility, as detailed in the next section. Consequently, a soft tissue or deep organ tumor seen only on contrast-enhanced CT or MRI, or PET-CT, should be evaluated for injectability with nonenhanced CT or ultrasound.

Accuracy of needle targeting is driven by several factors: size, deepness, conspicuity, and mobility of the tumor to be injected. Image guidance is often performed with either ultrasound or CT. Ultrasound is often the preferred imaging modality because of the wide availability, the less expensive cost, the potential for real-time guidance, and the frequently shorter procedural time (27). Many lesions, however, cannot be well visualized with ultrasound and will require access by CT guidance. CT can provide improved access to deep tumors and allows easy verification that the exact targeted lesion identified in preprocedure planning was injected, and not an adjacent lesion. Although the administered drug cannot be visualized by ultrasound or CT, the image guidance provides reassurance that the needle tip is located within the tumor. There are several radio-opaque HIT-IT agents, including hafnium nanoparticles used as radiotherapy enhancers (28) and the iodine-containing small molecule PV-10 (29). Imaging at the time of injection also allows for tumor evaluation such as measurements, and also allows immediate monitoring for complications.

For percutaneous injections, thin coaxial needles are used preferentially. The needle caliber must be kept as low as possible because needle caliber has been demonstrated to be linked to complications, such as bleeding and pneumothorax. Small 22G (0.64 mm external diameter, 0.4 mm internal lumen) provide a good compromise between complication risk and acceptable rigidity needed for guidance. Medication should be supplied and administered in Luer-lock syringes that can be screwed onto the needle to decrease the risk of leakage and contamination. Syringe size should be in accordance with the volume to be injected. A syringe no larger than 5 mL is recommended given the small internal lumen of 22G needles and overall small volume of medication delivered. In instances when a biopsy and injection are both requested for the same lesion in the same procedural setting, it might be appealing to use a coaxial needle for access, through which the biopsy can first be obtained and subsequently the injection can be performed.

Because of tumor heterogeneity, it might be of interest that the injected drug spread throughout the tumor volume. Unfortunately, many studies have shown that, when injected intratumorally with a needle, the distribution of drugs into a tumor is highly inhomogeneous and do not reach the all tumor volume (30–34). Thus, it can be recommended to manually spread the highly concentrated drug in as much tumor volume as possible (Fig. 4). For percutaneous intratumoral administration, two main techniques can be used. The first, called the “radial technique,” consists of moving the needle in the tumor to reach as many different parts of the tumor volume as possible at every cycle. It is important to keep a single-entry point in the punctured organ to avoid complications (such as pain, spreading, or hemorrhage) and, if possible, a single-entry point in the tumor to avoid drug leakage outside of the targeted tumor. The second technique, called the “sequential technique,” is simpler to execute for the physician, and faster and better tolerated by the patient. A different part of the tumor is punctured at each cycle, moving clockwise, and the aim is to cover the entire tumor volume after several cycles. The main drawback is that the entire tumor is not exposed homogeneously to the drug at every cycle, but sequentially (Supplementary Video S1). As previously mentioned, dedicated tools to improve the tumor coverage are under development and evaluation.

Whether injections should target the tumor itself or the peritumoral area is a matter of debate, and needs a clear definition of what are the peritumoral margins.

Specific evaluation criteria on imaging have been developed recently, allowing for a comprehensive assessment of potential benefits besides the obvious extent progression-free survival or overall survival (35). Intratumoral RECIST captures both response of injected and noninjected tumors and allows for in-depth evaluation of the HIT-IT strategy, including when used in combination with intravenous treatments. Such an evaluation strategy requires reliable identification of the injected tumor(s) at each injection cycle. It is thus advisable to save a screenshot image of each cycle baseline on the preinjection CT or MRI tagged with the tumor targeted for injection. Identification of these tumors might be difficult when several are present in the same liver segment, same lung lobe, or same anatomic region, not even taking into account the variation in size at different cycles of injection. In addition, when injection is performed under CT guidance, a volume acquisition image is recommended with the needle in place so that all physicians indisputably understand the location where the treatment has been injected. Another effective way would be to tag the targeted tumor by positioning a fiducial marker through the injection needle, or to use drugs or carriers that remain visible on subsequent imaging. (Supplementary Data; Supplementary Fig. S2).

This approach, of course, has some limitations. Although most territories can be reached using interventional radiology, tumor targeting is uncertain for some locations. Brain tumors are the most obvious example. Intravascular navigation is possible, but local delivery of drugs can be hazardous. Other major limitations are the discrepancies among interventional radiology groups and the variability of access to imaging modalities. This tends to improve since the recognition of interventional radiology as specific subspecialty in most countries.

Intratumoral injections of a combination of multiple drugs are already under investigation (i.e., intratumoral tilsotolimob + ipilimumab in the PRIMO Trial, NCT04270864, or intratumoral oncolytic virus Pexa-Vec + ipilimumab in the ISI-JX trial, NCT02977156). Among opportunities for further development of HIT-IT, it could be envisioned that variations in the administration route could be tested. Indeed, besides direct needle injections, intra-arterial, intracavitary, or intralymphatic administration routes could be of interest, depending on the injected product and disease treated.

Specific drug delivery devices are being evaluated to attempt uniform dispersal of the drug to further enhanced efficacy. Examples include multiperforated or multipronged needles, microporous catheters, and disposable pressure transducers. Novel, needle-free devices are also under evaluation in preclinical models. (Supplementary Data; Supplementary Fig. S3). Other technologies under investigation are infusion methods that would allow a subcutaneous port linked to a delivery system for repetitive or continuous injections into the tumor bed other than intravenous.

Imaging the drug distribution is also of interest to allow better tumor targeting and accurate evaluation of location of drug deposition (Table 2). Also, it would allow for a better understanding of technical issues associated with the injected drug efficacy. For instance, we recently reported that emulsions of anti CTLA-4 antibodies with radio-opaque oily contrast medium could render the injected drug visible by CT and extend the local time of drug diffusion (36). Other platforms are also under evaluation in preclinical models, such as nanoparticles, or scaphoid systems (37).

PET visible radiolabeled drugs, known as immuno-PET, are also in development to improve the analysis of distribution of the drug (38) or immune cells (39). Another potential imaging tool that can be applied include MRI sequences (40) or imaging analysis using artificial intelligence and radiomics analysis to guide tumor selection (41, 42).

Finally, the combination of local radiologic treatments, such as radiofrequency ablation, electroporation, or intra-arterial therapies, and local immunotherapies to enhance tumor antigen exposure and interaction with immunomodulating drugs (43), similar to what has been done with radiotherapy, could be of interest with the aim of enhancing abscopal responses. Preclinical and some early clinical results support this approach (3).

Local immunotherapy can offer new therapeutic perspectives for some patients with cancer. A safe and effective treatment requires careful patient and tumor selection, and a thorough coordination between oncology and interventional radiology teams. While this therapy strategy is in early development, it is important to establish procedural standards to optimize outcomes.

L. Tselikas reports grants from BMS Foundation and Terumo and other from Amgen during the conduct of the study; other from Boston Scientific, GE Healthcare, Guerbet, and Sirtex outside the submitted work; and a patent pending for Pickering emulsion. S. Champiat reports personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck, MSD, Novartis, and Roche; nonfinancial support from AstraZeneca, MSD, and Roche; other [as part of the Drug Development Department (DITEP), principal/subinvestigator of clinical trials] from AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S., Syros Pharmaceuticals, Taiho Pharma, Tesaro, and Xencor; other (as part of the DITEP, research grants) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Onxeo, Pfizer, Roche, and Sanofi, and other [as part of the DITEP, nonfinancial support (drug supplied)] from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Medimmune, Merck, NH TherAGuiX, Onxeo, Pfizer, and Roche outside the submitted work. F. Deschamps reports personal fees from General Electric and Medtronic, and grants from Terumo during the conduct of the study. C. Robert reports personal fees from Bristol-Myers Squibb, MSD, Roche, Novartis, Amgen, CureVac, AstraZeneca, Sanofi, and Pierre Fabre outside the submitted work. C. Massard reports consultant/advisory fees from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion, and has been principal/subinvestigator of clinical trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo Pharmaceuticals, Bayer, Beigene, Blueprint, Bristol-Myers Squibb, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GlaxoSmithKline, H3 Biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. F. Barlesi reports personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Seattle Genetics, and Takeda outside the submitted work. J.-C. Soria reports other from AstraZeneca (employee from September 2017 to December 2019; shares), Daiichi Sankyo, and Gritstone, and personal fees from Relay Therapeutics during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other from AstraZeneca, Bristol-Myers Squibb, MSD, Roche/Genentech, Pfizer, Merck Serono, and Lytix Pharma; other from Idera Pharma; grants, personal fees, and other from Transgene; and personal fees and other from EISAI outside the submitted work. No disclosures were reported by the other authors.

The authors would like to thank all patients and staff involved in the intratumoral program.

All figures are original and were created with BioRender.com.

The authors would like to thank Simon Gauvin from “Medical Professionals” for creating the Supplemental Data Video (authorization for publication was obtained).