Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer

Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Key Points Question What is the feasibility and IMPORTANCE Direct intratumoral delivery of immunotherapies is a compelling approach to safety of image-guided intratumoral overcoming barriers to systemic immunotherapy efficacy. While the use of intratumoral delivery of delivery of immunotherapies in patients immunotherapy drugs is increasing rapidly in both the investigational and standard of care domains, with advanced solid organ the feasibility and safety of these interventions, particularly for deeper lesions that require image- malignancies? guidance, remain unknown. Findings In this case series study that included 85 patients, there were no OBJECTIVE To address current knowledge gaps in image-guided techniques for intratumoral adverse events related to the technical immunotherapy delivery and the safety of these interventions. component of the procedure, specifically needle insertion or biopsy. DESIGN, SETTING, AND PARTICIPANTS This case series study was performed at a single tertiary Major adverse events due to immune- cancer center over a 2-year period from January 2016 to January 2018. Patients were followed until related systemic toxic effects occurred January 2019. All patients who underwent image-guided intratumoral delivery of immunotherapy in 2% of investigational agents and 4% agents in the standard of care, off-label, or investigational setting during the study period were of standard-of-care procedures (4%). included. Data were analyzed from February 1 to June 1, 2019. Meaning Intratumoral delivery of EXPOSURES Image-guided biopsies and intratumoral injections of immunotherapies across several immunotherapies is technically feasible clinical trials as well as standard of care talimogene laherparepvec therapy. with low major complication rates. MAIN OUTCOMES AND MEASURES Technical success, defined as the delivery of the prescribed Author affiliations and article information are injectate volume in its entirety, for image-guided biopsy and injections and procedure-related listed at the end of this article. adverse events. RESULTS A total of 85 patients (median [interquartile range] age, 61 [47-71] years; 42 [52%] men) underwent 498 encounters during the study period. These encounters comprised 327 image-guided intratumoral investigational agent injections in 67 patients in clinical trials, including 33 patients with melanoma (50%), 14 patients with sarcoma (21%), 3 patients with ovarian cancer (4.5%), 2 patients with breast cancer (3%), and 2 patients with colon cancer (3%). An additional 18 patients with melanoma underwent 113 image-guided talimogene laherparepvec injections. There were no adverse events reported related to the technical component of the procedure, specifically needle insertion or biopsy. Serious adverse events (Common Terminology Criteria for Adverse Events score 3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 3 of 327 investigational agent injections (2%) and 4 of 113 talimogene laherparepvec injections (4%). CONCLUSIONS AND RELEVANCE The findings of this case series study suggest that intratumoral injections of immunotherapies were feasible across a range of histological conditions and target organs. Immediate postdelivery anticipated adverse events occurred in a small number of instances. Performing physicians should have the necessary safeguards in place to respond as needed. Optimal (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 1/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Abstract (continued) methods for intratumoral drug delivery remain unresolved, and efforts to standardize drug delivery techniques are required. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 Introduction The conventional method for delivery of chemotherapy via intravenous administration allows for the distribution of the treatment drug throughout the body, but known challenges limit its effectiveness. Drug penetration into the tumor tissue can be inadequate owing to inherent barriers imposed by the 1,2 tumor microenvironment. Additionally, indiscriminate exposure of the nontumorous compartment often adversely influences the agents’ effectiveness or results in prohibitive toxic effects. Local intratumoral injection of anticancer therapies is a logical solution to overcoming these barriers to drug delivery. With the recent advancements in immune-based cancer therapies, there has been a resurgence of interest in the delivery of therapeutic agents directly into tumors, either as primary therapy or as an adjunct agent in combination with systemic immunotherapy. By successfully delivering a high concentration of immunostimulatory agents into a tumor site, local intratumoral drug delivery has the potential to drive sustained, systemic immune responses. The past 5 years have witnessed a tremendous proliferation of intratumoral immunotherapies. Types of agents are varied and range from cytokines and monoclonal antibodies to oncolytic viruses, cell-based therapies, and nanoparticles. There are more than 20 ongoing clinical trials for intratumoral injection of oncolytic viruses alone, and in 2015, the US Food and Drug Administration approved the first oncolytic virus, talimogene laherparepvec (TVEC), as immunotherapy for the treatment of patients with metastatic melanoma that cannot be surgically removed. To our knowledge, most studies investigating intratumoral injections have included patients with melanoma who have had injections to palpable subcutaneous lesions. As intratumoral injections expand from patients with melanoma to patients with other solid organ malignant tumors and lymphomas, there is increasing interest to perform injections to deeper targets using image guidance. However, little is known about the safety and feasibility of performing image-guided intratumoral injections. As intratumoral immunotherapy clinical protocols typically require repeated drug administrations, there are legitimate concerns regarding the risks of bleeding and organ injury due to frequent, repeated needle punctures. Furthermore, given the increased vascularity of visceral organs, such as the liver, compared with the dermis, there are likewise legitimate concerns about intravasation of the intratumoral drug resulting in systemic toxic effects. In this case series, we present our single-institution experience with image-guided intratumoral injections in the investigational, off-label, or standard-of-care settings in patients with solid tumors. We present our institution’s experience with performing image-guided intratumoral injections in a cohort of patients that spans a range of malignant tumors, injection sites, and immunotherapeutics. As this study represents the first characterization of such a cohort to our knowledge, the purpose of this study is to address current knowledge gaps in image-guided techniques and the safety of these interventions. Methods The MD Anderson Cancer Center review board approval was obtained for this single-institution, retrospective study. Waiver for informed consent was granted by the institutional review board because this study satisfied the criteria encoded in the Code of Federal Regulations Protection of Human Subjects 45CFR46. This report follows the reporting guideline for case series. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 2/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Study Population An institutional radiology database was queried for patients who underwent image-guided intratumoral delivery of immunotherapy agents over a 2-year period from January 2016 to January 9-19 2018. In addition, 4 patients who underwent image-guided intratumoral drug delivery in a clinical trial assessing PV-10 chemoablation of liver cancer from May to October 2018 were included in this study; given the study drug’s iodine content, this study provided a unique opportunity to visualize intratumoral drug distribution with intraprocedural computed tomography imaging. Patients who underwent intratumoral injection without image guidance (ie, by palpation alone) were excluded. Patients were followed by health record review until January 30, 2019. Evidence of adverse events recorded in the postanesthesia care unit as well as emergency department visits within 24 hours of the procedure were noted. Complications within 24 hours of the injection or trial-mandated biopsy were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system, version 5.0. Intratumoral Injections The selection of tumor lesions for intratumoral drug delivery or biopsy was made collaboratively by the patient’s primary oncologist and an interventional radiologist. The appropriate modality for image guidance during the injection procedure was determined by the interventional radiologist. Interventions on subcutaneous lesions were performed with local anesthesia (1% lidocaine) only, while those performed on deeper lesions or lesions within visceral organs were performed with conscious sedation (fentanyl/versed) or monitored anesthesia care. Figure 1. Distribution of Cancer Histological Conditions A B Underlying malignant tumors Site of injected tumor Cancer Site Adenoid cystic Abdomen 100 100 Bladder Adrenal Breast Deep pelvic Cervical Intramuscular 75 75 Colon Liver Lymphoma Lung Melanoma Parotid Neuroendocrine Subcutaneous 50 50 Other Submandibular Ovarian Thyroid Renal Sarcoma 25 25 Uterine 0 0 C Injection technique D Imaging modality used for injection Technique 17G 100 100 Modality 18G Computer 19G tomography 20G Ultrasonography 21G 22G 22G coaxial 22G coaxial curved 50 50 22G coaxial fanning 22G curved 22G fanning 25G 25G curved 25G fanning Not reported 0 0 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 3/9 Distribution, % Distribution, % Distribution, % Distribution, % JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer All intratumoral injection procedures were performed by interventional radiologists with 2 to 20 years of experience in image-guided interventions. The technique for intratumoral drug delivery was performed per clinical trial protocol when specified or by the operator’s best judgement when not specified. Technical success for intratumoral injection procedures was defined as the delivery of the prescribed injectate volume in its entirety. Technical success for clinical trial protocol-mandated biopsies was the acquisition of the requisite tissue samples. Statistical Analysis Quantitative, nonnormally distributed data were summarized by their medians and interquartile ranges (IQRs) or ranges. Categorical data were analyzed as percentages. Data were analyzed using R statistical software version 3.5.1 (R Foundation for Statistical Computing) from February 1 to June 1, 2019. Results A total of 85 patients (median [IQR] age, 61 [47-71] years, 42 [52%] men) underwent 498 encounters during the study period. This included 67 patients in clinical trials who underwent 385 encounters, with 327 image-guided intratumoral investigational agent injections (Figure 1) and 192 image-guided 9-20 biopsies across 12 clinical trials (Table 1). Malignant tumors included melanoma (33 patients [50%]), sarcoma (14 patients [21%]), ovarian cancer (3 patients [5%]), breast cancer (2 patients [3%]), colon cancer (2 patients [3%]), and other cancer (13 patients [19%]). Additionally, 18 patients (9 patients with cutaneous melanoma as standard-of-care, 9 patients with uveal melanoma as off-label use) underwent 113 image-guided intratumoral injections of TVEC. The median (range) number of encounters per patient was 6 (1-20) in the investigational setting and 5 (1-17) for TVEC. Subcutaneous lesions that required image guidance for intratumoral injection included 203 of 327 Table 1. Summary of the Clinical Trials, Their Investigational Immunotherapy Agents, and Instructions for Intratumoral Delivery Technique Based on the Information Provided by the Study Protocol Trial NCT No. Intratumoral Agent Phase Specified injection technique Safety study of intratumoral injection of clostridium novyi-NT spores to NCT01924689 Clostridium novyi-NT I 22-24G needles; injection may be treat patients with solid tumors that have not responded to standard spores redirected to 4 distinct sites in the tumor therapies Phase 1b safety study of CMB305 in patients with locally advanced, NCT02387125 G100 I Inject slowly; needle may be repositioned relapsed, or metastatic cancer expressing NY-ESO-1 A study to assess the safety and efficacy of intratumoral IMO-2125 in NCT02644967 IMO-2125 I/II 25G needle recommended, but choice at combination with ipilimumab in patients with metastatic melanoma IR’s discretion; coaxial with curved needle (ILLUMINATE-204) and fanning technique specified APX005M in combination with systemic pembrolizumab in patients with NCT02706353 APX005M I/II None specified metastatic melanoma A study of MEDI9197 in subjects with solid tumors or CTCL and in NCT02556463 MEDI9197 I 22G or 25G needle; inject under Doppler combination with durvalumab and/or palliative radiation in subjects with ultrasonographic guidance solid tumors Safety and efficacy of MIW815 (ADU-S100) +/− ipilimumab in patients NCT02675439 MIW815 (ADU-S100) I None specified with advanced/metastatic solid tumors or lymphomas Safety, tolerability, PK, dosimetry, MTD and preliminary efficacy of NCT03188328 AvidinOX I Multihole needle should be used intra-lesionally injected AvidinOX, followed by IV escalating doses of (no specifics provided) [177Lu]DOTA-biotin in pts with injectable solid tumors or lymphomas A study of ABBV-927 and ABBV-181, an immunotherapy, in subjects with NCT02988960 ABBV-927 I Needle size, injection rate, and duration of advanced solid tumors injection at IR’s discretion Study of the safety and efficacy of MIW815 with PDR001 to patients with NCT03172936 MIW815 (ADU-S100) I None specified advanced/metastatic solid tumors or lymphomas A study of intratumoral IMO-2125 in patients with refractory solid NCT03052205 IMO-2125 I 25G needle recommended but choice at tumors (ILLUMINATE-101) (single agent) IR’s discretion; fanning technique specified A Study of Toca 511, a retroviral replicating vector, combined with Toca NCT02576665 Vocimagene I No titanium needles; inject slowly, FC in patients with solid tumors or lymphoma (Toca 6) amiretrorepvec consider fanning method over 5-10 min (Toca 511) A study to assess PV-10 chemoablation of cancer of the liver NCT00986661 PV-10 (rose bengal I End-hole or multipronged needles may disodium) be used Abbreviations: IR, interventional radiologist; PK, pharmacokinetics; MTD, maximum tolerated dose; IV, intravenous; pts, patients. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 4/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer tumors (62%) in patients in clinical trials and 18 tumors (100%) in patients who received TVEC. Among 327 total image-guided injections, visceral lesions in deeper locations and solid organs were also injected pelvically (22 injections [7%]), abdominally (21 injections [6%]), intramuscularly (21 injections [6%]), adrenally (14 injections [4%]), in the liver (12 injections [4%]), and in the lung (8 injections [2%]). Among patients in clinical trials, the median (range) target lesion tumor volume was 6.4 (0.1-984) cm , and the median (range) target lesion length was 3.3 (0.9-12.8) cm; the median (range) injected volume was 2.0 (0.5-4.0) mL. Among patients who received TVEC, the median (range) target lesion tumor volume was 3.5 (0.2-250) cm , and the median (range) target lesion length was 2.4 (0.8-8.0) cm; the median (range) injected volume was 0.5 (0.3-4.0) mL. A variety of injection methods were used to optimize distribution within the lesion when using a single end-hole beveled needle (Figure 1). As most of immunotherapeutic agents in this study could not be directly visualized by conventional noninvasive imaging techniques, we were unable to directly assess the distribution and retention of the drug within the tumor after injection. However, as 1 investigational agent contained iodine, it could be detected by computed tomography. A tracer and fanning method was used to optimize distribution within the lesion using a single end-hole beveled needle for patients in this trial. Injections in this trial revealed a wide spectrum of intratumoral delivery outcomes (Figure 2). While some injections resulted in near-complete filling of the tumor volume with the drug, other injections led to leakage of the drug into the surrounding Figure 2. Spectrum of Intratumoral Drug Distribution and Influence of Injection Technique A Injection for patient A resulted in near complete B Injection for patient B resulted in leakage of almost C Injection for patient C resulted in leakage of almost distribution of drug throughout the tumor volume all of the injected drug into the surrounding tissues, all of the injected drug into the surrounding tissues, without any substantial leakage with minimal deposition within the tumor itself with minimal deposition within the tumor itself D Initial injection for patient D resulted in extensive E Patient D returned for repeated injection using F Use of multipronged needle for patient D resulted in leakage outside of the tumor a multipronged needle substantial improvement in drug delivery Intra-procedural non-contrast enhanced axial computed tomography images from 4 drug into the surrounding tissues, with minimal deposition within the tumor itself. For patients (A-F) demonstrate the range of intratumoral distribution outcomes. Target patient D, initial injection using a 21G end-hole needle (red asterisk) resulted in extensive tumors are outlined in dotted yellow ellipses. Injection for patient A resulted in near leakage outside of the tumor (D). The patient returned for repeat injection using a complete distribution of drug throughout the tumor volume without any substantial multi-pronged needle (E), which resulted in substantial improvement in intratumoral leakage. Injections for patients B and C resulted in leakage of almost all of the injected drug delivery (F). JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 5/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer parenchyma, with minimal drug retention within the target tumor. In 1 patient, after poor intratumoral delivery using a tracer and fanning method with a single end-hole needle, a second injection was performed using a multipronged injection needle (Quadrafuse; Rex Medical); this resulted in a substantial improvement in intratumoral drug delivery. There were no adverse events reported associated with the technical component of the procedure (ie, needle insertion or biopsy). However, serious adverse events (Common Terminology Criteria for Adverse Events score 3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 5 of 327 investigational agent injections (2%) and 4 of 113 TVEC injections (4%) (Table 2). Seven patients treated with investigational agents developed several adverse reactions immediately after intratumoral drug delivery resembling cytokine release syndrome. For example, 1 patient developed an immediate adverse reaction in the procedure room within minutes of receiving the intratumoral injection. Notably, the patient had received the same investigational agent to the same tumor site 4 times previously without an adverse reaction. The patient became tachycardic, hypotensive (ie, systolic blood pressure in the 70s mm Hg), and diaphoretic. The patient was resuscitated with intravenous fluids, supplemental oxygen, and intravenous diphenhydramine and was admitted to the hospital. The patient was treated conservatively and discharged in stable condition 24 hours after the procedure. One patient in an investigational clinical trial presented for a 24-hour postinjection biopsy procedure but was found to be symptomatically hypotensive with systolic blood pressures in the 60s mm Hg and was also noted to have rigors. The patient’s prior history of immune checkpoint inhibitor Table 2. Summary of AEs Within 24 Hours of Intratumoral Injections Cancer Injection site Adverse event De novo IRAE First injection histology TVEC Pelvic lymph Fever, vomiting, and headache requiring Yes Yes; subsequent 4 Cutaneous node presentation to emergency center; injections without melanoma managed with IV fluids and antibiotics AE Pelvic lymph Malaise and fever requiring presentation Yes No; 1 prior Cutaneous node to emergency center and hospitalization injection without melanoma AE Chest wall lesion Tachypnea and tachycardia requiring No, existing No; 1 prior and 4 Uveal presentation to emergency center and chronic lung subsequent melanoma hospitalization disease injections without AE Calf Asymptomatic hypertension (systolic Yes No; 3 prior and 4 Uveal subcutaneous 180s mm Hg) requiring IV subsequent melanoma lesion antihypertensives and monitoring injections without AE Investigational agents Axillary lesion Dyspnea, rigors, and tachycardia Yes Yes; 3 subsequent Cutaneous requiring presentation to emergency injections without melanoma center and hospitalization AE Thigh Hives and rigors, managed with Yes No; 5 prior Melanoma subcutaneous antihistamines and overnight injections without lesion observation AE Liver lesion Tachycardia and chills requiring Yes No; 1 prior and one Colon cancer hospitalization subsequent injection without AE Thigh Tachycardia and hypertension followed Yes No; 4 prior Melanoma subcutaneous by symptomatic hypotension (systolic injections without lesion blood pressure in the 70s mm Hg); AE managed with fluids, antihistamines, and hospitalization Abbreviations: AE, adverse event; IRAE, immune- Head and neck Hypotension (systolic blood pressure in No, history of Yes; 5 subsequent Melanoma related adverse event; IV, intravenous; TVEC, lesion the 60s mm Hg) and rigors, requiring adrenal injections without admission to intensive care unit and insufficiency AE talimogene laherparepvec. managed with steroids for adrenal from prior Adverse events were defined as those with Common insufficiency checkpoint inhibitor Terminology Criteria for Adverse Events score of 3 therapy or greater. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 6/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer therapy related-adrenal insufficiency lowered their threshold for adverse events, and they were successfully treated with fluids and corticosteroids and discharged after a brief admission in the intensive care unit. Minor adverse events (Common Terminology Criteria for Adverse Events score <3), including allergic reactions that did not require an escalation of care, occurred in 11 of 327 (3%) clinical trial injections and 1 of 113 (1%) TVEC injections. Discussion The findings of this case series suggest that intratumoral injections of immunotherapies are feasible across a range of histological conditions and target organs. While the adverse event rate was low, performing physicians need to be aware and equipped to handle these types of systemic immune- related reactions in addition to typical postprocedure complications. The optimal method for drug delivery that maximizes intratumoral drug distribution and retention remains unresolved. As with any invasive intervention, outcomes after intratumoral drug delivery depend on procedural technique. This is corroborated by the substantial difference in intratumoral drug delivery outcome observed when the same tumor in the same patient was injected with 2 different injection techniques. However, detailed and standardized guidelines for intratumoral injection methods are lacking. The negative ramifications of imperfect procedural technique are 2-fold. Limited delivery of the immunotherapy drug to its target site may result in diminished efficacy, but a more immediate challenge is the potential for systemic exposure to high doses of these very potent drugs. Efforts to standardize drug delivery techniques may be required. Limitations This study has several limitations. Given the diversity of intratumoral immunotherapies in development, each with its own safety profile, it is challenging to extrapolate the outcomes of this study broadly across the spectrum of intratumoral therapies. For example, given the myriad mechanisms of action, the degree to which off-target deposition can lead to systemic toxic effects is likely highly variable from one therapy to another. Furthermore, while this study’s low procedural complication rate represents an important finding, it precludes further analysis to identify technical factors, such as lesion location, lesion size, or injection technique, that may be associated with greater risk for complications. Conclusions Our findings in approximately 500 intratumoral injections during a 2-year period demonstrates that multiple image-guided intratumoral injections, including tumors in deep and visceral organ locations, are feasible for patients with advanced solid tumors. Incorporating standardized, evidence-based instructions for drug delivery technique into investigational and standard-of-care protocols will be essential to optimizing the efficacy of intratumoral therapy. ARTICLE INFORMATION Accepted for Publication: March 29, 2020. Published: July 29, 2020. doi:10.1001/jamanetworkopen.2020.7911 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Sheth RA et al. JAMA Network Open. Corresponding Author: Rahul A. Sheth, MD, Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1471, Houston, TX 77030 (rasheth@mdanderson.org). Author Affiliations: Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 7/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Houston (Sheth, Murthy, Tam); Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston (Murthy, Hong); Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Patel, Diab, Hwu); Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Overman). Author Contributions: Drs Sheth and Tam had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Sheth, Murthy, Diab, Tam. Acquisition, analysis, or interpretation of data: Sheth, Murthy, Hong, Patel, Overman, Hwu, Tam. Drafting of the manuscript: Sheth, Murthy, Tam. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Sheth, Tam. Administrative, technical, or material support: Sheth, Murthy. Supervision: Murthy, Diab, Hwu. Conflict of Interest Disclosures: Dr Hong reported receiving grants from Abbvie, Aldi-Norte, Astra-Zeneca, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, GlaxoSmithKline, Ignyta, Kite Pharma, Kyowa, Eli Lilly and Company, Loxo Oncology, Merck, MedImmune, Mirati Therapeutics, Mirna Therapeutics, Molecular Templates, Mologen, Novartis, Seattle Genetics, Turning Point Therapeutics, and the National Cancer Institute Cancer Therapy Evaluation Program; grants and personal fees from Adaptimmune Therapeutics, Amgen, Genentech, Infinity Pharmaceuticals, Pfizer, and Takeda; personal fees from Alpha Insights, Axiom Therapeutics, Baxter, Gerson Lehrman Group, groupH, Guidepoint, Medscape, Numab, prIME Oncology, Trieza Therapeutics, WebMD, eCancer, Oncology Education Project Association; grants, personal fees, and nonfinancial support from Bayer; grants and nonfinancial support from Genmab; nonfinancial support from the American Association for Cancer Research, American Society of Clinical Oncology, and Society for Immunotherapy of Cancer; and serving as an advisor for Molecular Match and Presagia and as founder of OncoResponse outside the submitted work. Dr Patel reported receiving institutional funding from Provectus Biopharmaceuticals during the conduct of the study and personal fees from Castle Biosciences, Merck & Co, and Incyte and institutional funding from Bristol-Myers Squibb outside the submitted work. Dr Hwu reported receiving personal fees from Dragonfly Therapeutics, GlaskoSmithKline, Immatics Biotechnologies, and Sanofi outside the submitted work. Dr Tam reported receiving grants from Angiodynamics, BTG, and Guerbet and personal fees from Jounce Therapeutics, Boston Scientific, Merit Medical, and Galil Medical outside the submitted work. No other disclosures were reported. REFERENCES 1. Sheth RA, Hesketh R, Kong DS, Wicky S, Oklu R. Barriers to drug delivery in interventional oncology. J Vasc Interv Radiol. 2013;24(8):1201-1207. doi:10.1016/j.jvir.2013.03.034 2. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583-592. doi:10. 1038/nrc1893 3. Bilusic M, Gulley JL. Editorial: local immunotherapy: a way to convert tumors from “cold” to “hot”. J Natl Cancer Inst. 2017;109(12):1-2. doi:10.1093/jnci/djx132 4. Marabelle A, Andtbacka R, Harrington K, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29(11):2163-2174. doi:10.1093/ annonc/mdy423 5. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-1119.e10. doi:10.1016/j.cell.2017.08.027 6. Murthy V, Minehart J, Sterman DH. Local immunotherapy of cancer: innovative approaches to harnessing tumor-specific immune responses. J Natl Cancer Inst. 2017;109(12):1-12. doi:10.1093/jnci/djx097 7. Andtbacka RHI, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol. 2016;23(13):4169-4177. doi: 10.1245/s10434-016-5286-0 8. Kempen JH. Appropriate use and reporting of uncontrolled case series in the medical literature. Am J Ophthalmol. 2011;151(1):7-10.e1. doi:10.1016/j.ajo.2010.08.047 9. ClinicalTrials.gov. Safety study of intratumoral injection of Clostridium novyi-NT spores to treat patients with solid tumors that have not responded to standard therapies. Accessed January 31, 2020. https://clinicaltrials.gov/ ct2/show/NCT01924689 10. ClinicalTrials.gov. Phase 1b safety study of CMB305 in patients with locally advanced, relapsed, or metastatic cancer expressing NY-ESO-1. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02387125 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 8/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer 11. ClinicalTrials.gov. A study to assess the safety and efficacy of intratumoral IMO-2125 in combination with ipilimumab or pembrolizumab in patients with metastatic melanoma (ILLUMINATE-204). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02644967 12. ClinicalTrials.gov. APX005M in combination with systemic pembrolizumab in patients with metastatic melanoma. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02706353 13. ClinicalTrials.gov. A study of MEDI9197 in subjects with solid tumors or CTCL and in combination with durvalumab and/or palliative radiation in subjects with solid tumors. Accessed January 31, 2020. https://clinicaltrials. gov/ct2/show/NCT02556463 14. ClinicalTrials.gov. Safety and efficacy of MIW815 (ADU-S100) +/- ipilimumab in patients with advanced/ metastatic solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02675439 15. ClinicalTrials.gov. Safety, tolerability, PK, dosimetry, MTD and preliminary efficacy of intra-lesionally injected AvidinOX, followed by IV escalating doses of [177Lu]DOTA-biotin in pts with injectable solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03188328 16. ClinicalTrials.gov. A study of ABBV-927 and ABBV-181, an immunotherapy, in participants with advanced solid tumors. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02988960 17. ClinicalTrials.gov. Study of the safety and efficacy of MIW815 with PDR001 to patients with advanced/ metastatic solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03172936 18. ClinicalTrials.gov. A study of intratumoral IMO-2125 in patients with refractory solid tumors (ILLUMINATE-101). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03052205 19. ClinicalTrials.gov. A study of Toca 511, a retroviral replicating vector, combined with Toca FC in patients with solid tumors or lymphoma (Toca 6). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02576665 20. ClinicalTrials.gov. A study to assess PV-10 chemoablation of cancer of the liver. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT00986661 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 9/9 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer

Loading next page...
 
/lp/american-medical-association/assessment-of-image-guided-intratumoral-delivery-of-immunotherapeutics-77I8UQJ79k

References (24)

Publisher
American Medical Association
Copyright
Copyright 2020 Sheth RA et al. JAMA Network Open.
eISSN
2574-3805
DOI
10.1001/jamanetworkopen.2020.7911
Publisher site
See Article on Publisher Site

Abstract

Key Points Question What is the feasibility and IMPORTANCE Direct intratumoral delivery of immunotherapies is a compelling approach to safety of image-guided intratumoral overcoming barriers to systemic immunotherapy efficacy. While the use of intratumoral delivery of delivery of immunotherapies in patients immunotherapy drugs is increasing rapidly in both the investigational and standard of care domains, with advanced solid organ the feasibility and safety of these interventions, particularly for deeper lesions that require image- malignancies? guidance, remain unknown. Findings In this case series study that included 85 patients, there were no OBJECTIVE To address current knowledge gaps in image-guided techniques for intratumoral adverse events related to the technical immunotherapy delivery and the safety of these interventions. component of the procedure, specifically needle insertion or biopsy. DESIGN, SETTING, AND PARTICIPANTS This case series study was performed at a single tertiary Major adverse events due to immune- cancer center over a 2-year period from January 2016 to January 2018. Patients were followed until related systemic toxic effects occurred January 2019. All patients who underwent image-guided intratumoral delivery of immunotherapy in 2% of investigational agents and 4% agents in the standard of care, off-label, or investigational setting during the study period were of standard-of-care procedures (4%). included. Data were analyzed from February 1 to June 1, 2019. Meaning Intratumoral delivery of EXPOSURES Image-guided biopsies and intratumoral injections of immunotherapies across several immunotherapies is technically feasible clinical trials as well as standard of care talimogene laherparepvec therapy. with low major complication rates. MAIN OUTCOMES AND MEASURES Technical success, defined as the delivery of the prescribed Author affiliations and article information are injectate volume in its entirety, for image-guided biopsy and injections and procedure-related listed at the end of this article. adverse events. RESULTS A total of 85 patients (median [interquartile range] age, 61 [47-71] years; 42 [52%] men) underwent 498 encounters during the study period. These encounters comprised 327 image-guided intratumoral investigational agent injections in 67 patients in clinical trials, including 33 patients with melanoma (50%), 14 patients with sarcoma (21%), 3 patients with ovarian cancer (4.5%), 2 patients with breast cancer (3%), and 2 patients with colon cancer (3%). An additional 18 patients with melanoma underwent 113 image-guided talimogene laherparepvec injections. There were no adverse events reported related to the technical component of the procedure, specifically needle insertion or biopsy. Serious adverse events (Common Terminology Criteria for Adverse Events score 3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 3 of 327 investigational agent injections (2%) and 4 of 113 talimogene laherparepvec injections (4%). CONCLUSIONS AND RELEVANCE The findings of this case series study suggest that intratumoral injections of immunotherapies were feasible across a range of histological conditions and target organs. Immediate postdelivery anticipated adverse events occurred in a small number of instances. Performing physicians should have the necessary safeguards in place to respond as needed. Optimal (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 1/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Abstract (continued) methods for intratumoral drug delivery remain unresolved, and efforts to standardize drug delivery techniques are required. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 Introduction The conventional method for delivery of chemotherapy via intravenous administration allows for the distribution of the treatment drug throughout the body, but known challenges limit its effectiveness. Drug penetration into the tumor tissue can be inadequate owing to inherent barriers imposed by the 1,2 tumor microenvironment. Additionally, indiscriminate exposure of the nontumorous compartment often adversely influences the agents’ effectiveness or results in prohibitive toxic effects. Local intratumoral injection of anticancer therapies is a logical solution to overcoming these barriers to drug delivery. With the recent advancements in immune-based cancer therapies, there has been a resurgence of interest in the delivery of therapeutic agents directly into tumors, either as primary therapy or as an adjunct agent in combination with systemic immunotherapy. By successfully delivering a high concentration of immunostimulatory agents into a tumor site, local intratumoral drug delivery has the potential to drive sustained, systemic immune responses. The past 5 years have witnessed a tremendous proliferation of intratumoral immunotherapies. Types of agents are varied and range from cytokines and monoclonal antibodies to oncolytic viruses, cell-based therapies, and nanoparticles. There are more than 20 ongoing clinical trials for intratumoral injection of oncolytic viruses alone, and in 2015, the US Food and Drug Administration approved the first oncolytic virus, talimogene laherparepvec (TVEC), as immunotherapy for the treatment of patients with metastatic melanoma that cannot be surgically removed. To our knowledge, most studies investigating intratumoral injections have included patients with melanoma who have had injections to palpable subcutaneous lesions. As intratumoral injections expand from patients with melanoma to patients with other solid organ malignant tumors and lymphomas, there is increasing interest to perform injections to deeper targets using image guidance. However, little is known about the safety and feasibility of performing image-guided intratumoral injections. As intratumoral immunotherapy clinical protocols typically require repeated drug administrations, there are legitimate concerns regarding the risks of bleeding and organ injury due to frequent, repeated needle punctures. Furthermore, given the increased vascularity of visceral organs, such as the liver, compared with the dermis, there are likewise legitimate concerns about intravasation of the intratumoral drug resulting in systemic toxic effects. In this case series, we present our single-institution experience with image-guided intratumoral injections in the investigational, off-label, or standard-of-care settings in patients with solid tumors. We present our institution’s experience with performing image-guided intratumoral injections in a cohort of patients that spans a range of malignant tumors, injection sites, and immunotherapeutics. As this study represents the first characterization of such a cohort to our knowledge, the purpose of this study is to address current knowledge gaps in image-guided techniques and the safety of these interventions. Methods The MD Anderson Cancer Center review board approval was obtained for this single-institution, retrospective study. Waiver for informed consent was granted by the institutional review board because this study satisfied the criteria encoded in the Code of Federal Regulations Protection of Human Subjects 45CFR46. This report follows the reporting guideline for case series. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 2/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Study Population An institutional radiology database was queried for patients who underwent image-guided intratumoral delivery of immunotherapy agents over a 2-year period from January 2016 to January 9-19 2018. In addition, 4 patients who underwent image-guided intratumoral drug delivery in a clinical trial assessing PV-10 chemoablation of liver cancer from May to October 2018 were included in this study; given the study drug’s iodine content, this study provided a unique opportunity to visualize intratumoral drug distribution with intraprocedural computed tomography imaging. Patients who underwent intratumoral injection without image guidance (ie, by palpation alone) were excluded. Patients were followed by health record review until January 30, 2019. Evidence of adverse events recorded in the postanesthesia care unit as well as emergency department visits within 24 hours of the procedure were noted. Complications within 24 hours of the injection or trial-mandated biopsy were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system, version 5.0. Intratumoral Injections The selection of tumor lesions for intratumoral drug delivery or biopsy was made collaboratively by the patient’s primary oncologist and an interventional radiologist. The appropriate modality for image guidance during the injection procedure was determined by the interventional radiologist. Interventions on subcutaneous lesions were performed with local anesthesia (1% lidocaine) only, while those performed on deeper lesions or lesions within visceral organs were performed with conscious sedation (fentanyl/versed) or monitored anesthesia care. Figure 1. Distribution of Cancer Histological Conditions A B Underlying malignant tumors Site of injected tumor Cancer Site Adenoid cystic Abdomen 100 100 Bladder Adrenal Breast Deep pelvic Cervical Intramuscular 75 75 Colon Liver Lymphoma Lung Melanoma Parotid Neuroendocrine Subcutaneous 50 50 Other Submandibular Ovarian Thyroid Renal Sarcoma 25 25 Uterine 0 0 C Injection technique D Imaging modality used for injection Technique 17G 100 100 Modality 18G Computer 19G tomography 20G Ultrasonography 21G 22G 22G coaxial 22G coaxial curved 50 50 22G coaxial fanning 22G curved 22G fanning 25G 25G curved 25G fanning Not reported 0 0 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 3/9 Distribution, % Distribution, % Distribution, % Distribution, % JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer All intratumoral injection procedures were performed by interventional radiologists with 2 to 20 years of experience in image-guided interventions. The technique for intratumoral drug delivery was performed per clinical trial protocol when specified or by the operator’s best judgement when not specified. Technical success for intratumoral injection procedures was defined as the delivery of the prescribed injectate volume in its entirety. Technical success for clinical trial protocol-mandated biopsies was the acquisition of the requisite tissue samples. Statistical Analysis Quantitative, nonnormally distributed data were summarized by their medians and interquartile ranges (IQRs) or ranges. Categorical data were analyzed as percentages. Data were analyzed using R statistical software version 3.5.1 (R Foundation for Statistical Computing) from February 1 to June 1, 2019. Results A total of 85 patients (median [IQR] age, 61 [47-71] years, 42 [52%] men) underwent 498 encounters during the study period. This included 67 patients in clinical trials who underwent 385 encounters, with 327 image-guided intratumoral investigational agent injections (Figure 1) and 192 image-guided 9-20 biopsies across 12 clinical trials (Table 1). Malignant tumors included melanoma (33 patients [50%]), sarcoma (14 patients [21%]), ovarian cancer (3 patients [5%]), breast cancer (2 patients [3%]), colon cancer (2 patients [3%]), and other cancer (13 patients [19%]). Additionally, 18 patients (9 patients with cutaneous melanoma as standard-of-care, 9 patients with uveal melanoma as off-label use) underwent 113 image-guided intratumoral injections of TVEC. The median (range) number of encounters per patient was 6 (1-20) in the investigational setting and 5 (1-17) for TVEC. Subcutaneous lesions that required image guidance for intratumoral injection included 203 of 327 Table 1. Summary of the Clinical Trials, Their Investigational Immunotherapy Agents, and Instructions for Intratumoral Delivery Technique Based on the Information Provided by the Study Protocol Trial NCT No. Intratumoral Agent Phase Specified injection technique Safety study of intratumoral injection of clostridium novyi-NT spores to NCT01924689 Clostridium novyi-NT I 22-24G needles; injection may be treat patients with solid tumors that have not responded to standard spores redirected to 4 distinct sites in the tumor therapies Phase 1b safety study of CMB305 in patients with locally advanced, NCT02387125 G100 I Inject slowly; needle may be repositioned relapsed, or metastatic cancer expressing NY-ESO-1 A study to assess the safety and efficacy of intratumoral IMO-2125 in NCT02644967 IMO-2125 I/II 25G needle recommended, but choice at combination with ipilimumab in patients with metastatic melanoma IR’s discretion; coaxial with curved needle (ILLUMINATE-204) and fanning technique specified APX005M in combination with systemic pembrolizumab in patients with NCT02706353 APX005M I/II None specified metastatic melanoma A study of MEDI9197 in subjects with solid tumors or CTCL and in NCT02556463 MEDI9197 I 22G or 25G needle; inject under Doppler combination with durvalumab and/or palliative radiation in subjects with ultrasonographic guidance solid tumors Safety and efficacy of MIW815 (ADU-S100) +/− ipilimumab in patients NCT02675439 MIW815 (ADU-S100) I None specified with advanced/metastatic solid tumors or lymphomas Safety, tolerability, PK, dosimetry, MTD and preliminary efficacy of NCT03188328 AvidinOX I Multihole needle should be used intra-lesionally injected AvidinOX, followed by IV escalating doses of (no specifics provided) [177Lu]DOTA-biotin in pts with injectable solid tumors or lymphomas A study of ABBV-927 and ABBV-181, an immunotherapy, in subjects with NCT02988960 ABBV-927 I Needle size, injection rate, and duration of advanced solid tumors injection at IR’s discretion Study of the safety and efficacy of MIW815 with PDR001 to patients with NCT03172936 MIW815 (ADU-S100) I None specified advanced/metastatic solid tumors or lymphomas A study of intratumoral IMO-2125 in patients with refractory solid NCT03052205 IMO-2125 I 25G needle recommended but choice at tumors (ILLUMINATE-101) (single agent) IR’s discretion; fanning technique specified A Study of Toca 511, a retroviral replicating vector, combined with Toca NCT02576665 Vocimagene I No titanium needles; inject slowly, FC in patients with solid tumors or lymphoma (Toca 6) amiretrorepvec consider fanning method over 5-10 min (Toca 511) A study to assess PV-10 chemoablation of cancer of the liver NCT00986661 PV-10 (rose bengal I End-hole or multipronged needles may disodium) be used Abbreviations: IR, interventional radiologist; PK, pharmacokinetics; MTD, maximum tolerated dose; IV, intravenous; pts, patients. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 4/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer tumors (62%) in patients in clinical trials and 18 tumors (100%) in patients who received TVEC. Among 327 total image-guided injections, visceral lesions in deeper locations and solid organs were also injected pelvically (22 injections [7%]), abdominally (21 injections [6%]), intramuscularly (21 injections [6%]), adrenally (14 injections [4%]), in the liver (12 injections [4%]), and in the lung (8 injections [2%]). Among patients in clinical trials, the median (range) target lesion tumor volume was 6.4 (0.1-984) cm , and the median (range) target lesion length was 3.3 (0.9-12.8) cm; the median (range) injected volume was 2.0 (0.5-4.0) mL. Among patients who received TVEC, the median (range) target lesion tumor volume was 3.5 (0.2-250) cm , and the median (range) target lesion length was 2.4 (0.8-8.0) cm; the median (range) injected volume was 0.5 (0.3-4.0) mL. A variety of injection methods were used to optimize distribution within the lesion when using a single end-hole beveled needle (Figure 1). As most of immunotherapeutic agents in this study could not be directly visualized by conventional noninvasive imaging techniques, we were unable to directly assess the distribution and retention of the drug within the tumor after injection. However, as 1 investigational agent contained iodine, it could be detected by computed tomography. A tracer and fanning method was used to optimize distribution within the lesion using a single end-hole beveled needle for patients in this trial. Injections in this trial revealed a wide spectrum of intratumoral delivery outcomes (Figure 2). While some injections resulted in near-complete filling of the tumor volume with the drug, other injections led to leakage of the drug into the surrounding Figure 2. Spectrum of Intratumoral Drug Distribution and Influence of Injection Technique A Injection for patient A resulted in near complete B Injection for patient B resulted in leakage of almost C Injection for patient C resulted in leakage of almost distribution of drug throughout the tumor volume all of the injected drug into the surrounding tissues, all of the injected drug into the surrounding tissues, without any substantial leakage with minimal deposition within the tumor itself with minimal deposition within the tumor itself D Initial injection for patient D resulted in extensive E Patient D returned for repeated injection using F Use of multipronged needle for patient D resulted in leakage outside of the tumor a multipronged needle substantial improvement in drug delivery Intra-procedural non-contrast enhanced axial computed tomography images from 4 drug into the surrounding tissues, with minimal deposition within the tumor itself. For patients (A-F) demonstrate the range of intratumoral distribution outcomes. Target patient D, initial injection using a 21G end-hole needle (red asterisk) resulted in extensive tumors are outlined in dotted yellow ellipses. Injection for patient A resulted in near leakage outside of the tumor (D). The patient returned for repeat injection using a complete distribution of drug throughout the tumor volume without any substantial multi-pronged needle (E), which resulted in substantial improvement in intratumoral leakage. Injections for patients B and C resulted in leakage of almost all of the injected drug delivery (F). JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 5/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer parenchyma, with minimal drug retention within the target tumor. In 1 patient, after poor intratumoral delivery using a tracer and fanning method with a single end-hole needle, a second injection was performed using a multipronged injection needle (Quadrafuse; Rex Medical); this resulted in a substantial improvement in intratumoral drug delivery. There were no adverse events reported associated with the technical component of the procedure (ie, needle insertion or biopsy). However, serious adverse events (Common Terminology Criteria for Adverse Events score 3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 5 of 327 investigational agent injections (2%) and 4 of 113 TVEC injections (4%) (Table 2). Seven patients treated with investigational agents developed several adverse reactions immediately after intratumoral drug delivery resembling cytokine release syndrome. For example, 1 patient developed an immediate adverse reaction in the procedure room within minutes of receiving the intratumoral injection. Notably, the patient had received the same investigational agent to the same tumor site 4 times previously without an adverse reaction. The patient became tachycardic, hypotensive (ie, systolic blood pressure in the 70s mm Hg), and diaphoretic. The patient was resuscitated with intravenous fluids, supplemental oxygen, and intravenous diphenhydramine and was admitted to the hospital. The patient was treated conservatively and discharged in stable condition 24 hours after the procedure. One patient in an investigational clinical trial presented for a 24-hour postinjection biopsy procedure but was found to be symptomatically hypotensive with systolic blood pressures in the 60s mm Hg and was also noted to have rigors. The patient’s prior history of immune checkpoint inhibitor Table 2. Summary of AEs Within 24 Hours of Intratumoral Injections Cancer Injection site Adverse event De novo IRAE First injection histology TVEC Pelvic lymph Fever, vomiting, and headache requiring Yes Yes; subsequent 4 Cutaneous node presentation to emergency center; injections without melanoma managed with IV fluids and antibiotics AE Pelvic lymph Malaise and fever requiring presentation Yes No; 1 prior Cutaneous node to emergency center and hospitalization injection without melanoma AE Chest wall lesion Tachypnea and tachycardia requiring No, existing No; 1 prior and 4 Uveal presentation to emergency center and chronic lung subsequent melanoma hospitalization disease injections without AE Calf Asymptomatic hypertension (systolic Yes No; 3 prior and 4 Uveal subcutaneous 180s mm Hg) requiring IV subsequent melanoma lesion antihypertensives and monitoring injections without AE Investigational agents Axillary lesion Dyspnea, rigors, and tachycardia Yes Yes; 3 subsequent Cutaneous requiring presentation to emergency injections without melanoma center and hospitalization AE Thigh Hives and rigors, managed with Yes No; 5 prior Melanoma subcutaneous antihistamines and overnight injections without lesion observation AE Liver lesion Tachycardia and chills requiring Yes No; 1 prior and one Colon cancer hospitalization subsequent injection without AE Thigh Tachycardia and hypertension followed Yes No; 4 prior Melanoma subcutaneous by symptomatic hypotension (systolic injections without lesion blood pressure in the 70s mm Hg); AE managed with fluids, antihistamines, and hospitalization Abbreviations: AE, adverse event; IRAE, immune- Head and neck Hypotension (systolic blood pressure in No, history of Yes; 5 subsequent Melanoma related adverse event; IV, intravenous; TVEC, lesion the 60s mm Hg) and rigors, requiring adrenal injections without admission to intensive care unit and insufficiency AE talimogene laherparepvec. managed with steroids for adrenal from prior Adverse events were defined as those with Common insufficiency checkpoint inhibitor Terminology Criteria for Adverse Events score of 3 therapy or greater. JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 6/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer therapy related-adrenal insufficiency lowered their threshold for adverse events, and they were successfully treated with fluids and corticosteroids and discharged after a brief admission in the intensive care unit. Minor adverse events (Common Terminology Criteria for Adverse Events score <3), including allergic reactions that did not require an escalation of care, occurred in 11 of 327 (3%) clinical trial injections and 1 of 113 (1%) TVEC injections. Discussion The findings of this case series suggest that intratumoral injections of immunotherapies are feasible across a range of histological conditions and target organs. While the adverse event rate was low, performing physicians need to be aware and equipped to handle these types of systemic immune- related reactions in addition to typical postprocedure complications. The optimal method for drug delivery that maximizes intratumoral drug distribution and retention remains unresolved. As with any invasive intervention, outcomes after intratumoral drug delivery depend on procedural technique. This is corroborated by the substantial difference in intratumoral drug delivery outcome observed when the same tumor in the same patient was injected with 2 different injection techniques. However, detailed and standardized guidelines for intratumoral injection methods are lacking. The negative ramifications of imperfect procedural technique are 2-fold. Limited delivery of the immunotherapy drug to its target site may result in diminished efficacy, but a more immediate challenge is the potential for systemic exposure to high doses of these very potent drugs. Efforts to standardize drug delivery techniques may be required. Limitations This study has several limitations. Given the diversity of intratumoral immunotherapies in development, each with its own safety profile, it is challenging to extrapolate the outcomes of this study broadly across the spectrum of intratumoral therapies. For example, given the myriad mechanisms of action, the degree to which off-target deposition can lead to systemic toxic effects is likely highly variable from one therapy to another. Furthermore, while this study’s low procedural complication rate represents an important finding, it precludes further analysis to identify technical factors, such as lesion location, lesion size, or injection technique, that may be associated with greater risk for complications. Conclusions Our findings in approximately 500 intratumoral injections during a 2-year period demonstrates that multiple image-guided intratumoral injections, including tumors in deep and visceral organ locations, are feasible for patients with advanced solid tumors. Incorporating standardized, evidence-based instructions for drug delivery technique into investigational and standard-of-care protocols will be essential to optimizing the efficacy of intratumoral therapy. ARTICLE INFORMATION Accepted for Publication: March 29, 2020. Published: July 29, 2020. doi:10.1001/jamanetworkopen.2020.7911 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Sheth RA et al. JAMA Network Open. Corresponding Author: Rahul A. Sheth, MD, Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1471, Houston, TX 77030 (rasheth@mdanderson.org). Author Affiliations: Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 7/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer Houston (Sheth, Murthy, Tam); Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston (Murthy, Hong); Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Patel, Diab, Hwu); Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Overman). Author Contributions: Drs Sheth and Tam had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Sheth, Murthy, Diab, Tam. Acquisition, analysis, or interpretation of data: Sheth, Murthy, Hong, Patel, Overman, Hwu, Tam. Drafting of the manuscript: Sheth, Murthy, Tam. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Sheth, Tam. Administrative, technical, or material support: Sheth, Murthy. Supervision: Murthy, Diab, Hwu. Conflict of Interest Disclosures: Dr Hong reported receiving grants from Abbvie, Aldi-Norte, Astra-Zeneca, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, GlaxoSmithKline, Ignyta, Kite Pharma, Kyowa, Eli Lilly and Company, Loxo Oncology, Merck, MedImmune, Mirati Therapeutics, Mirna Therapeutics, Molecular Templates, Mologen, Novartis, Seattle Genetics, Turning Point Therapeutics, and the National Cancer Institute Cancer Therapy Evaluation Program; grants and personal fees from Adaptimmune Therapeutics, Amgen, Genentech, Infinity Pharmaceuticals, Pfizer, and Takeda; personal fees from Alpha Insights, Axiom Therapeutics, Baxter, Gerson Lehrman Group, groupH, Guidepoint, Medscape, Numab, prIME Oncology, Trieza Therapeutics, WebMD, eCancer, Oncology Education Project Association; grants, personal fees, and nonfinancial support from Bayer; grants and nonfinancial support from Genmab; nonfinancial support from the American Association for Cancer Research, American Society of Clinical Oncology, and Society for Immunotherapy of Cancer; and serving as an advisor for Molecular Match and Presagia and as founder of OncoResponse outside the submitted work. Dr Patel reported receiving institutional funding from Provectus Biopharmaceuticals during the conduct of the study and personal fees from Castle Biosciences, Merck & Co, and Incyte and institutional funding from Bristol-Myers Squibb outside the submitted work. Dr Hwu reported receiving personal fees from Dragonfly Therapeutics, GlaskoSmithKline, Immatics Biotechnologies, and Sanofi outside the submitted work. Dr Tam reported receiving grants from Angiodynamics, BTG, and Guerbet and personal fees from Jounce Therapeutics, Boston Scientific, Merit Medical, and Galil Medical outside the submitted work. No other disclosures were reported. REFERENCES 1. Sheth RA, Hesketh R, Kong DS, Wicky S, Oklu R. Barriers to drug delivery in interventional oncology. J Vasc Interv Radiol. 2013;24(8):1201-1207. doi:10.1016/j.jvir.2013.03.034 2. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583-592. doi:10. 1038/nrc1893 3. Bilusic M, Gulley JL. Editorial: local immunotherapy: a way to convert tumors from “cold” to “hot”. J Natl Cancer Inst. 2017;109(12):1-2. doi:10.1093/jnci/djx132 4. Marabelle A, Andtbacka R, Harrington K, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29(11):2163-2174. doi:10.1093/ annonc/mdy423 5. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-1119.e10. doi:10.1016/j.cell.2017.08.027 6. Murthy V, Minehart J, Sterman DH. Local immunotherapy of cancer: innovative approaches to harnessing tumor-specific immune responses. J Natl Cancer Inst. 2017;109(12):1-12. doi:10.1093/jnci/djx097 7. Andtbacka RHI, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol. 2016;23(13):4169-4177. doi: 10.1245/s10434-016-5286-0 8. Kempen JH. Appropriate use and reporting of uncontrolled case series in the medical literature. Am J Ophthalmol. 2011;151(1):7-10.e1. doi:10.1016/j.ajo.2010.08.047 9. ClinicalTrials.gov. Safety study of intratumoral injection of Clostridium novyi-NT spores to treat patients with solid tumors that have not responded to standard therapies. Accessed January 31, 2020. https://clinicaltrials.gov/ ct2/show/NCT01924689 10. ClinicalTrials.gov. Phase 1b safety study of CMB305 in patients with locally advanced, relapsed, or metastatic cancer expressing NY-ESO-1. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02387125 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 8/9 JAMA Network Open | Oncology Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer 11. ClinicalTrials.gov. A study to assess the safety and efficacy of intratumoral IMO-2125 in combination with ipilimumab or pembrolizumab in patients with metastatic melanoma (ILLUMINATE-204). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02644967 12. ClinicalTrials.gov. APX005M in combination with systemic pembrolizumab in patients with metastatic melanoma. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02706353 13. ClinicalTrials.gov. A study of MEDI9197 in subjects with solid tumors or CTCL and in combination with durvalumab and/or palliative radiation in subjects with solid tumors. Accessed January 31, 2020. https://clinicaltrials. gov/ct2/show/NCT02556463 14. ClinicalTrials.gov. Safety and efficacy of MIW815 (ADU-S100) +/- ipilimumab in patients with advanced/ metastatic solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02675439 15. ClinicalTrials.gov. Safety, tolerability, PK, dosimetry, MTD and preliminary efficacy of intra-lesionally injected AvidinOX, followed by IV escalating doses of [177Lu]DOTA-biotin in pts with injectable solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03188328 16. ClinicalTrials.gov. A study of ABBV-927 and ABBV-181, an immunotherapy, in participants with advanced solid tumors. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02988960 17. ClinicalTrials.gov. Study of the safety and efficacy of MIW815 with PDR001 to patients with advanced/ metastatic solid tumors or lymphomas. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03172936 18. ClinicalTrials.gov. A study of intratumoral IMO-2125 in patients with refractory solid tumors (ILLUMINATE-101). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT03052205 19. ClinicalTrials.gov. A study of Toca 511, a retroviral replicating vector, combined with Toca FC in patients with solid tumors or lymphoma (Toca 6). Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT02576665 20. ClinicalTrials.gov. A study to assess PV-10 chemoablation of cancer of the liver. Accessed January 31, 2020. https://clinicaltrials.gov/ct2/show/NCT00986661 JAMA Network Open. 2020;3(7):e207911. doi:10.1001/jamanetworkopen.2020.7911 (Reprinted) July 29, 2020 9/9

Journal

JAMA Network OpenAmerican Medical Association

Published: Jul 29, 2020

There are no references for this article.