Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy
Background Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2021-02-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/2/e001800.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832544761375883264 |
|---|---|
| author | Patrick Hwu Ravi Murthy Aung Naing Sapna P. Patel Simon Young Alda Tam Nina M. Muñoz Malea Williams Katherine Dixon Crystal Dupuis Amanda McWatters Rony Avritscher Soraya Zorro Manrique Kevin McHugh David Leach Jeffrey D. Hartgerink Punit Prakash Rahul A. Sheth |
| author_facet | Patrick Hwu Ravi Murthy Aung Naing Sapna P. Patel Simon Young Alda Tam Nina M. Muñoz Malea Williams Katherine Dixon Crystal Dupuis Amanda McWatters Rony Avritscher Soraya Zorro Manrique Kevin McHugh David Leach Jeffrey D. Hartgerink Punit Prakash Rahul A. Sheth |
| author_sort | Patrick Hwu |
| collection | DOAJ |
| description | Background Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy.Methods Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution.Results Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal).Conclusions Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics. |
| format | Article |
| id | doaj-art-7f53a27182084eda9d4c4b3cba2d5e18 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7f53a27182084eda9d4c4b3cba2d5e182025-02-03T09:50:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-02-019210.1136/jitc-2020-001800Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacyPatrick Hwu0Ravi Murthy1Aung Naing2Sapna P. Patel3Simon Young4Alda Tam5Nina M. Muñoz6Malea Williams7Katherine Dixon8Crystal Dupuis9Amanda McWatters10Rony Avritscher11Soraya Zorro Manrique12Kevin McHugh13David Leach14Jeffrey D. Hartgerink15Punit Prakash16Rahul A. Sheth17Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USAAff10 grid.240145.60000000122914776The University of Texas MD Anderson Cancer Center 77030 Houston TX USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USAMD Anderson Cancer Center, Houston, TX, USAInterventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAInterventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA2 Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, CanadaInterventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAInterventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USA2Moffitt Cancer Center and Research Institute, Tampa, FL, USADepartment of Bioengineering, Rice University, Houston, Texas, USADepartment of Chemistry, Rice University, Houston, Texas, USADepartment of Chemistry, Rice University, Houston, Texas, USADepartment of Electrical and Computer Engineering, Kansas State University, Manhattan, Kansas, USAInterventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USABackground Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy.Methods Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution.Results Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal).Conclusions Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.https://jitc.bmj.com/content/9/2/e001800.full |
| spellingShingle | Patrick Hwu Ravi Murthy Aung Naing Sapna P. Patel Simon Young Alda Tam Nina M. Muñoz Malea Williams Katherine Dixon Crystal Dupuis Amanda McWatters Rony Avritscher Soraya Zorro Manrique Kevin McHugh David Leach Jeffrey D. Hartgerink Punit Prakash Rahul A. Sheth Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy Journal for ImmunoTherapy of Cancer |
| title | Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| title_full | Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| title_fullStr | Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| title_full_unstemmed | Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| title_short | Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| title_sort | influence of injection technique drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy |
| url | https://jitc.bmj.com/content/9/2/e001800.full |
| work_keys_str_mv | AT patrickhwu influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT ravimurthy influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT aungnaing influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT sapnappatel influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT simonyoung influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT aldatam influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT ninammunoz influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT maleawilliams influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT katherinedixon influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT crystaldupuis influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT amandamcwatters influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT ronyavritscher influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT sorayazorromanrique influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT kevinmchugh influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT davidleach influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT jeffreydhartgerink influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT punitprakash influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy AT rahulasheth influenceofinjectiontechniquedrugformulationandtumormicroenvironmentonintratumoralimmunotherapydeliveryandefficacy |