Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy

Abstract

BackgroundIntratumoral 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.MethodsIntratumoral 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.ResultsVariations 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).ConclusionsInjection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.

Hyperthermia and Tumor Immunity

“…The generation of ICD has been identified in multiple locoregional cancer therapies including radiation therapy [ 18 ], direct intratumoral immunotherapies [ 41 , 42 , 43 ] and hyperthermia [ 40 ]. One potential advantage of hyperthermia over radiation is the absence of lymphopenia that can follow radiation therapy [ 44 , 45 , 46 ].…”

STING Signaling and Skin Cancers

“…Therefore, STING-targeted treatment is currently seen as a possible alternative or additive treatment for melanoma. STING enhances anti-tumor immunity against melanoma mediated by IFN [37][38][39][40][41], which activates immune cells such as CD11c+ DC, CD8+ cells and NK cells in response to melanoma cells [42][43][44]. STING also upregulates MHC class I molecules, thereby enhancing the recognition or killing effect of cytotoxic T-cells [45].…”

Immunotherapy and Interventional Radiology (IR): Time to Change the Paradigm—Keynote Lecture PAIRS 2021

“…are controlled by IRs and also need research. 8 Close collaboration between medical oncologists, diagnostic radiologists, IRs, and planning nurses are key to successful implementation of intratumoral immunotherapy trials and clinical practice, to the point that a multidisciplinary tumor board dedicated to this practice is recommended. 9 Many questions remain to be answered, and IRs must be part of this research: dose by body weight versus dose per tumor?…”

“…Do we need delivery platform, as suggested by early animal experiment? 8,10,11 IRs must investigate other intratumoral routes such as intralymphatic and intra-arterial. Maybe in the future, we can inject in size of the particle theory.…”