Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors.

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.

Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity.

The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression.

An Ex Vivo 3D Tumor Microenvironment-Mimicry Culture to Study TAM Modulation of Cancer Immunotherapy.

Tumor-associated macrophages (TAMs) accumulate in the solid tumor microenvironment (TME) and have been shown to promote tumor growth and dampen antitumor immune responses. TAM-mediated suppression of T-cell antitumor reactivity is considered to be a major obstacle for many immunotherapies, including immune checkpoint blockade and adoptive T/CAR-T-cell therapies. An ex vivo culture system closely mimicking the TME can greatly facilitate the study of cancer immunotherapies. Here, we report the development of a 3D TME-mimicry culture that is comprised of the three major components of a human TME, including human tumor cells, TAMs, and tumor antigen-specific T cells. This TME-mimicry culture can readout the TAM-mediated suppression of T-cell antitumor reactivity, and therefore can be used to study TAM modulation of T-cell-based cancer immunotherapy. As a proof-of-principle, the studies of a PD-1/PD-L1 blockade therapy and a MAO-A blockade therapy were performed and validated.

Prefabricated contoured foot orthoses to reduce pain and increase physical activity in people with hip osteoarthritis: protocol for a randomised feasibility trial.

INTRODUCTION: The aim of this randomised feasibility trial is to determine the feasibility of conducting an adequately powered randomised controlled trial (RCT) investigating the efficacy of prefabricated contoured foot orthoses in people with hip osteoarthritis (OA). The secondary aims of the trial are to compare the effect of prefabricated contoured foot orthoses to a flat shoe insert comparator on outcomes of hip-related pain, physical activity and quality of life. We hypothesise that the demand, implementation, acceptability and practicality of foot orthoses as a treatment option for people with hip OA will be deemed feasible, informing the development of an adequately powered RCT to evaluate the efficacy and long term outcomes. METHODS AND ANALYSIS: We will recruit 28 people with hip OA who will be randomised to receive either prefabricated contoured foot orthoses or flat shoe inserts to use for a 6-week period. Both groups will receive standardised education on hip OA and physical activity. The study's primary outcome is the feasibility domains of demand, implementation, acceptability and practicality. The secondary outcomes include the change in Hip Osteoarthritis Outcome Score-12, Patient Health Questionnaire-9, Brief Fear of Movement Scale for OA, Physical activity accelerometry and the Physical Activity Questionnaire-short form. Descriptive statistics will be used to describe feasibility outcomes with limited efficacy analysis used for the secondary outcomes. Linear mixed models will be used to analyse between-group differences at 6 weeks, with baseline values used as covariates, treatment allocation as a fixed factor and participant as a random factor. ETHICS AND DISSEMINATION: This trial has been approved by the La Trobe University Human Research Ethics Committee (HEC20427), St. Vincent's Hospital Melbourne, Human Research Ethics Committee (HREC 266/20) and Northern Health Research Governance (NH-2021-292862). The results will be disseminated via a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT05138380.