Detection of immune-mediated tumour cell death in vivo using Zirconium-89-labeled APOMAB®
Vasilios Liapis1,2, Nicole L Wittwer3,4, William Tieu5,6
1Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Level 9 Bradley Building, North Terrace, Adelaide, SA, 5000, Australia. Vasilios.Liapis@sa.gov.au.
Background:
Inconsistent responses to anticancer immunotherapies demonstrate the need for non-invasive methods to detect treatment responses earlier than conventional medical imaging methods allow. The chimeric monoclonal antibody, APOMAB®, targets dead tumour cells following DNA-damaging anticancer treatments via binding of the ribonuclear protein, La/SSB, an intracellular protein overexpressed by tumour cells. La/SSB only becomes accessible to APOMAB binding in post-apoptotic necrotic tumour cells.
Methods:
We assessed the ability of APOMAB to detect dead tumour cells after immune-mediated cell death. Co-culture of GD2-specific chimeric antigen receptor (CAR) T-cells with GD2-expressing cancer cell lines demonstrated specific and dose-dependent binding of APOMAB to the resulting dead target cells, confirming detection of immune-mediated cell death. Then, using four distinct preclinical tumour models and in a cancer patient, we investigated APOMAB-immunoPET as a technique to detect immune-mediated tumour cell death.
Results:
Within days of treatment, APOMAB-immunoPET showed increased tumour uptake of 89Zirconium-labelled APOMAB (89Zr-APOMAB) after CAR-T cell therapy, immune checkpoint inhibitor (ICI) therapy with and without chemotherapy, and via endogenous T-cell mediated tumour clearance. In a metastatic melanoma patient after ICI therapy, a previously FDG-avid pulmonary tumour reduced in size as tumour 89Zr-APOMAB uptake increased over the 12-day scanning period.
Conclusions:
This study demonstrates for the first time that not only does radiolabelled APOMAB provide an initial direct measure of the extent of immune-mediated tumour cell death in vivo but also reveals the heterogeneous nature of tumour responses to T-cell based therapies both within and between individuals.
Insights
APOMAB-immunoPET imaging can detect immune-mediated tumor cell death early after cancer immunotherapy. This novel method reveals diverse treatment responses, improving patient monitoring and therapeutic strategies.
Area of Science:
- Oncology
- Immunotherapy
- Radiochemistry
Background:
- Conventional imaging delays detection of anticancer immunotherapy response.
- APOMAB targets dead tumor cells by binding La/SSB, accessible post-apoptosis.
- Need for early, non-invasive methods to assess treatment efficacy.
Purpose of the Study:
- Assess APOMAB's ability to detect immune-mediated tumor cell death.
- Investigate APOMAB-immunoPET for visualizing treatment-induced cell death.
- Evaluate APOMAB-immunoPET in preclinical models and a human patient.
Main Methods:
- Co-culture of CAR T-cells with cancer cells to confirm APOMAB binding to dead cells.
- Utilized four preclinical tumor models for APOMAB-immunoPET studies.
- Administered 89Zr-APOMAB to a metastatic melanoma patient post-immunotherapy.
Main Results:
- APOMAB-immunoPET detected increased tumor uptake of 89Zr-APOMAB within days of various immunotherapies.
- Observed increased tumor 89Zr-APOMAB uptake correlating with decreased tumor size in a melanoma patient.
- Demonstrated APOMAB binding to tumor cells undergoing immune-mediated death.
Conclusions:
- Radiolabeled APOMAB offers a direct in vivo measure of immune-mediated tumor cell death.
- APOMAB-immunoPET reveals heterogeneity in tumor response to T-cell therapies.
- This imaging technique enhances understanding of individual patient responses to immunotherapy.
