Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes

J L Goggi,L Jiang,A M Chacko,Y X Tan,J R Tang,P Cheng,L Renia,R Boominathan,H X Chin,B Jieu,S V Hartimath,T Y Yuen,Edward G Robins,Y Y Hwang,A Larbi,C Johannes

doi:10.1007/s11307-020-01519-3

Abstract

PurposeImmune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes.ProceduresWe have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations.Results[18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours.Conclusions[18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

Highlights

Immune checkpoint receptors are crucial molecules that regulate the immune system, dampening T cell activation
[18F]AlF-mNOTA-GZP was efficiently prepared by adaptation of the peptide labelling method described by McBride et al in 2009 [22]
Immune checkpoint inhibitor (ICI) monotherapy has been shown to trigger activation of compensatory T cellassociated checkpoints [5], such as PD-1 blockade upregulating TIM-3, an effect that could perhaps be mitigated by combined therapy

Summary

Introduction

Immune checkpoint receptors are crucial molecules that regulate the immune system, dampening T cell activation. LAG3 is a checkpoint modulator, is thought to be involved in immune tolerance by mediating T cell exhaustion [7] and has been shown to be expressed on expressed on natural killer (NK), activated T cells and Treg TILs [5, 10]. OX40 antibody agonists have shown significant therapeutic efficacy both as monotherapies and in combination with PD-1 blockade leading to significant tumour regression [11]. Certain phenotypes, such as microsatellite instability (MSI), mutational burden, and neoantigenic load have been demonstrated to enrich response to PD-1 monotherapy [2, 12]. Accurate stratification of treatment response to monotherapies and especially combination therapies, across all tumour phenotypes, is paramount to ensure safe and effective patient management

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Discussion

Conclusion