Summary
Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer after hepatocellular
carcinoma (HCC), is an aggressive malignancy with dismal overall prognosis. While frontline combination of
chemotherapy with immune checkpoint inhibition (ICI) has been a major recent advance in therapy for patients
with unresectable iCCA, there remains an unmet critical need to improve the current median progression free
survival of about 8 months. With data supporting the need for a pre-existing immune response in the tumor for
ICI response, here we propose to add high-dose conformal external beam radiotherapy (EBRT) followed by
intra-tumor injection of autologous dendritic cells (DC) to dual PD-L1 (atezolizumab)/TIGIT (tiragolumab)
blockade to further enhance the immune stimulatory effect. Radiation can induce inflammatory tumor cell death
that can be favorable for tumor neoantigen presentation. Injection of autologous DC after EBRT would be a
novel method of boosting in vivo tumor antigen uptake and presentation to expand tumor-reactive cytotoxic T
cells. We have treated subjects with unresectable liver tumors (HCC and iCCA) in a pilot study with this EBRT
and DC approach with promising response and acceptable toxicity (no grade ≥ 3 toxicity). Three of the 8
subjects had partial response, including an iCCA patient with ongoing response at 48 months. Both emergence
of new T cell receptor (TCR) clones and expansion of existing TCR clones, including clones with tumor
reactive and cytotoxic profile, have been observed, suggesting this combination could enhance tumor reactive
cytotoxic T cell response. However, many of the TCR clones also have early exhaustion signal with
upregulation of multiple checkpoint receptors including PD-L1 and TIGIT. Thus, combining DC injection with
atezolizumab and tiragolumab may help further enhance the cytotoxic functions of these TCR clones. We
hypothesize that combining EBRT followed by intratumor DC injections with atezolizumab and tiragolumab can
improve the PFS for patients with unresectable iCCA and that the effect is mediated by systemic expansion of
a tumor reactive T cell repertoire. We will test the hypothesis through 2 aims. 1) Assess the clinical efficacy
of this combination therapy in a phase II study with a safety run-in phase. PFS will be the primary
endpoint. 2) identify the effect of this novel combination immunotherapy on tumor reactive T cell
repertoire. We will use scRNAseq and TCRseq to identify TCR clonal expansion and transcriptome profile of
the TCR clones in the blood and tumor, with a focus on tumor reactive TCR clones. We will also use
scRNAseq and flow to profile the changes of other immune cells in the tumor and blood. Finally, we will use
imaging cytometry to examine the tumor and immune spatial relationship in the tumor. Our study will not only
identify the clinical activities of this novel combination therapy but also use state-of-the-art technology to
improve our understanding on the mechanism of action and potential resistance to this immunotherapy.