Assessing the Magnitude of Immunogenic Cell Death Following Chemotherapy and Irradiation Reveals a New Strategy to Treat Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to have a dismal prognosis in part due to ineffective treatment strategies. The efficacy of some chemotherapies and especially radiotherapy are mediated partially by the immune system. Therefore, we hypothesized that profiling the immune response following chemotherapy and/or irradiation can be used as a readout for treatment efficacy, but also to help identify optimal therapeutic schedules for PDAC. Using murine models of PDAC, we demonstrated that concurrent administration of stereotactic body radiotherapy (SBRT) and a modified dose of FOLFIRINOX (mFX) resulted in superior tumor control when compared to single or sequential treatment groups. Importantly, this combined treatment schedule enhanced the magnitude of immunogenic cell death, which in turn amplified tumor antigen presentation by dendritic cells and intratumoral CD8 + T cell infiltration. Concurrent therapy also resulted in systemic immunity contributing to the control of established metastases. These findings provide rationale for pursuing concurrent treatment schedules of SBRT with mFX in PDAC.

Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: two cohorts of an open-label, phase 1b study

“…A clonal expansion of the neoantigen-specific T cells is expected after the response to anti-PD-1/PD-L1 regimens [ 16 ]. In multiple cancers, increased TCR clonality after ICPs is associated with an improved treatment efficacy [ 26 ].…”

“…Before treatment, high TCR diversity indicates a better immune status, with the mechanism that high diversity could preclude the magnitude of immune escape via increasing more potential tumor-specific T cells, which can control tumor cell growth and recognize corresponding antigens [ 17 ]. In patients with NSCLC, those with an increased peripheral PD-1 + CD8 + (double-positive PD-1 and CD8) clonality after ICPi treatment, and with a high PD-1 + CD8 + diversity pre-ICPi exhibited a better response and a longer PFS, as compared to those with low clonality and diversity [ 16 ]. Consistent with this finding, in our study, the higher TCRC clonality (which reflected an increased TCR clonality post-treatment) or lower TCRC diversity (indicating a high TCR diversity pre-treatment) had an evident association with a prolonged OS or PFS benefit from the sintilimab-chemo treatment.…”

“…T cell receptor (TCR) plays significant roles in antigen recognition with the main variable region of complementarity determining region 3 (CDR3) [ 16 ]. TCR diversity and clonality are suggested to indicate the clinical outcomes among immune checkpoint inhibitor (ICPi)-treated patients, but controversial results exist among different solid tumors [ 17 , 18 ].…”

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

“…The high sensitivity of the GI limits the radiation dose in treating PDAC patients. However, advances in stereotactic body irradiation therapy (SBRT), proton therapy, or heavy ion therapy can minimize the radiation dose to the critical organ, enhancing the number of PDAC patients that can be treated with RT [ 29 , 30 ]. This study aimed to compare the effect of an ablative RT protocol versus a fractionated one on the TME of pancreatic tumors and its subsequent impact on the combination with anti-PD-L1 ICBT.…”

Combined chemotherapy and endoscopic ultrasound-guided intratumoral 32P implantation for locally advanced pancreatic adenocarcinoma: a pilot study

“…Previous animal studies support this theory showing greater tumor antigen presentation in concurrent versus sequential chemoradiotherapy. Hence, the timing of therapy along with a low dose of sustained radiation may lead to a better clinical response to FOLFIRINOX [14].…”