Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC.Patients and Methods: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day À3 to þ1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day À3 to þ1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT.Results: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2.Conclusions: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer

“…We next evaluated immunophenotypes associated with E-TLS in PDAC tumors by quantifying immune infiltrates by IHC and analyzing transcriptomic signatures from RNA-seq data of whole tumor tissue from FFPE sections as previously described for this patient cohort. 43 As expected, tumors with E-TLS contained significantly more CD3 + and CD8 + T cells and CD20 + B cells per/mm 2 1 of tumor tissue compared to TLS − tumors ( Figure 2a-b ). Recent studies in other tumor types have shown that CD103 is a marker of tumor reactive, 44 terminally differentiated, 45 and/or tissue resident memory 46–48 CD8 + T cells that may associate with B cell recruitment in cancer.…”

“…Single stained sections were digitally scanned using a Leica autoscanner at 20x magnification. Positive cells/mm 2 were analyzed using ScanScope software (Leica Biosystems), or Qupath. 23 Whole tissue regions (1 section/patient) were selected for analysis by identifying tumor cells surrounded by clear desmoplastic stroma in consultation with a pathologist (C.B.)…”

Prognostic value of eight immune gene signatures in pancreatic cancer patients

“…More and more clinical data show that cancer immunotherapy is a key step in clinical cancer treatment [19,20]. Cancer management methods, especially non-small cell lung cancer, melanoma, urothelial cancer, and kidney cancer, and some preclinical and clinical trials have confirmed that immunotherapy has achieved encouraging results in many malignancies, including pancreatic cancer [21][22][23]. However, based on available data, it is clear that ICB has limited success in pancreatic cancer, which is also related to the low immunogenicity and immunosuppressive tumor microenvironment of pancreatic cancer [24,25].…”

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

“…However, this study only included three patients with metastatic PDAC, and their ORR to this strategy was not reported. Recently, a single-center phase I study tested SBRT plus durvalumab with or without tremelimumab as a second- or later-line therapy for metastatic PDAC patients [ 58 ]. Unexpectedly, the ORR for this strategy was only 5.1% [ 57 ].…”