◥KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a doublestranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m 2 ) and pelareorep (1 Â 10 10 TCID 50 -3 Â 10 10 TCID 50 )] was implemented in adult patients with oxaliplatin refractory/intolerant, KRASmutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-na€ ve patients, the highest dose of FOLFIRI/ bevacizumab (180 mg/m 2 irinotecan) and pelareorep (3 Â 10 10 TCID 50 ) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid s-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/ bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.

Pancreatic ductal adenocarcinoma (PDAC) accounts for about 3% of all cancers in the United States and about 7% of all cancer deaths. Despite the lower prevalence relative to other solid tumors, it is one of the leading causes of cancer-related death in the US. PDAC is highly resistant to chemotherapy as well as radiation therapy. Current standard-of-care chemotherapeutic regimens provide transient disease control but eventually tumors develop chemoresistance. Tumors that are deficient in DNA damage repair mechanisms such as BRCA mutants respond better to platinum-based chemotherapies. However, these tumor cells can utilize the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) as a salvage DNA repair pathway to prolong survival. Hence, in the presence of BRCA mutations, the inhibition of the PARP pathway can lead to tumor cell death. This provides the rationale for using PARP inhibitors in patients with BRCA mutated PDAC. The phase III POLO trial showed a near doubling of progression-free survival (PFS) compared with placebo in advanced PDAC when a PARP inhibitor, olaparib, was used as maintenance therapy. As a result, the US Food and Drug Administration (FDA) approved olaparib as a maintenance treatment for germline BRCA mutated advanced PDAC that has not progressed on platinum-based chemotherapy. The success of olaparib in treating advanced PDAC opened the new field for utilizing PARP inhibitors in patients with DNA damage repair (DDR) gene defects. Currently, many clinical trials with various PARP inhibitors are ongoing either as monotherapy or in combination with other agents. In addition to germline/somatic BRCA mutations, some trials are enrolling patients with defects in other DDR genes such as ATM, PALB2, and CHEK2. With many ongoing PARP inhibitor trials, it is hopeful that the management of PDAC will continuously evolve and eventually lead to improved patient outcomes.

Background: KRAS mutations are prevalent in 40-45% of patients with colorectal cancer (CRC) and targeting this gene has remained elusive. Viruses are well known immune sensitizing agents. The therapeutic efficacy of oncolytic reovirus in combination with chemotherapy is examined in a phase 1 study of metastatic CRC. This study evaluates the nature of immune response by determining the cytokine expression pattern in peripheral circulation along with the distribution of antigen presenting cells (APCs) and activated T lymphocytes. Further the study evaluates the alterations in exosomal and cellular microRNA levels along with the effect of reovirus on leukocyte transcriptome. Methods: Reovirus was administered as a 60-min intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID 50) of 3 × 10 10. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood prior to reovirus administration and post-reovirus on days 2, 8, and 15. The expression profile of 25 cytokines in plasma was assessed (post PBMC isolation) on an EMD Millipore multiplex Luminex platform. Exosome and cellular levels of miR-29a-3p was determined in pre and post reovirus treated samples. Peripheral blood mononuclear cells were stained with fluorophore labelled antibodies against CD4, CD8, CD56, CD70, and CD123, fixed and evaluated by flow cytometry. The expression of granzyme B was determined on core biopsy of one patient. Finally, Clariom D Assay was used to determine the expression of 847 immune-related genes when compared to pre reovirus treatment by RNA sequencing analysis. A change was considered if the expression level either doubled or halved and the significance was determined at a p value of 0.001.

Cancer is an important global issue with increasing incidence and mortality, placing a substantial burden on the healthcare system. Colorectal cancer is the third most common cancer diagnosed among men and women in US. It is estimated that in 2018 there will be 319,160 new diagnosis and 160,820 deaths related to cancer of the digestive system including both genders in the United States alone. Considering limited success of chemotherapy, radiotherapy, and surgery in treatment of these cancer patients, new therapeutic avenues are under constant investigation. Therapy options have consistently moved away from typical cytotoxic chemotherapy where patients with a given type and stage of the disease were treated similarly, to an individualized approach where a tumor is defined by its specific tissue characteristics /epigenetic profile, protein expression and genetic mutations. This review takes a deeper look at the immune-biological aspects of cancers in the gastrointestinal tract (entire digestive tract extending from esophagus/stomach to rectum, including pancreatico-biliary apparatus) and discusses the different treatment modalities that are available or being developed to target the immune system for better disease outcome.