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Background/aim: Our multicenter phase II TAS-CC3 study demonstrated favorable median progression-free survival (PFS) and overall survival (OS) of 32 metastatic colorectal cancer (mCRC) patients treated with TAS-102 + bevacizumab as 3 rd -line treatment., Patients and Methods: We investigated the predictive and prognostic values of pre-treatment blood inflammation-based scores, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte ratio (LMR) on disease-control (DC), PFS and OS by a post-hoc analysis., Results: Receiver operating characteristic curve analyses of the 3 inflammation-based scores versus DC showed the best predictive performance for LMR, followed by NLR and PLR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). The high-LMR group showed significantly longer survival than the low group (4.9 vs. 2.3 m for median PFS) (21.0 vs. 6.1 m for median OS)., Conclusion: The pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients undergoing TAS-102 and bevacizumab treatment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Roles for mutant (mt) KRAS in the innate immune microenvironment in colorectal cancer (CRC) were explored., Materials and Methods: Human CRC HCT116-derived, mtKRAS-disrupted (HKe3) cells that express exogenous mtKRAS and allogenic cytokine-activated killer (CAK) cells were co-cultured in 3D floating (3DF) culture. The anti-CD155 antibody was used for function blocking and immuno histochemistry., Results: Infiltration of CAK cells, including NKG2D + T cells, into the deep layer of HKe3-mtKRAS spheroids, was observed. Surface expression of CD155 was found to be up-regulated by mtKRAS in 3DF culture and CRC tissues. Further, the number of CD3 + tumor-infiltrating cells in the invasion front that show substantial CD155 expression was significantly larger than the number showing weak expression in CRC tissues with mtKRAS. CD155 blockade decreased the growth of spheroids directly and indirectly through the release of CAK cells., Conclusion: CD155 blockade may be useful for therapies targeting tumors containing mtKRAS., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Adoptive immunotherapy for cancer has evolved through development of novel technologies for generating a large number of activated killer cells, such as αβ T-cells, γδ T-cells, and natural killer cells. There has been no prospective trial of combination therapy involving adoptive immunotherapy and first-line chemotherapy for stage IV colorectal cancer. The present pilot study aimed to evaluate the safety and feasibility of combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer (COMVI study)., Patients and Methods: The COMVI study was a prospective, single-arm pilot trial. Therapy in each 21-day treatment cycle involved XELOX (130 mg/m 2 of oxaliplatin on day 1 plus 1,000 mg/m 2 of capecitabine twice daily on days 1-14), bevacizumab (7.5 mg/kg on day 1), and αβ T-lymphocytes (over 5×10 9 on day 18) cultured ex vivo with an immobilized antibody to CD3 and interleukin-2., Results: The study included six patients (two men and four women) between June 2013 and September 2014. The median patient age was 68 years (range=55-75 years). The overall response rate was 83.3% [complete response in two (33.3%); partial response in three (50.0%); stable disease in one (16.7%); no cases of progressive disease]. The tumor volume reduction rate was 53% (range=38.0-100%). The median progression-free and overall survival durations were 567 and 966 days, respectively. Most adverse events were mild-to-moderate in intensity, and no grade 4 adverse events occurred in the six patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study., Conclusion: Combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are needed to confirm the safety and efficacy of such chemoimmunotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Various types of chemoimmunotherapies for malignant tumors have been reported. However, there are few reports on hepatectomy after chemoimmunotherapy. We evaluated the safety and efficacy of hepatectomy for patients with stage IV colorectal liver metastases (CLM) after chemoimmunotherapy using activated αβ T-cells., Patients and Methods: From June 2012 to December 2016, five patients who underwent hepatectomy after receiving capecitabine and oxaliplatin (XELOX) plus bevacizumab and ex vivo-expanded αβ T-lymphocytes as first-line chemoimmunotherapy were included., Results: The median age of the five patients (two men, three women) was 61.4 (range=56-75) years. The surgical procedure was partial hepatectomy in two, laparoscopic partial hepatectomy in two, and one case of partial hepatectomy with subsegmentectomy. There was no postoperative complication of Clavien-Dindo grade 3A or higher. One patient had multiple lung metastases., Conclusion: Hepatectomy after chemoimmunotherapy using activated αβ T-cells for CLM can be performed safely., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large numbers of αβ and γδ T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for stage IV colorectal cancer (CRC)., Patients and Methods: Fifteen patients with advanced or recurrent CRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy., Results: Median age of the 15 patients (4 men, 11 women) was 65 years (range=49-80). Median progression-free survival was 21.3 months. Response rate was 80% (complete response (CR)=26.7%, partial response (PR)=53.3%, stable disease (SD)=20% and progressive disease (PD)=0%). Most adverse events were mild to moderate regarding their intensity and immunotherapy-associated toxicity was minimal., Conclusion: Combination of adoptive αβ T cell immunotherapy with chemotherapy for stage IV CRC is feasible and safe., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Dihydropyrimidine dehydrogenase (DPD) degrades approximately 85% of administered 5-fluorouracil (5-FU). With a reported high mortality rate, chemotherapy is generally contraindicated for patients with DPD deficiency., Patients and Methods: Chemotherapy was initiated for a 73-year-old man with DPD deficiency. Capecitabine was administered in incrementally increasing doses, beginning with a single pill while monitoring plasma 5-FU concentration, and neutrophil and platelet counts., Results: DPD protein level was 2.35 U/mg. After increasing the capecitabine dose to 1,800 mg, oxaliplatin and bevacizumab were added. Subsequent DPD protein measurement showed that the level had increased to approximately 12-fold the one before chemotherapy. Sequencing of all 23 exons of DPYD gene revealed a mutation of guanine to thymine in exon 11 (1156 G>T)., Conclusion: This is the first report to indicate that DPD activity can be induced. These findings may provide early indications of a new method for chemotherapy for DPD-deficient patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)