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Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy 1-4 . Glypican-3 (GPC3) is expressed in a group of solid cancers 5-10 , and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks. Cohort 2 patients ( NCT05103631 and NCT04377932 ) received GPC3 CAR T cells that co-expressed IL-15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumour response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared with non-responders, tumour-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to type I interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients., Competing Interests: Competing interests: A.H., G.D., S.G. and L.S.M. have patents related to GPC3 CARs. A.H. is consultant for Waypoint Bio and serves on the Scientific Advisory Board of CARGO Therapeutics. A.H. has equity in CARGO. A.H. and L.S.M. received research support from Kuur/Athenex Therapeutics. A.H. and P.R. have a pending patent application related to cytokine co-expression in CAR T cells. N.V. is cofounder of CellChorus and AuraVax Therapeutics. M.K.B. has equity in AlloVir Inc., Marker Therapeutics, Tessa Therapeutics Ltd and March Biosciences, and serves on advisory boards for Marker Therapeutics, Allogene, Walking Fish, Abintus, Tessa Therapeutics, Athenex, Onk Therapeutics, Coya Therapeutics, Triumvira, Adaptimmune, Vor Therapeutics, Tscan, Kuur, Memgen and Turnstone Biologics Ltd. M.K.B. is the inventor of the iC9 safety switch. M.K.B. received royalties from Bellicum Pharmaceuticals. H.E.H. has equity in AlloVir Inc. and Marker Therapeutics and share options in CoRegen; has served on advisory boards for March Biosciences, Fresh Wind Biotechnologies, Kiadis, GSK, Marker Therapeutics and Tessa Therapeutics; and has received research support from Tessa Therapeutics and Kuur Therapeutics. S.G. is coinventor on patent applications in the fields of cell or gene therapy for cancer, and is a member of the Scientific Advisory Board of Be Biopharma and CARGO, and of the Data and Safety Monitoring Board of Immatics. B.J.G. owns QB Regulatory Consulting which has, or has had, agreements with Tessa Therapeutics, AlloVir (including equity), Marker Therapeutics, Lokon Pharma and March Biosciences. C.A.R. has participated in advisory boards for Novartis, Genentech and CRISPR Therapeutics, and has received research funding from Athenex and Tessa Therapeutics. P.L. served on the advisory board for Janssen Therapeutics and receives research funding from Marker Therapeutics. A.M. has equity in Immunai Inc. The other authors declare no competing interests. N.L. received research support from Tessa Therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy 1-4 . Glypican-3 (GPC3) is expressed in a group of solid cancers 5-10 , and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.

Background: It is estimated that 6% to 20% of all cholangiocarcinoma (CCA) diagnoses are explained by primary sclerosing cholangitis (PSC), but the underlying risk factors in the absence of PSC are unclear. We examined associations of different risk factors with intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States., Methods: We conducted a case-control study of 121 patients with ECC and 308 patients with ICC treated at MD Anderson Cancer Center between May 2014 and March 2020, compared with 1,061 healthy controls. Multivariable logistic regression analysis was applied to estimate the adjusted OR (AOR) and 95% confidence interval (CI) for each risk factor., Results: Being Asian, diabetes mellitus, family history of cancer, and gallbladder stones were associated with higher odds of developing ICC and ECC. Each 1-unit increase in body mass index in early adulthood (ages 20-40 years) was associated with a decrease in age at diagnosis of CCA (6.7 months, P < 0.001; 6.1 months for ICC, P = 0.001; 8.2 months for ECC, P = 0.007). A family history of cancer was significantly associated with the risk of ICC and ECC development; the AORs (95% CI) were 1.11 (1.06-1.48) and 1.32 (1.01-2.00) for ICC and ECC, respectively., Conclusions: In this study, early adulthood onset of obesity was significantly associated with CCA and may predict early diagnosis at younger age than normal weight individuals., Impact: The study highlights the association between obesity and CCA, independent of PSC. There is a need to consider the mechanistic pathways of obesity in the absence of fatty liver and cirrhosis., (©2023 American Association for Cancer Research.)

Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. Both genetic and epigenetic alterations are common in CRC and are the driving force of tumorigenesis. The adenoma-carcinoma sequence was proposed in the 1980s that described transformation of normal colorectal epithelium to an adenoma and ultimately to an invasive and metastatic tumor. Initial genetic changes start in an early adenoma and accumulate as it transforms to carcinoma. Chromosomal instability, microsatellite instability and CpG island methylator phenotype pathways are responsible for genetic instability in colorectal cancer. Chromosomal instability pathway consist of activation of proto-oncogenes (KRAS) and inactivation of at least three tumor suppression genes, namely loss of APC, p53 and loss of heterozogosity (LOH) of long arm of chromosome 18. Mutations of TGFBR and PIK3CA genes have also been recently described. Herein we briefly discuss the basic concepts of genetic integrity and the consequences of defects in the DNA repair relevant to CRC. Epigenetic alterations, essential in CRC tumorigenesis, are also reviewed alongside clinical information relevant to CRC.