IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin

Abstract

Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7 × 19) and found that these 7 × 19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7 × 19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7 × 19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7 × 19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7 × 19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor. Trial registration: NCT03198546. Registered 26 June 2017, https://clinicaltrials.gov/ct2/show/NCT03198546?term=NCT03198546&draw=2&rank=1

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

“…Tumors showed increased infiltration with T recipient no-CAR-T cells as well as downregulation of exhaustion markers PD-1 and T cell immunoreceptor with Ig and ITIM domains (TIGIT) on T cells ( 67 ). Similar results were obtained with 7 × 19 CAR-T cells in vivo in the context of hepatocellular carcinoma (HCC) and pancreatic carcinoma ( 68 ).…”

“…Results from a first six-case cohort preliminary phase I clinical study (NCT03198546) in advanced HCC/PC/ ovarian carcinoma (OC) patients with glypican-3 (GPC3) or MSLN expression have been published recently and show encouraging results: two complete responses (CR), two partial responses (PR) and 2 steady diseases (SD). There were no grade 2-4 adverse events or major complications (68). Another ongoing clinical trial (NCT03932565) evaluates intratumoral injection of Nectin4/FAP-targeted fourth-generation CAR-T cells (expressing IL-7 and CCL19, or IL12) for the treatment of Nectin4-positive advanced malignant solid tumors (NSCLC, breast, ovarian, bladder or pancreatic cancer).…”

Interleukin-7 Biology and Its Effects on Immune Cells: Mediator of Generation, Differentiation, Survival, and Homeostasis

“…More recently, scientists tried to apply IL-7 to CAR-T cells given the great success chimeric antigen receptor (CAR)-engineered T cells showed in cancer treatment. Surprisingly, they found that expression of IL-7 and CCL19 significantly improved T-cell infiltration and survival of CAR-T cells in mouse tumors, enhancing the anti-tumor activity against solid tumors ( 31 ).…”

T-cell intrinsic Toll-like receptor signaling: implications for cancer immunotherapy and CAR T-cells

“…When engineered to secrete human IL-7 and CCL19, glypican-3-specific (g28T2z) and mesothelinspecific (m28T2z) CAR T-cells displayed enhanced tumor clearance in both xenograft models and a phase I clinical trial (NCT03198546). 111 In addition to CARs, TLR pathway signaling domains are showing success in other synthetic T-cell stimulatory molecules. CD8α:MyD88, a synthetic coreceptor that fuses together the extracellular and transmembrane domains of CD8α and the intermediate and death domains of MyD88 (figure 3C), is being used as another way of activating the TLR signaling pathway in T-cells.…”