CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors

Abstract

Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.Results: B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

Immunobiology of chimeric antigen receptor T cells and novel designs

“…This is in contrast to the B7-H3 CAR, which is unable to significantly produce IFNγ or IL-2 in response to target cells expressing ~ 50,000 B7-H3 molecules/cell, while CARs targeting CD19, CD22, anaplastic lymphoma kinase (ALK), and CD30 demonstrated antigen density thresholds between those of CD20 and B7-H3 CARs. [72][73][74][75][76] Importantly, these antigen thresholds not only affect in vitro functions, but also impact in vivo efficacy, as has been demonstrated in preclinical models using the CD22, B7-H3, and ALK CARs. 72,74,75 From such observations, it is evident that the inability of CARs to respond to low levels of antigen represents an obstacle to current and future CAR T cell therapy.…”

“…[72][73][74][75][76] Importantly, these antigen thresholds not only affect in vitro functions, but also impact in vivo efficacy, as has been demonstrated in preclinical models using the CD22, B7-H3, and ALK CARs. 72,74,75 From such observations, it is evident that the inability of CARs to respond to low levels of antigen represents an obstacle to current and future CAR T cell therapy. Strategies have evolved to immediately overcome the problem of insensitivity to low levels of antigen by modulating the level of antigen expression on the malignant cells.…”

“…For example, the CD20 CAR has been shown to degranulate in response to as few as ~ 200 CD20 molecules/target cell and to produce cytokines in response to >2000 CD20 molecules/cell. This is in contrast to the B7‐H3 CAR, which is unable to significantly produce IFNγ or IL‐2 in response to target cells expressing ~ 50,000 B7‐H3 molecules/cell, while CARs targeting CD19, CD22, anaplastic lymphoma kinase (ALK), and CD30 demonstrated antigen density thresholds between those of CD20 and B7‐H3 CARs . Importantly, these antigen thresholds not only affect in vitro functions, but also impact in vivo efficacy, as has been demonstrated in preclinical models using the CD22, B7‐H3, and ALK CARs .…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…An analysis on the TCGA database showed that B7‐H3 expression is up‐regulated particularly in high‐grade gliomas . Majzner and colleagues developed a CAR‐targeting B7‐H3, showing preclinical anti‐tumor activity against multiple types of pediatric tumors including medulloblastoma, indicating potential clinical application of B7‐H3‐CAR T cells against certain types of brain tumors.…”

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…82,83 Careful selection and design of CAR T-cell constructs may potentially alleviate some of the issues associated with differences in antigen expression between healthy and tumor tissues. A recent study by Majzner et al 84 demonstrated that CAR T cells targeting the pan-cancer antigen B7-H3 mediated cytolysis of high antigen-expressing tumor cells whilst displaying minimal reactivity towards low antigen-expressing cells. This suggests that antigens that are found on normal tissues may still serve as safe targets, provided that their expression on tumor cells is sufficiently distinguishable by CAR T cells.…”