Dataset Information

A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

ABSTRACT:

Background

The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection.

Methods

We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors.

Findings

We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor.

Conclusions

Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors.

Funding

Funded by Fate Therapeutics and NIH (R01CA238039).

SUBMITTER: Goulding J

PROVIDER: S-EPMC10524375 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

Goulding John J Yeh Wen-I WI Hancock Bryan B Blum Robert R Xu Tianhao T Yang Bi-Huei BH Chang Chia-Wei CW Groff Brian B Avramis Earl E Pribadi Mochtar M Pan Yijia Y Chu Hui-Yi HY Sikaroodi Shohreh S Fong Lauren L Brookhouser Nicholas N Dailey Thomas T Meza Miguel M Denholtz Matthew M Diaz Evelyn E Martin Judy J Szabo Peter P Cooley Sarah S Ferrari de Andrade Lucas L Lee Tom T TT Bjordahl Ryan R Wucherpfennig Kai W KW Valamehr Bahram B

Med (New York, N.Y.) 20230511 7

<h4>Background</h4>The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection.<h4>Methods</h4>We have developed a novel CAR targeting the ...[more]

PMID: 37172578

Similar Datasets

Project description:BackgroundChimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in the treatment of hematologic malignancies, while the success has not yet been replicated in solid tumors. To some extent, the disappointing results can be attributed to the paucity and heterogeneity of target antigens in solid tumors since adequate antigens are the cornerstone for CAR-T cells to recognize and attack tumor cells.MethodsWe established a target-redirected universal CAR-T (TRUE CAR-T) cell therapeutic modality, in which exogenous antigens are loaded onto fusogenic nanoparticles to achieve in situ modification of cell membrane in solid tumors, providing targets for subsequent CAR-T cell therapy. The modification effect was evaluated by flow cytometry and confocal microscopic imaging. The in vivo metabolism and biodistribution of fusogenic antigen loaded nanoparticles (F-AgNPs) was explored using near infrared living imaging. Then F-AgNPs mediated in situ antigen modification were cooperated with corresponding CAR-T cell therapy, and its antitumor efficacy was evaluated using immune function experiments and further investigated in different tumor models.ResultsUsing F-AgNPs, exogenous antigens were selectively modified onto tumor cell membranes through membrane fusion, spread deeper into tumor tissues through intercellular lipid transfer, further activating corresponding CAR-T cells and mediating antitumor immune responses towards multiple types of tumor cells, despite of their inherent antigen profiles. The cooperative treatment of F-AgNPs and CAR-T cell therapy successfully suppressed tumor proliferation and prolonged survival in both subcutaneous and peritoneally disseminated tumor models.ConclusionThe fusogenic nanoparticle-based in situ antigen modification overcome the limitation of target antigens paucity and heterogeneity in solid tumors, improving the efficacy and broadening the applications of CAR-T cells, thus establishing a novel TRUE CAR-T cell therapeutic modality with universal application and translational potential in immunotherapies for solid tumors.

Dataset Information

A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

Background

Methods

Findings

Conclusions

Funding

Publications

A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

Similar Datasets

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