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

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

  • Med. 2023 May 9;S2666-6340(23)00136-8. doi: 10.1016/j.medj.2023.04.004.
John Goulding 1,  Wen-I Yeh 2,  Bryan Hancock 2,  Robert Blum 2,  Tianhao Xu 2,  Bi-Huei Yang 2,  Chia-Wei Chang 2,  Brian Groff 2,  Earl Avramis 2,  Mochtar Pribadi 2,  Yijia Pan 2,  Hui-Yi Chu 2,  Shohreh Sikaroodi 2,  Lauren Fong 2,  Nicholas Brookhouser 2,  Thomas Dailey 2,  Miguel Meza 2,  Matthew Denholtz 2,  Evelyn Diaz 2,  Judy Martin 2,  Peter Szabo 2,  Sarah Cooley 2,  Lucas Ferrari de Andrade 3,  Tom T Lee 2,  Ryan Bjordahl 2,  Kai W Wucherpfennig 4,  Bahram Valamehr 5
Affiliations

Affiliations

  • 1 Fate Therapeutics Inc., San Diego, CA 92131, USA. Electronic address: [email protected].
  • 2 Fate Therapeutics Inc., San Diego, CA 92131, USA.
  • 3 Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Neurology, Brigham & Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Fate Therapeutics Inc., San Diego, CA 92131, USA. Electronic address: [email protected].
PMID: 37172578 DOI: 10.1016/j.medj.2023.04.004
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).

Keywords

MICA/B; NK cell; Pre-clinical research; antigen heterogeneity; cell therapy; chimeric antigen receptor; iPSC; pan tumor antigen; solid tumor; stress ligand; tumor immune evasion.

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