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
  • 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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