Details

Autor(en) / Beteiligte

• Goulding, John
• Yeh, Wen-I
• Hancock, Bryan
• Blum, Robert
• Xu, Tianhao
• Yang, Bi-Huei
• Chang, Chia-Wei
• Groff, Brian
• Avramis, Earl
• Pribadi, Mochtar
• Pan, Yijia
• Chu, Hui-Yi
• Sikaroodi, Shohreh
• Fong, Lauren
• Brookhouser, Nicholas
• Dailey, Thomas
• Meza, Miguel
• Denholtz, Matthew
• Diaz, Evelyn
• Martin, Judy
• Szabo, Peter
• Cooley, Sarah
• Ferrari de Andrade, Lucas
• Lee, Tom T.
• Bjordahl, Ryan
• Wucherpfennig, Kai W.
• Valamehr, Bahram

Titel

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

Ist Teil von

• Med (New York, N.Y. : Online), 2023-07, Vol.4 (7), p.457-477.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. Funded by Fate Therapeutics and NIH (R01CA238039). [Display omitted] •MICA and MICB (MICA/B) are polyallelic stress proteins expressed on many human tumors•Targeting the conserved α3 domain of MICA/B mitigates tumor immune evasion•MICA/B-targeting chimeric antigen receptor (CAR) provides broad tumor recognition•iPSC-derived NK cells expressing MICA/B CAR and CD16 show potent anti-tumor activity Cell-based cancer therapies are an exciting new treatment approach that has proven clinical success against certain blood cancers. However, they remain ineffective against other cancer types, in part due to the difficulty in targeting cancer proteins that are absent on healthy tissue. Researchers from Fate Therapeutics have shown that targeting stress proteins, found on many cancers, can prevent cancer from escaping immune detection and allow for cancer cell killing whilst leaving healthy tissue intact. The authors engineered this targeting approach into stem cell-derived immune cells that can synergize with existing antibody-based cancer drugs to further enhance tumor killing. This new therapeutic strategy is poised for broad applicability across many cancer indications and has the potential to elicit durable responses. Cancer therapies that distinguish tumors from healthy tissue and mitigate tumor immune escape are highly sought after. Goulding et al. employed a novel stress-ligand targeting system in combination with a multiplexed-engineered stem cell-derived immune cell to overcome these challenges and kill a broad array of tumor types.