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CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Engineered immune cell therapy to treat malignancies refractory to conventional therapies is modernizing oncology. Although αβ T cells are time-tested chassis for CAR, potential graft versus host disease (GvHD) apart from cytokine toxicity and antigen escape pose limitations to this approach. αβ T cell malignancy challenges isolation and expansion of therapeutic T cells. Moreover, αβ T cells may pose toxicity risk to inflammation sensitive vital tissues bearing the tumor. The HLA independent, multivalent, versatile and systemic anti-tumor immunity increases the desirability of γδ T cells as an alternate chassis for CAR. Indeed, CD19 γδ CAR T cell therapy to treat advanced lymphoma reached a milestone with the fast track status by FDA. However, reduced tumor-toxicity, homing, in vivo persistence and heterogeneity limits the translation of this therapy. The field is gaining momentum in recent years with optimization of gene delivery approaches and mechanistic insights into co-signaling requirements in γδ T cells. There is a renewed interest in customizing design of CAR guided by the biology of the host immune cells. Progress has been made in the current good manufacturing practice compatible expansion and engineering protocols for the δ1 and δ2 T cells. γδ CAR T cells may find its niche in the clinical situations wherein conventional CAR therapy is less suitable due to propensity for cytokine toxicity or off-tumor effect. As the therapy is moving towards clinical trials, this review chronicles the hitherto progress in the therapeutic engineering of γδ T cells for cancer immunotherapy.

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Abbreviations

aAPC:

Antigen presenting cells

ADCC:

Antibody dependant cellular toxicity

CCR:

Chimeric Co-Stimulatory Receptors

CNS:

Central nervous system

CRISPR/cas9:

Clustered regularly interspaced short palindromic repeats

DAP10:

DNAX—activating Protein 10 Endoplasmic reticulum kinase

FDA:

Food and drug administration

GD2:

Disialoganglioside

GMP:

Good Manufacturing Practice

GvHD:

Graft versus host disease

HLA:

Human leucocyte antigen

IFNγ:

Interferon gamma

IL-2:

Interleukin -2

iPSC:

Induced pluripotent stem cell

LAN1:

A human neuroblastoma cell line

MART-1:

Melanoma—associated antigen recognized by T cells

MCSP:

Maternal and child survival program

MHC:

Major histocompatibility complex

MICA/B:

MHC class I chain-related protein A and B

mRNA:

Messenger RNA

NK:

Natural killer cells

NKG2D:

Natural killer cell receptor

NKG2DL:

Natural killer group 2D receptor and ligands

NSCAR:

Non signalling chimeric antigen receptor

NSG:

NOD-SCID IL2Rγcnull mice

pERK:

Type I transmembrane ER-resident protein kinase /protein kinase RNA-like

RORC:

Register of registrable controllers

scFv:

Single-chain variable fragment

TCR:

T-cell receptor

ZA:

Zoledronic acid

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Acknowledgements

The authors acknowledge Ramalingaswamy Re-entry Fellowship from the Department of Biotechnology, Government of India (BT/ RLF/Re-entry/35/2016/ dated 19/07/2018) for the funding. Dean and Office of the Director—Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram for the administrative support.

Funding

The research is supported by the Ramalingaswamy Re-entry Fellowship (RRF) to SM, Department of Biotechnology, Government of India.

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  1. Thamizhselvi Ganapathy and Rajalingam Radhakrishnan have contributed equally. All authors read and approved the final manuscript.

Authors and Affiliations

  1. Immune Cell Engineering and Therapy (iCET) Laboratory, Christian Medical College Vellore, Bagayam, Tamil Nadu, 632002, India

    Thamizhselvi Ganapathy & Seth Sakshi

  2. Synthetic Immunology Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India

    Rajalingam Radhakrishnan & Sunil Martin

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  1. Thamizhselvi Ganapathy
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Correspondence to Sunil Martin.

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Ganapathy, T., Radhakrishnan, R., Sakshi, S. et al. CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green?. Cancer Immunol Immunother 72, 277–286 (2023). https://doi.org/10.1007/s00262-022-03260-y

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