# Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity

Source: https://onco.cc/key-papers/paper-gross-eshhar-chimeric-receptor-pnas-1989/  
OnCo record `paper-gross-eshhar-chimeric-receptor-pnas-1989` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The paper that invented the CAR. A T cell was given the business end of an antibody, and it killed what the antibody recognised without needing the immune system's usual permission step.

## Summary

Zelig Eshhar's group at the Weizmann Institute of Science asked whether the specificity of a T cell could be designed rather than selected. They built chimeric T-cell receptor genes in which the variable domains of the heavy and light chains of an anti-trinitrophenyl antibody (SP6) were spliced to the constant regions of the T-cell receptor alpha or beta chain, and expressed them in a cytotoxic T-cell hybridoma.

The transfectants expressed a functional receptor carrying the antibody's idiotope, and responded to trinitrophenyl-bearing targets without major histocompatibility complex restriction, killing them and producing interleukin-2 across strain and species barriers. They also responded to immobilised trinitrophenyl-protein conjugates, which means cellular processing and presentation were bypassed entirely. Because the binding site of this particular antibody lies almost wholly in the heavy chain, a construct containing only the heavy-chain variable domain fused to either constant region was enough.

Eshhar called the construct a T-body. Everything that followed, the single-chain variable fragment format, the CD28 and 4-1BB costimulatory domains added by Michel Sadelain, Carl June and Dario Campana, and the manufacturing that turns the idea into a product, is built on this experiment.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Proceedings of the National Academy of Sciences
- Year: 1989
- DOI: 10.1073/pnas.86.24.10024
- Authors: Gross G, Waks T, Eshhar Z
- Findings: Chimeric genes joining antibody variable domains to T-cell receptor constant domains produced a functional surface receptor on a cytotoxic T-cell hybridoma.; The chimeric receptor conferred non-MHC-restricted killing and interleukin-2 production against hapten-bearing targets across strain and species barriers.; Transfectants responded to immobilised hapten-protein conjugates, bypassing antigen processing and presentation altogether.; A construct carrying only the heavy-chain variable domain fused to the alpha or beta constant region was sufficient in this system.
- What it means: Every approved CAR-T product descends from this design. It is the reason a T cell can be pointed at CD19 or BCMA at all, and the reason the question of what to point it at in solid tumours is a question about antigens rather than about the receptor.
- Caveats: A model antigen (trinitrophenyl) in a hybridoma, not a tumour antigen in a patient. The construct had no costimulatory domain, so first-generation CARs of this kind proved too weak in the clinic; the additions that made CAR-T work came a decade or more later from other groups.

## Sources

- PNAS 1989: https://doi.org/10.1073/pnas.86.24.10024
- PubMed: https://pubmed.ncbi.nlm.nih.gov/2513569/

## Connected records

- fronts: [Cell Therapy](https://onco.cc/fronts/cell-therapy/)
- technologies: [CAR-T cell therapy](https://onco.cc/technologies/car-t/)
- targets: [CD19](https://onco.cc/targets/cd19/)
- institutions: [Weizmann Institute of Science](https://onco.cc/institutions/weizmann/)
- people: [Zelig Eshhar](https://onco.cc/people/zelig-eshhar/)
- bottlenecks: [Manufacturing cost and time for living and radioactive medicines](https://onco.cc/bottlenecks/b-manufacturing-cell-therapy/)
- journals: [Proceedings of the National Academy of Sciences](https://onco.cc/journals/pnas/)

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